Being bionic: the future of regenerative medicine – Toronto Star
Six decades ago, two researchers at the Ontario Cancer Institute at Princess Margaret Hospital made a startling discovery. James Till and Ernest McCulloch had found transplantable stem cells, special building block cells that have the ability to grow into any kind of human tissue.
Till and McCulloch were studying the effects of radiation at the time, but their work set off an explosion of research aimed at harnessing stem cells to treat all kinds of diseases and conditions. Subsequent breakthroughs in stem cell therapy have been used to treat more than 42,000 patients for hemophilia, restore sight to blind mice and even help a 78-year-old man regrow the end of a sliced-off fingertip. And researchers are still unlocking what might be possible.
The potential of regenerative medicine is astounding, says Michael May, president of the Centre for Commercialization of Regenerative Medicine (CCRM), a Toronto non-profit that helps bring new stem cell therapies and other regenerative medicine technologies to market. Researchers are harnessing stem cells to repair, replace or regenerate human cells, tissues and organs with the aim of improving treatments for conditions ranging from diabetes to blindness to heart failure and cancer.
More recent advances most notably Shinya Yamanakas Nobel Prize-winning 2012 discovery that regular adult tissue cells can be reprogrammed to become stem cells again, therefore endowing them with the ability to become any type of cell in the body have also ushered in a new wave of regenerative medicine research and what May calls a global race to bring newly possible cell therapies to market.
As president of CCRM, Mays job is to help move some of that research from the laboratory into the real world. Over the last decade, his organization has helped 11 companies come to market with regenerative medicine technologies, such as Montreals ExCellThera, which provides new therapeutic options for patients who suffer from myeloid leukemia and lack a traditional bone marrow donor.
While the last decade was defined by research and technological breakthroughs, May says the next decade will be all about lowering manufacturing costs and tackling patient access bottlenecks. Last November, CCRM announced that it would partner with McMaster Innovation Park in Hamilton to create Canadas first commercial-scale factory for making cells, which will be able to produce billions of cells enough to treat thousands of patients per week.
Weve just scratched the surface of whats possible in regenerative medicine, May says. He envisions a time when well eventually use these techniques not just to cure and fix human bodies, but also make them better. Now we can make cells, we can design them by genetically engineering them to do things that they naturally do, but that can be more than nature designed, says May. He says the editing of human traits in this way could eventually augment human abilities to such an extent that theyre unrecognizable.
Biomaterials are another technology that could transform regenerative medicine. Before joining CCRM, May himself helped found a Toronto biomaterials startup called Rimon Therapeutics, which developed a smart dressing for chronic wounds that used special polymers to support the bodys natural healing process. Similar advanced biomaterials could eventually be used in combination with cell therapies to not just fight aging and degeneration, but to also prevent it entirely, and even improve upon the human bodys natural baseline health.
Fifty years from now if theres some sort of blindness, well have a lens on the eye that will automatically focus and react or change as the eye ages, he says.
Nick Zarzycki is a freelancer who writes about technology for MaRS. Torstar, the parent company of the Toronto Star, has partnered with MaRS to highlight innovation in Canadian companies.
Disclaimer This content was produced as part of a partnership and therefore it may not meet the standards of impartial or independent journalism.
Originally posted here:
Being bionic: the future of regenerative medicine - Toronto Star
Recommendation and review posted by Bethany Smith
‘Natural Killer Cells’ and Other Promising Cancer Treatments – Barron’s
Text size
Last weekends online meeting of the American Association for Cancer Research gave a glimpse at the newest ideas for fighting cancer. Among the most exciting were treatments that engineer natural cells into cancer-targeting torpedoes.
Engineered-cell treatments from Affimed (ticker: AFMD), Fate Therapeutics (FATE), and Rubius Therapeutics (RUBY) drew attention from Wall Street analysts.
The German company Affimed reported exciting results in a four-patient test of its AFM13 antibodies in patients with the blood cancer lymphoma. When administered with a kind of immune cell known as a natural killer cell, Affimeds antibody binds the NK cells to a target found on many cancer cells.
Before treatment started at the end of last year, all four lymphoma patients had been very sick. One had even been consigned to hospice.
The cancer receded in all four patients after treatment, with complete responses in two of them. The patient who had been sent to hospice is now eligible for a bone-marrow transplant. Side effects werent a problem.
They had all failed multiple lines of treatmentup to 14 lines of therapy, said Katy Rezvani, a professor at the University of Texas MD Anderson Cancer Center who is leading the study, on a Thursday morning conference call. The fact that we are seeing responses as it is, I think, is just incredible.
Dose levels of the Affimed-primed killer cells were kept deliberately low in the first administrations of the treatment. Higher doses may show deeper response and greater persistence of the natural killer cells, notes BMO Capital Markets analyst Do Kim in a Thursday note. Affimed is testing other antibodies in Phase 1 studies that target solid tumors.
Excitement over the lymphoma study results lifted Affimed stock from about $7.70 to $10.70 since last week. In recent trading, the shares were down 9.3%, at $9.38, after the development-stage company reported a slightly higher-than-expected loss of 0.50 euros a share (about 60 cents) for the 2020 year. BMOs Kim rates Affimed at Outperform, with a $15 price target.
One promising feature of natural-killer-cell treatments is that the cells can be obtained from donors and stored on the shelf. Current treatments with other engineered immune cells must harvest a patients own cells, then modify and grow them for re-administration. Another pioneer in developing NK cell therapies is Fate Therapeutics, and the company provided several updates at the AACR meeting on its treatments.
Fates stock enjoyed a remarkable run in the past year, soaring from $19 to a January 2021 peak of $119, before settling back to a recent $84.87. That puts an $8 billion market cap on a company thats yet to report revenue. But Fate has 10 clinical trials in Phase 1 for its NK cell technology, which takes undifferentiated stem cells (stored on the shelf) and transforms them into NK cells targeting a variety of solid and blood tumors.
At AACR, Fate focused on its laboratory studies that show the flexibility of its NK cell technology. In planned meetings later this year, it will review its human trials against various cancers. The stocks gain has some analysts rating it Neutral. Among them is H.C. Wainwrights Robert Burns, who wrote in January about the excitement that followed Fates report that its treatment had reversed the cancer in a patient whose lymphoma had resisted seven other kinds of therapy.
Burns may have a Neutral rating on Fates stock, but he thinks it could rise to $108 as the company reports more clinical trial results this year. Thats a better than 25% upside.
One more engineered cell therapy discussed at AACR was the unusual approach of Rubius Therapeutics, which turns off-the-shelf red blood cells into therapies that stimulate an immune system attack on cancer. Researchers detailed results first reported in March, from a Phase 1 trial against several different cancers. The treatment reversed cancers in one patient with metastatic melanoma and another with metastatic anal cancer, while stabilizing the disease in six other patients.
Rubius will escalate doses in the Phase 1 study, while proceeding with other trials that target different kinds of cancer or combine its treatment with other cancer therapies. Guggenheims Michael Schmidt projects that Rubius could start to see revenue from its unique approach in 2024, and rates the stock a Buy. He argues that its stock, now trading at $23.86, is worth at least $30.
Write to Bill Alpert at william.alpert@barrons.com
Read more:
'Natural Killer Cells' and Other Promising Cancer Treatments - Barron's
Recommendation and review posted by Bethany Smith
While ElsaLys continues to work on the filing of marketing approval in Europe and the US for inolimomab, the company confirms the renew of its cohort…
Get inside Wall Street with StreetInsider Premium. Claim your 1-week free trial here.
While ElsaLys continues to work on the filing of marketing approval in Europe and the U.S. for inolimomab, the company confirms the renew of its cohort ATU in France and compassionate use programs submissions in several other countries
Lyon, FRANCE, April 15, 2020, ElsaLys Biotech confirmed that The French National Agency for the Medicines and Health Products Safety (ANSM) has renewed the Temporary Authorisation for Use (ATU) so-called cohort ATU (cATU) for inolimomab (LEUKOTAC) on December 24, 2020.
This renewed authorization includes the implementation of a reinforced monitoring (defined in the Protocol for Therapeutic Use) of the efficacy and safety data obtained in patients treated within the framework of this cATU.
Inolimomab is available to hematologists and physicians treating blood disorders and to hospital pharmacists for the treatment of acute cortico-resistant or corticosteroid-dependent graft-versus-host disease in adults and pediatric patients over 28 days of age. The indication should be discussed during a multidisciplinary consultation meeting. Inolimomab treatment can only be considered if the patient cannot be included in an ongoing clinical trial.
During its first year of administration under cATU and despite the pandemic, around 30 patients in France have been treated with inolimomab as it is considered a reliable treatment of this high-risk patient population.The number of patients included in the cohort ATU in France since December 2019 reflects a real medical need. This is the reason why ElsaLys is working on expanding compassionate use programs for inolimomab in a number of European countries. Several early access applications will be submitted.
" Inolimomab is already being administered in France before marketing autorisation in Europe and hopefully soon in other countries through compassionate use programs as it is considered a reliable treatment of this high-risk patient population with acute cortico-resistant or corticosteroid-dependent graft-versus-host disease. said Dr. Christine GUILLEN, CEO and co-founder of ElsaLys Biotech. " Data on clinical benefit and safety profile we expect to collect through these compassionate use programs will support our work on the filing of marketing authorization applications (MAA) in Europe and in the U.S.
About inolimomab
Inolimomab is an anti-IL-2 R monoclonal antibody active as an immunotherapy product for the treatment of steroid-refractory acute GvHD.
In acute GvHD, activated T cell lymphocytes from the allografts donor recognize and attack recipient tissues. T cell lymphocyte activation and proliferation is governed by the key IL-2/IL-2 receptor (IL-2 R) pathway.
By recognizing the subunit of the IL-2 Receptor complex (IL-2 R) which is upregulated on T cells upon activation, inolimomab blocks the binding of the cytokine IL-2 on IL-2 R thereby inhibiting IL-2 signalling and donor T cell proliferation.
The efficacy of inolimomab in aGvHD relies on its specific potent immunosuppression on T cell lymphocytes through the blocking of the IL-2/IL-2 R pathway triggering the disease.
Inolimomab received Orphan Drug Designation in Europe (March 2001) and in the U.S. (October 2002).
About steroid-resistant aGvHD
Formerly called bone marrow transplant, Hematopoietic Stem Cell Transplantation (HSCT) is the last therapeutic option for patients with certain blood cancers or severe immunodeficiency. In practice, the treatment is designed to replace the diseased blood cells of the patient with the hematopoietic stem cells of a matching donor (allograft).
Once grafted, these stem cells will produce new healthy and functional blood cells, including white blood cells that will allow patients to bridge their immune deficiency or to eliminate surviving cancer cells.
If this technique has made considerable progress in 60 years, half of transplant recipients are still victims of complications: side effects of conditioning treatments, immunosuppressive treatments before allograft (that aims to prevent transplant rejection), long-term susceptibility to infections and GvHD. In the latter case, the donors over-active T-cells turn against the patients tissues: mucous membranes, skin, gastro-intestinal tract, liver and lungs. The acute form appears just after the transplant, the chronic form occurring several months later (preceded or not by an acute GvHD episode).
Affecting between 30 to 50% of patients, GvHD is the main complication of hematopoietic stem cell transplantation. To halt this disease, physicians use corticosteroids. The fact remains that some 30 to 50% of aGvHD patients are refractory or dependent to the steroid treatment. To date limited therapeutic options are available for these patients with no standard treatment approved so far in Europe and only one in the US.
About ElsaLys Biotech
ElsaLys Biotech is a specialty pharmaceutical company, part of the Mediolanum Farmaceutici Spa group, focused on innovative medicines to address haemato-oncology related life-threatening and rare diseases.
Following strategic acquisitions and targeted developments, ElsaLys is establishing an immunotherapeutic portfolio focused on niche specialty pharmaceuticals to answer unmet medical needs.
Our commitment is to offer essential drugs meeting Public Health needs.
Founded in 2013, ElsaLys Biotech is located in the heart of the European cluster Lyon Biopole, in Lyon, France.
Stay in touch with ElsaLys Biotech and receive directly our press releases by filling our contact form on https://www.elsalysbiotech.com
And follow us on Twitter @ElsalysBiotech and on linkedin.com/company/elsalys-biotech/
Contacts
Read this article:
While ElsaLys continues to work on the filing of marketing approval in Europe and the US for inolimomab, the company confirms the renew of its cohort...
Recommendation and review posted by Bethany Smith
Chemotherapy for Prostate Cancer: When It’s Used and What to Expect – Healthline
The American Cancer Society says that nearly 250,000 American men are expected to be diagnosed with prostate cancer in 2021. And about 1 in 8 men will be diagnosed with prostate cancer at some point in their lives.
Prostate cancers tend to grow slowly and have a fairly good outlook compared to many types of cancer. From 2010 to 2016, the 5-year survival rate in the United States was 97.8 percent, according to the National Cancer Institute.
Chemotherapy is a drug therapy thats sometimes used to treat prostate cancer. Its most commonly used to treat aggressive tumors or advanced prostate cancer that hasnt responded well to other treatments.
In this article, we break down when your doctor may recommend chemotherapy for prostate cancer and what you can expect while taking chemotherapy drugs.
Chemotherapy is a cancer treatment that involves taking drugs that kill rapidly dividing cells. Chemicals in these drugs can kill cancer cells and healthy cells in your body that quickly divide such as bone marrow and hair cells.
According to the American Cancer Society, chemotherapy is not a standard treatment for early prostate cancer. Its most likely to be used for aggressive cancer or cancer that has started growing outside the prostate.
Most men receiving chemotherapy for advanced prostate cancer will also receive androgen deprivation therapy (ADT) or anti-hormone therapy.
Chemotherapy may also be used to treat castrate-resistant prostate cancer (CRPC). CRPC is a type of prostate cancer that stops responding to hormone therapy. Prostate cancer needs male sex hormones to grow, and hormone therapy aims to lower male sex hormones to slow tumor growth.
A 2018 research review showed that docetaxel (developed in 2004) is the first chemotherapy drug that improved the survival rate of men with prostate cancer. Today, its the most commonly used chemotherapy drug to treat prostate cancer.
Docetaxel falls into a group of drugs called taxanes. These drugs block cellular processes cancer cells need to divide.
Docetaxel is often combined with the steroid prednisone. A 2016 research review showed that prednisone may help:
If docetaxel treatment doesnt work best for your health needs, doctors often recommend trying cabazitaxel. Cabazitaxel falls into the same class of drugs as docetaxel.
The following treatments are newer treatment options that often work when hormone therapy doesnt work for you:
However, there are no studies available yet directly comparing these drugs, and its not clear which is most effective.
Enzalutamide and apalutamide are in a class of drugs called androgen receptor inhibitors. They block male sex hormones from binding to receptors on your prostate.
Abiraterone is in a class of drugs called androgen biosynthesis inhibitors. They work by blocking the production of testosterone.
Other chemotherapy drugs that may be used to treat prostate cancer include:
Chemotherapy drugs are typically administered intravenously (through an IV) by a doctor who specializes in cancer treatment. The medications can be administered at a:
Drugs are administered in cycles to help give your body time to recover. Cycles are often 2 to 3 weeks long, and each session takes roughly an hour, according to the American Cancer Society.
The schedule of your cycle depends on which drugs are being used. You may only be given chemotherapy drugs on the first day of your treatment or for several days in a row.
The total length of your treatment depends on how well the chemotherapy is working and your side effects.
Some types of chemotherapy drugs like enzalutamide can be given as oral pills.
Chemotherapy can cause your red and white blood cell counts to drop, so youll likely have a blood test before each of your sessions.
If you have a very low white blood cell count, your doctor may recommend lowering the dose or stopping treatment.
Chemicals in chemotherapy drugs kill cells that divide quickly, but they cant differentiate between cancer cells and healthy cells in your body.
Many of chemotherapys side effects are due to drugs targeting healthy cells that divide rapidly such as cells in your:
Some common side effects of chemotherapy include:
Severity of symptoms can vary between people. Many of the side effects of chemotherapy go away shortly after treatment.
Docetaxel and cabazitaxel can cause neuropathy, or nerve dysfunction, that leads to the following feelings in your hands or feet:
A 2014 research review showed that about 10 percent of participants have grade 3 or 4 neuropathies, which are the highest classifications of nerve dysfunction. Your chances of developing neuropathy depend on your dose.
According to the American Cancer Society, the drug mitoxantrone can cause leukemia in rare cases, and estramustine increases your risk of developing blood clots.
Its important to discuss prostate cancer treatment options with your doctor. They can help you understand the pros and cons of chemotherapy and answer any specific questions you have about your treatment.
An oncologist, a doctor specializing in cancer, can help you develop strategies to lower your chances of developing side effects.
An oncologist can also put you in touch with support groups in your area. Many people find it helpful to talk with other people who have gone through the same treatment.
You can find online support groups or support groups in your area from these websites:
Chemotherapy is most commonly used to treat prostate cancer that has spread beyond the prostate. Chemicals in chemotherapy drugs kill cancer cells and other cells in your body that rapidly divide such as cells in your hair follicles and digestive system.
Your doctor can help you determine if you may benefit from chemotherapy. You may also find it helpful to join a support group that connects you with other people who have undergone the same treatment in the past.
See the original post:
Chemotherapy for Prostate Cancer: When It's Used and What to Expect - Healthline
Recommendation and review posted by Bethany Smith
What If I Had Gotten a Head Start on Hormones? – The Cut
Photo: Getty Images/EyeEm
Last week, Arkansas lawmakers passed a bill that could have life-threatening consequences for transgender youths. HB1570 the Save Adolescents From Experimentation (SAFE) Act bans any trans person under 18 from receiving gender-affirming health care, including puberty blockers and hormone therapy. Arkansas is the first state to pass these extreme measures, though at least nine other states are considering similar bills and more than 45,000 trans youths could be affected.
While the lawmakers who support HB1570 claim to be protecting kids from making medical decisions they cant take back, they are actually putting them at risk. Studies have shown that not only do transgender children very rarely regret these treatments but their rates of depression and suicide are greatly reduced by them. One study found that access to hormone therapy over the course of one year decreased suicide rates in transgender youths by 75 percent. This law cuts them off from potentially life-saving options.
The Cut spoke with 19-year-old Vaniel Simmons, who was raised in Arkansas, about how access to gender-affirming health care saved his life.
By the time I was 15, I felt confident that I was trans. I started wearing a binder and three layers of clothing to hide my body, even in the summer. A year earlier, I had come out to my family as bisexual, but that never felt quite right. They were more or less supportive but would still pressure me to wear makeup or dresses. It made me incredibly uncomfortable, but I couldnt articulate why. I couldnt put into words why I would have a panic attack every time my mom tried to take me shopping. I just knew that I couldnt stand looking at myself in the mirror. I started getting really depressed and began self-harming. I starved myself and overexercised, thinking weight was the reason I didnt like my body.
I did not fit in at my school, which was filled with homophobic or incredibly religious people. Every day, other students would tell me, Youre gonna go to hell. You need to come to a Christian fellowship group. One girl walked around wearing a T-shirt that spelled fag in sign language, and the teacher and principal said they couldnt do anything about it. But every year on National Coming Out Day, I would do a fun outfit when I showed up in a rainbow cape, they said I had to take it off. By my junior year, I had decided to transfer somewhere else. I applied to a boarding school in Hot Springs, Arkansas, where people dyed their hair blue and green and wore sparkly shoes. My mom was supportive, since it was a very academically prestigious place, and as I was a low-income student, they would pay the tuition. I felt a desperation that I needed to be anywhere but here.
I started finding online LGBTQ groups where people explained trans identities. I started thinking, Maybe thats me, and using he/him pronouns. I began researching hormone treatments. I was watching famous trans YouTubers and Googling, What does testosterone do to your body? and How can I get top surgery? Any provider I called said I had to be 18 to make an appointment, and I didnt have a family doctor I trusted enough to talk about these kinds of issues. I was resigned to waiting.
I felt stuck. I knew that starting hormone therapy would help. Knowing what I needed to do and not being able to do it was soul-crushing. By the time I was 16, I couldnt picture a future. That Christmas, I had a full panic attack. My family kept misgendering me, and I remember sitting on the floor of my room, crying. My grandmother came in, and I told her: Im a guy. I dont know why they cant see that. She is very accepting; whatever makes me happy will make her happy. About a month later, I got in an argument with my mom I dont remember exactly what about and I stormed out of the house. My stepdad would make uncomfortable comments about my body, and we were arguing a lot about him. My grandmother followed me to the nearby lake, and I told her, Im hiding who I am at school. I dont feel safe at home. I would rather not exist at all than continue to exist like this. That was my lowest point. And she was like, So youre going to move in with me.
I didnt expect to live long enough to have access to the health care I needed. If a teenager can make the major life decision to want to harm or kill themselves, why wouldnt they be able to make major life decisions about their health? I couldnt stand the thought of living this way any longer. Every single day was a hellscape. That feeling is more torturous than taking testosterone and deciding later on I dont want to do this anymore.
In 2018, I started boarding school, and my first semester was definitely the hardest. Everyone there was great, and they didnt mess up pronouns but I still had to live in the female hall with the girls. Then I found a booth for the Arkansas Childrens Hospital Gender Spectrum Clinic at a pride event and booked my first appointment to talk about hormone therapy. I was 16 at the time. I told my mom that if she refused her support, Id just do it when I was 18 and resent her. She showed up for the first appointment but not to any others. They did a full psychological evaluation of me, my mother, and my grandmother. They wanted every detail. Then the doctors conferred to make sure hormones were the right option for me, and there was another three- or four-month waiting period to make sure I was feeling consistent. I wasnt able to actually start the treatment until seven months after the first consultation. But while waiting, I successfully petitioned the school to move me to the guys hall in my second semester. The other students just started letting me exist as a dude, though it was still slightly dysphoric for me. They all had their deep voices, and I was still trying to get there.
About six months into testosterone treatment, my voice finally started to drop. I was 17. I remember walking into school after the Christmas break and greeting a counselor. She said, I didnt recognize your voice for a second because of how much it had deepened. It felt like, Youre finally able to hear me as I actually am. That feeling was like Christmas all over again.
These lawmakers dont understand that these treatments arent just something trans people want; they mean actual life or death for a lot of us. This bill is a death sentence. It takes away peoples chances to live. I am happy with myself now I had top surgery last August. But theres always the thought in the back of my head, How much further could I be had I gotten a head start on hormones? My teenage years were mostly spent hating my body and isolating myself so I didnt have to be around people who saw me as a woman. I didnt get to experience having casual fun with my friends on the weekends. It took me years to get to the place where Im at now. I could have spent all those years being happy.
In the U.S., the National Suicide Prevention Lifeline is 1-800-273-8255.
Get the Cut newsletter delivered daily
Follow this link:
What If I Had Gotten a Head Start on Hormones? - The Cut
Recommendation and review posted by Bethany Smith
New Ontario clinic offers diverse health and beauty services – Richland Source
ONTARIO Jenny Swisher opened The CRU Clinic at the beginning of April. It is a business not so common in the area.
She said the diversity of CRUs services differentiate it from others. The clinic offers aesthetics services, IV hydration, testosterone replacement and weight loss programs.
CRU stands for contemporary, refined and unique. Swisher said the business goal is to provide contemporary care for refined wellness that is unique to each individual.
Richland Area Chamber and Economic Development held a ribbon-cutting ceremony for CRU on Thursday afternoon.
Richland Area Chamber and Economic Development held a ribbon-cutting ceremony for CRU on Thursday afternoon. Richland County commissioners Cliff Mears and Tony Vero and Ontario Mayor Randy Hutchinson joined the event and welcomed the new business.
Swisher, a certified nurse practitioner, said the IV hydration service is nutrient infusion therapy. Depending on the need, customers can get anything from calcium to vitamin B complex through the infusion.
When you take oral vitamins, you only get about 50 percent (of what you eat) if you have a good GI (gastrointestinal tract)absorption system. But sometimes, less than 50 percent is actually absorbed, Swisher said.
And with the IVs, you get 90 to 100 percent of what you get infused.
She said the service is rare in the area and some people have been driving to Columbus or Cleveland for it.
Those who are nutritionally deficient would benefit from the infusion, Swisher said. It can help rehydrate a hangover as well. For those who do weight-lifting or activities consuming a lot of energy within a short time, the infusion will help them replenish essential nutrients quickly.
Swisher said the aesthetics services have been popular since the clinic was open. It offers Botox injection, lip fillers and dermal fillers. The owner filled her own lips about a week ago to get rid of some wrinkles around.
She said she wanted to be able to experience what her patients go through during the process.
CRU also targets male customers with hormone replacement therapy. Swisher said men go through andropause just like women go through menopause. They might feel fatigued, be unable to gain muscle or have a decline in sex drive. The clinic can tailor the therapy and meet an individuals needs.
The CRU Clinic is located at 2293 Village Park Court. It opens from 8 a.m. to 5 p.m. on weekdays. Swisher said most services are provided through appointments, but walk-in IV infusions are available from 10 a.m. to 2 p.m.
Those interested can check The CRU Clinics website or call 419-775-5457 for more information.
Like local businesses, local journalism depends on community support. Do you enjoy our coverage of the latest in local business? Become a member for the price of one large vanilla latte.
Read more here:
New Ontario clinic offers diverse health and beauty services - Richland Source
Recommendation and review posted by Bethany Smith
What Are the Most Common Sexual Side Effects Survivors of Cancer Face, And How Are They Treated? – Curetoday.com
A month after Alegra Woodard received a diagnosis of stage 1 cervical cancer, she underwent a radical hysterectomy, a surgery that removes the uterus, ovaries, fallopian tubes, left and right pelvic nodes, cervix, tissue around the cervix, and the upper part of the vagina. She was just 36 years old, a wife and mother working as an information technology practitioner in Honolulu.
Her life changed overnight.
The next day I felt like another person, Woodard says. The change was drastic. I went into full menopause. I started sweating, my sexual desire (was) nonexistent, and intercourse became very difficult because it felt like someone had poured sand in my vaginal area.
Woodard isnt alone. A study out of Sidney Kimmel Cancer Center (SKCC) at Thomas Jefferson University in Philadelphia found that 87% of survivors of breast, pelvic, endometrial, prostate, bladder and rectal cancer said treatment affected their sexual function or desire. Although sexual side effects are more often reported by women, they affect men as well.
Steven Dupin, a personal trainer, comedian, author and patient advocate for the Prostate Cancer Foundation, (visit their site to learn more about the side effects of prostate cancer), lives in Los Angeles and was 42 when he started having problems with frequent urination and prostate pain. However, he didnt receive a diagnosis of prostate cancer until two years later, when his doctor ran a routine PSA blood test, which is used to screen for prostate cancer. Dupin says that his biggest fear, besides dying, was that he would have problems with sexual intimacy as a result of treatment. Both of these fears are common.
The No. 1 question I get from other men I talk to is Does the plumbing still work? Dupin says. I always say, Sure. The only difference is that now instead of ejaculate, fairy dust and glitter come out.
That last part, of course, isnt true. But the stories patients tell of sexual side effects resulting from cancer treatment are.
So, what causes these problems, and what solutions are available for survivors?
The SKCC study found that the most common sexual side effects were painful intercourse (73%), body image distortion (54%) and the inability to achieve orgasm (42%).
According to Ashley Arkema, a nurse practitioner in the Female Sexual Medicine and Womens Health Program at Memorial Sloan Kettering Cancer Center, the most common concerns reported by the patients she sees are low libido, sexual pain, diminished arousal and changes in body image. Fatigue, anxiety and depression can also affect sexual function. And she attributes these problems primarily to cancer treatment, including surgery, chemotherapy, hormone therapy and pelvic radiation, which often cause sexual side effects that are associated with hormone depletion. For younger patients this is especially true. Abrupt early surgical menopause or chemical menopause causes a rapid drop in estrogen, leading to more severe and sudden symptoms. Hormone therapy, including tamoxifen and aromatase inhibitors, commonly used in breast cancer treatment, can also have a negative impact on sexual function. And pelvic radiation can lead to menopause, vaginal narrowing and scarring.
Dr. Mindy Goldman, director of the Gynecology Center for Cancer Survivors and At-Risk Women at the University of California, San Francisco, who serves as the chair of the menopause panel and the co-chair of the sexual function panel for the National Comprehensive Cancer Network (NCCN), agrees that the lack of estrogen causes many of the most common forms of sexual dysfunction in women. However, there are other causes.
There are many aspects of cancer treatment that can cause sexual dysfunction, and the causes are often multifactorial, Goldman says. Vaginal dryness can lead to pain and decreased desire. Surgeries can lead to body image changes. Stem cell transplants can cause graft-versus-host disease that can lead to scarring, pain and decreased arousal. Radiation can lead to pain and scarring. The cancer itself can cause pain. And then (a lot of women) also have cancer-related stress, anxiety and depression that can affect their overall sexual functioning.
She says the key to treating patients is a multifactorial approach and finding safe and effective options, especially for those who shouldnt use hormone therapies.
Dr. Gregory Broderick, a urologist at Mayo Clinic and a professor of urology with Mayo Clinic Alix School of Medical Education in Jacksonville, Florida, sees male patients who have cancer whove experienced sexual dysfunction, incontinence (loss of bladder control) and urethral strictures (scarring that narrows the tube that carries urine out of the body).
Together, Goldman and Broderick co-chair NCCNs panel on sexual health. NCCN is a nonprofit alliance of 30 cancer centers that partner to improve cancer care and survivor issues by reviewing and updating guidelines. They want to make sure certain side effects (like this one) are not overlooked.
The most common problems he sees are erectile and ejaculatory dysfunction, loss of libido, incontinence or other urinary problems like climacturia (when a man leaks urine as he ejaculates). There can also be body image challenges, especially for men who live with a stoma or ostomy bag after colorectal or bladder surgery.
In terms of the prostate surgery, a significant risk to a mans erectile function status is whether or not the pelvic nerves that regulate erection can be spared at the time of surgery, Broderick says, noting that a more recent approach to the operation, called robotic prostatectomy, has advantages because patients dont require a large abdominal incision, have much less bleeding, and can get back to work sooner.
Dupin was able to have robotic surgery, and he is able to have sex and achieve orgasm. He doesnt have problems with a lack of libido or incontinence. The only sexual side effect hes experienced is the loss of ejaculate.
After Woodwards surgery in 1999, she was prescribed a topical vaginal medication called Premarin (conjugated estrogens) to lubricate and improve dryness. But this still left her unsatisfied.
All of the large guiding organizations say to use over-the-counter topical agents first, Goldman says. This includes things like moisturizers, pH balanced gels, soothing agents, oils and lubricants. Some of these things can alleviate symptoms if theyre used regularly.
Arkema says her first few recommendations include a variety of over-the-counter products, but these solutions dont always work for everyone.
Goldman notes there are vaginal hormones that can help treat dryness and sexual pain by targeting the tissue directly. The most common are vaginal estrogens which exist in a cream, a ring formulation and a suppository.
Furthermore, Goldman says there are now Food and Drug Administration (FDA) approved prescription medications that treat various types of sexual dysfunction. Osphena (ospemifene) and Intrarosa (prasterone) are approved for treatment of painful sex. Finally, there are also female versions of Viagra, as well as the FDA approved Addyi (fibanserin) and Vyleesi (bremelanotide), which are both approved for treatment of hypoactive sexual desire disorder in women.
I think theres a common misconception that nothing can be done, Goldman notes. Some providers assume the only treatment options are hormones, and for many breast cancer patients these are contraindicated (not advisable). Even so, there are lots of other options.
Broderick says that when meeting with a new patient, he starts by looking into how they were treated because the type of therapy often dictates the sexual side effects and recommendations. The primary treatment options include PDE5 inhibitors (which block the PDE5 enzyme, allowing blood vessels to relax and increasing blood flow), such as Viagra (sildenafil cirate), Levitra (vardenafil), Cialis (tadalafil) or Stendra (avanafil); penile injectable therapy; penile prosthesis; and the use of a vacuum erection device.
Although robotic surgery has come a long way, some men still struggle with incontinence, which quickly becomes a critical sexual side effect.
When a male patient comes to me with incontinence and erectile dysfunction, I start by asking where their partner is sleeping, because one thing Ive learned is that partners will not sleep in the bed with someone who is incontinent, Broderick notes. And theyre less likely to become intimate with someone who isnt in the same bed. So, you really need to address the incontinence first.
After a prostatectomy, Broderick says all patients go through a phase of neuropraxia (when the nerves arent working quite right). It takes time to return to normal erectile status. Generally, erectile function begins to come back after about six months. He says if it hasnt come back by 18 months, it probably wont.
Furthermore, radiotherapy, which is good at killing cancer, affects small-vessel blood flow, so patients who have been through radiation can have difficulty initiating and maintaining erections. Most of these patients, however, respond to PDE5 inhibitors like Viagra. On the other hand, a man who has lost nerve function from a prostatectomy needs direct vascular stimulants like penile injectable therapy.
So, I have a counseling plan for patients depending upon whether Im seeing him six, 12 or 18 months after his operation and his willingness to undergo rehabilitative strategies, Broderick says. Some patients come in and theyre part of a couple who are both in their 70s, and the erectile dysfunction is not as impactful for them simply because they werent all that sexually active prior to the surgery. Maybe his partner has gone through menopause and is less receptive of penetrative sex. What shes really looking for is the maintenance of their intimacy without penetrative sex. Sometimes my job is just getting the two partners to understand where they both are with all of that.
Although the range and severity of sexual side effects can vary greatly, one thing that helps across the board to increase treatment rates is talking about whats going on.
Findings from the SKCC survey of 400 survivors found that 87% said they experienced sexual side effects but most also said their oncologist had not asked them about these side effects. And patients often dont bring up the topic themselves, reporting that they feel embarrassed, think theres no help for the problem or dont know which type of physician to talk to about it.
Woodard says she wishes someone would have talked to her about what to expect before her surgery, but at the time she was being treated in a military clinic. She received her diagnosis from a nurse practitioner and then transferred to the hospital to meet with the surgeon and oncologist.
I remember that session when I met with the oncologist who looked at my chart and said, You have cancer? Thats odd, Woodard recalls. These conversations were never about gutting me out like a fish and what would happen afterward.
She went into surgery without any idea about what was coming.
Theres a stigma or discomfort for many physicians in talking about this, Goldman says. Theres a study that showed that if the patient feels discomfort coming from their provider, they often wont bring the issue up. So there (are) a lot of people who may assume that this is something they have to live with.
Goldman sees no reason that sexual dysfunction cant be talked about like the other side effects of treatment, such as neuropathy, hair loss and pain.
At Mayo Clinic, Broderick says they train their surgeons to do exactly that: talk about all the possible side effects.
Fortunately for Dupin, the possibility of sexual side effects was addressed. His doctor told him he may experience erectile dysfunction and gave him a prescription for Viagra that he decided not to use.
Sexual side effects of cancer treatment are common, and Goldman wants patients to understand this and feel comfortable asking about what treatments are available.
Woodard, who now volunteers with the National Cervical Cancer Coalition, (their website can help patients and survivors understand their side effects more and offers support), agrees that patients need to speak up.
My advice is to be more demanding, she says. Ask for resources. Often treatment is not only a physical procedure but one that affects your mental and emotional health. You should be in touch with an advisor or someone that can help you navigate the emotional part of this.
More importantly, Woodard wants patients to know theyre not alone. There (are) a number of us out here, she says. Seek help, ask questions, be persistent and dont give up. Dont give in.
For more news on cancer updates, research and education, dont forget tosubscribe to CUREs newsletters here.
Recommendation and review posted by Bethany Smith
Tolmar Publishes Study in the February Issue of Journal of Urology on the Impact of Late Dosing on Testosterone Suppression with Two Different…
BUFFALO GROVE, Ill., April 12, 2021 /PRNewswire/ --Tolmar Pharmaceuticals, Inc., a privately held specialty pharmaceutical company, announced the publication of a manuscript entitled "Impact of Late Dosing on Testosterone Suppression with Two Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere An Analysis of US Clinical Data" in the February issue of Journal of Urology.
This retrospective analysis of real-world data is a more detailed follow-up of the results to "The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data," which was published in the April 2020 issue of Journal of Urology. Leuprolide acetate is the most commonly used drug for androgen deprivation therapy (ADT) in men with advanced prostate cancer. The article reported the impact on testosterone suppression of late dosing of GnRH agonists in general.
Androgen deprivation therapy (ADT) is the standard of care for the treatment of advanced prostate cancer. It aims to reduce circulating testosterone (T) to castration levels in order to remove the 'fuel' that simulates cancer cells to grow. The goal is to reduce testosterone (T) to <50ng/dl, however there is a strong body of evidence recommending <20ng/dl as the benchmark.
"This new study reflects Tolmar's ongoing commitment to furthering research on the treatment of advanced prostate cancer through peer-reviewed publications," said David Crawford, M.D., Clinical Professor of Urology, University of California San Diego
This study was supported by Tolmar Pharmaceuticals, Inc. For more information, please click here
About Tolmar and ELIGARD
Tolmar is a fully integrated pharmaceutical company focused on the technology-driven development, approval, manufacturing, and commercialization of specialty pharmaceuticals. The Company's lead product, ELIGARD, is a luteinizing hormone releasing hormone (LHRH) agonist indicated for the treatment of advanced prostate cancer.
"Tolmar" refers to Tolmar Holding, Inc. and its wholly owned operating subsidiaries, Tolmar Inc., Tolmar Therapeutics, Inc., and Tolmar Pharmaceuticals, Inc. ELIGARD was developed and is manufactured by Tolmar Inc. Tolmar global headquarters, product development and manufacturing facilities are based in northern Colorado, while TOLMAR Pharmaceuticals' U.S. commercial business is based in Buffalo Grove, Illinois. For more information about the company, please visit http://www.TOLMAR.com. Information about ELIGARD is available at http://www.eligard.com.
IMPORTANT SAFETY INFORMATION
ELIGARD (leuprolide acetate for injectable suspension) is a medicine for the treatment of advanced prostate cancer. It works by reducing the amount of testosterone in the blood. It is not a cure.
ELIGARD should not be used by anyone who is allergic to any of the ingredients in ELIGARD or to any medicines that reduce testosterone the same way. ELIGARD should not be used by women who are pregnant or may become pregnant. ELIGARD can cause pregnancy loss or harm to an unborn baby if used in pregnant women.
Severe and possibly life-threatening reactions called anaphylaxis have occurred in people receiving ELIGARD.
Increased risk of heart attack, sudden death due to heart problems and stroke have also been reported in men taking ELIGARD. ELIGARD may also affect electrical activity in the heart that can cause an irregular heartbeat. Your doctor will monitor you for heart conditions.
Elevated blood sugar and an increased risk of developing diabetes have been reported in men receiving ELIGARD. Your doctor will monitor blood sugar levels.
ELIGARD causes an increase in testosterone during the first few weeks of therapy and some men may experience new or worsening symptoms of prostate cancer e.g., bone pain, urinary symptoms, or nerve problems such as numbness, during this period. If your cancer has spread to the urinary tract or spine, urinary blockage or pressure on the spine that can lead to paralysis may occur. Your doctor will discuss with you the benefits and risks of taking ELIGARD.
The most common injection site reactions are transient burning and stinging, pain, bruising, and redness. The most common side effects include hot flashes/sweats, fatigue, weakness, muscle pain, dizziness, clamminess, testicular shrinkage, decreased erections and enlargement of breasts. Other side effects, including thinning of bones that may lead to fracture, and rare but serious problems with the pituitary gland in the brain, have been reported with ELIGARD.
Please see Full Prescribing Information for additional important safety information.
Media Contact Information:
Julie Ferguson[emailprotected](312) 385-0098
SOURCE Tolmar Pharmaceuticals, Inc.
Go here to read the rest:
Tolmar Publishes Study in the February Issue of Journal of Urology on the Impact of Late Dosing on Testosterone Suppression with Two Different...
Recommendation and review posted by Bethany Smith
Why the Transgender Conversation Is Changing – ChristianityToday.com
Last Friday, a bill that would ban transgender athletes from competing in middle, high school, and college sports passed in the West Virginia legislature. At least 20 different state legislatures have introduced transgender athlete bans in 2021. While South Dakotas governor Kristi Noem vetoed a proposed ban, Tennessee, Arkansas, and Mississippi have signed these changes into law.
Arkansas governor, Asa Hutchinson, did, however, veto legislation that would have banned gender confirming treatments or sex reassignment surgery for transgender youth under 18. That bill would have been the first in the country to ban this practice. Meanwhile, last Monday, GOP legislators in North Carolina introduced a bill that that would prevent doctors from performing sex reassignment surgery for transgender people under the age of 21.
This flurry of state billsa month ago LGBT advocacy group Human Rights Campaign had counted more than 80has once again provoked impassioned fighting, much of it centered around children. Its led to questions of fairness in youth sports, if adolescent judgement and diagnosis should be trusted, and what role and what say parents should have in how their children express their gender.
Mark Yarhouse is a pyschology professor at Wheaton College and the director of the Sexual and Gender Identity Institute. His books include Understanding Gender Dysphoria and most recently, Emerging Gender Identities. He joined global media manager Morgan Lee and editorial director Ted Olsen on this weeks episode of Quick to Listen.
What is Quick to Listen? Read more
Rate Quick to Listen on Apple Podcasts
Follow the podcast on Twitter
Follow our hosts on Twitter: Morgan Lee and Ted Olsen
Follow our guest on Twitter: Mark Yarhouse
Go down Teds music rabbit hole
Music by Sweeps
Quick to Listen is produced by Morgan Lee and Matt Linder
The transcript is edited by Yvonne Su and Bunmi Ishola
What is the same and what has changed in the conversation around gender over the past five or six years?
Mark Yarhouse: The conversation around gender has become more pronounced and centered into cultural discussions.
You see an increase in the number of people who identify as transgender or what I refer to as emerging gender identities. There's a splintering of gender categories into different experiences, different language for describing people's experiences.
Things have become more polarized as well. You saw that with the reaction to legislation like the bathroom bill, and you see that now with the law passed in Alabama. 20 or more states have gender identitychange laws in place for minors to keep that from happening. Theres an increase on both sides of a divisive topic.
What led to this development?
Mark Yarhouse: When I wrote my first book on understanding gender dysphoria, I was trying to introduce evangelical Christians to the concept of transgender experiences. Gender dysphoria is this experience that's distressing when a person's gender identity doesn't align with their biological sex.
When I talk about emerging gender identities, it's beyond that basic framework of transgender. Young people say that theyre gender-expansive, theyre gender-creative, theyre bi-gender, theyre pan-gender and the different identifiers go from there.
It helps us as Christians to be thoughtful in how we engage in a culture that's shifted so dramatically and where language has been shifting. You're interacting now with younger people for whom these are taken-for-granted realities and the generation that went before them had a limited scope of categories and language. Theres a real high likelihood of our misunderstanding and talking past one another.
Do the lessons about transgender issues from before map onto the emerging gender identities?
Mark Yarhouse: Some of the lessons learned will map onto that. It's challenging to know exactly how to, as Christians, enter into this conversation because we have had norms around sexuality and gender that we want to be able to articulate.
But sometimes when we articulate those norms, we can do it in ways that seem to cast doubt on the experience of other people around us, who don't use those same norms as anchor points that we do. It ends up becoming more of a risk of speaking past each other or being entrenched in not understanding.
You can both teach norms around sexuality and gender and recognize that there are exceptions to those that are likely the result of a fallen world and the challenges that people face in that space. There are also clinical differences and issues from a classic transgender presentation and some of the emerging gender identities.
To seek common ground, is it helpful to talk about how we also have dysphoria or dont conform to cultural or biblical notions of what it means to be male or female?
Mark Yarhouse: There are an upside and a downside to that approach. Christians would hold that we have so much in common as we bear the image of God and we should start there. People are beloved by God. God wants a relationship with people. Theres so much in that sense as a starting point for shared human experience.
But if you overplay that, you look past how some people's experience is so far on the margins that you might not fully appreciate the challenges that they're facing, particularly when it is dysphoria, a painful experience that you've never experienced.
There are also people saying that this is willful disobedience on your part. We're not speaking the same terms here about people's experiences.
How do you define gender dysphoria? Is the term interchangeable with the idea of transgenderism?
Mark Yarhouse: Gender dysphoria is the discomfort or distress that's associated with the lack of concordance between someone's biological sex, usually thought of in terms of chromosomes, genitalia and gonads, and the person's gender identity, their experience as a man or a woman or a different gender identity than that.
When that's distressing to them, it's dysphoria versus euphoria, a positive emotional state. It's a negative emotional state. I don't think of that as synonymous with transgender but many people who would identify as transgender would report gender dysphoria. It can vary in severity from mild to severe, and it can ebb and flow in severity in a person's life.
Historically, gender dysphoria was thought of as having an early onset. A boy or a girl is aware of their gender between ages two and four, developmentally. They're aware that they're a boy or a girl, or they're going to express a different experience than that.
What we've seen in the last six years has been a remarkable increase in the number of cases that we would call late-onset. That means at or after puberty, the person is reporting dysphoria that they didn't appear to have much evidence of, if at all, in childhood.
That's what's concerning to some mental health professionals and others. Theres not been a satisfying explanation that accounts for that increase.
Is it true that, before the last five or six years, people that were saying Im trans most likely started feeling those feelings well before puberty?
Mark Yarhouse: Most of the cases had been what we would call early onset. Parents would wonder if their child was going through a phase. They would probably go to a specialty clinic when that child turned six or seven, maybe when they were going to preschool or kindergarten, when the comparison would be their peer group, rather than at home with their family.
Historically, that would be the more typical presentation. It was more often biological males rather than females, at about a four- or five-to-one ratio that would be referred to these specialty clinics. That was probably the result of having a narrower box for what a boy can be like.
If they're outside of that expectation, then it raises more flags for parents. Whereas girls can have a little more latitude in how they present; and if they're gender atypical in some ways, you have positive language for that. They could be tomboyish and no one's going to be particularly concerned.
That probably accounted for that ratio, but now you're seeing quite a flip. Now we're seeing not just the late-onset cases at a higher rate, but also seeing it among biological females at a higher rate than you do males. We don't understand what's going on with that switch.
How do you distinguish between someone who expresses themselves outside the cultural understanding of masculinity or femininity, versus someone who feels uncomfortable being a particular gender?
Mark Yarhouse: When you meet with somebody to make a diagnosis of gender dysphoria, you rule out that they're within the range of what a boy or girl, or a man or a woman, would be like. They maybe have different characteristics, different presentations, different ways different interests, and so forth that are gender atypical. They don't fit into maybe stereotypes, but they're not gender dysphoric.
So how do you make that distinction? Several things go into that. You can have a conversation with an adult and theyre telling you. It's harder when you're trying to make that determination with a child who might not be able to pull all that together. But there are certain criteria that you follow around what they're able to say about their gender identity.
It's usually their response to primary and secondary sex characteristics. It's the desire for the sex characteristics of the other gender. These things aren't for a few weeks or a few months; it's over time and it's significant. It's significant in their body image and how they experience and see themselves. It's distressing to them.
What advice would you give to adults who have recently learned that a young person in their life is trans?
Mark Yarhouse: Christians typically have this skill set. We are used to applying it to other groups of people whose individual characteristics are different than our own. For example, we don't seem to have difficulty relating to our agnostic neighbors, even though their characteristics around their religious identity are different than ours.
We have a sense of how to relate to that person who's different in terms of racial or cultural background. When people's characteristics vary from ours, we can relate to them, talk with them, recognize God's love for them, value them as a person, to encourage them to bring all of their experiences into the relationship that we're forming with them as an acquaintance and maybe a friend.
You use the same skill set here. It's doesn't have to be more difficult than that.
I don't normally speak into the lives of adolescents around me unless I have a relationship with them and I'm invited into that space. It would run a significant risk of me overstepping the nature of the relationship I have with them, and then likely speaking past them. Then what they may know about me is that I'm a Christian whos now a witness to them. I have this top-down approach where I'm telling them that they're at-risk or they're doing something wrong.
I would probably take the position more with an adolescent than I do as a neighbor, as a family friend, or something like that. To listen more about what their experience has been like, remember that they're navigating at their age.
Their generation has a lot more categories for language around categories and linguistic constructs around gender and sexuality than my generation did. They're probably deeply shaped by what's been made available to them and they're interacting with those categories and they're making sense to them, or they might not make sense to me.
I might have a reaction to that, but it would be better to understand how the language functions for an adolescent rather than begin with the place that they're wrong or that they need to be corrected. That kind of mutational strategy does not work with adolescents period. It doesnt work in this conversation because our connection to their language has been so different and they've been exposed to so many different categories.
How do you counsel people on the basic questions of name and identity?
Mark Yarhouse: If a person is able to live in a way that reflects their birth sex, its going to be less complicated.
There are so many layers of complexity. Some people are in this place where they're considering a social transition or a partial transition, and they're trying on different names and pronouns.
If the person's trying to do that because they've been suffering from gender dysphoria and it's been distressing to them, and they've used other strategies to manage that (like the clothing they wear, the way they keep their hair, and these things have taken the edge off that dysphoria and been helpful to them), but it's sufficiently distressing that they think that using pronouns that they would prefer might be helpful to them, then I'd like to understand what's behind the request and how it's functioning for them.
That's not an uncommon strategy that people use. They try to use these strategies usually in a trial-and-error way and in a stepwise fashion. They can always reverse and go back to their original pronouns.
They can always do that; they're trying to figure this out. I don't want to be overly reactive to that. I want to meet them where they are. I want to have a sustained relationship with them. I err on the side of hospitality towards somebody to be in a relationship with them rather than do things on the front end that would sever the tie that they might otherwise want to have with me.
What advice do you have for parents as they try to understand where their child is coming from?
Mark Yarhouse: When you have early onset, parents are not that surprised when a child says to them, I'm transgender, or I experience my gender identity differently than most people do, or however they frame it. Parents knew something was going on. They just didn't have language for it. But when you have late-onset cases, it is blindsiding. Parents feel like their world has been rocked and there's no reference point for what their teenager is saying. There's little or no history to understand it.
There has been some concern that there might be teens who have other issues going on in their life and they're finding a sense of identity and community in something that has such social salience today. It's moved to the center of some of the cultural discourse around sexuality and gender, where some time ago, being gay had occupied that space.
The transgender conversation has moved into that space culturally and maybe a generation ago, a young person might've landed in a different area and explored different aspects of themselves. But today this has the kind of salience that might be appealing to some people where they might not have gender dysphoria.
There may be other things going on and they're finding something in this space. I want to be careful when I say that because I don't think that's most of what I'm seeing in my clinic. Some people have been trying to research that as a possible phenomenon.
Is that something that is trending among adolescents and we should be cautious about? I want parents to be wise and discerning to check things out with a provider, someone who has expertise in this area and to realize there could be multiple things going on here and it would take discernment and time to figure out what's going on.
Are there important ways that we should differentiate between dysphoria and transgender issues, versus same-sex attraction issues?
Mark Yarhouse: They are different experiences. When someone describes themselves as gay, they're talking about their attraction towards the same sex and their orientation towards the same sex. When someone says that they're transgender, they're talking about their experience of their gender identity as a man or a woman or a different gender identity than that.
Gender identity doesn't have to do with who you're physically, emotionally, or sexually attracted to. A lot of times when people are wrestling with dysphoria, they're often being asked about their sexual orientation. That's a confusing topic for some people.
They're not sure what they could even say about that. They're trying to figure out what's going on around gender. Sometimes Christians are more preoccupied with sexual behavior. I don't think that's where a lot of people are when they're figuring out gender. That's a different thing for them. Distinguishing that is helpful. S
Some Christians see that Scripture speaks more to the question around sexual behavior than it does to gender identity. That complicates this conversation more. It's not that Scripture doesn't say anything about gender, but it doesn't certain passages that stand out around sexual behavior. It's not quite as clear if you're looking for direct scriptural passages.
What effect do you expect banning surgery for young people to have?
Mark Yarhouse: There are several things that minors might consider, like whether to block going through puberty. That's right at the beginning of the development of puberty. Then young people might consider using cross-sex hormones at some point, maybe a year or two later. If they did the puberty-blocking intervention, then that becomes a consideration. Some of the legislation may be looking at that. There are surgical procedures as well.
On both sides of this debate, people have young people's best interests at heart. They're both trying to address vulnerable young people that they're concerned about, but they're landing diametrically in places to express their concern. Those who are saying we shouldn't allow these types of procedures are saying young people dont have the capacity to make these kinds of decisions, to understand the consequences of these decisions, and what that could mean for them five or 10 years out.
Other people believe that young people are at great risk and that these are the kinds of things that medical and psychiatric providers think should be on the table and considered for a young person. They can make that decision.
What are some of the consequences that people proposing these bans are concerned about? To what extent are they valid or exaggerated?
Mark Yarhouse: With the use of cross-sex hormones, this would be a lifelong regimen that a young person would have to take to have the clinical effects of using the other hormones of the other sex. If you stop taking the hormone, you stop having that clinical benefit.
We don't have the kind of long-term research on the effects of an adolescent using cross-sex hormones over 30 years. The greatest risk would be the risk for sterility.
Another topic that people are concerned about is that a young person at 16 or 17 doesnt understand what that would mean in 10 years. Do they understand the risks that they're taking there?
I'm not a fan of legislating around these complex clinical issues on either side. Once you move towards legislation on either side of these complex issues, ultimately, it ends up not being nimble enough to respond to the needs of the next person in front of you. I'd love for those needs to be met more by the mental health profession and the people who are working with them.
Those that regulate the mental health professions, that's where typically complaints would be adjudicated. It would be through the people who were licensing the providers to provide services rather than through legislation that creates a statement that's applied to everybody across the board. That doesn't end up being as flexible on members as we would.
Have you seen any examples of school districts figuring out how to have trans girls and women play in youth or collegiate sports without resorting to laws?
Mark Yarhouse: We need more time to research how to measure advantage and what that looks like. When you develop a policy like the NCAA has tried to, looking at the length of time to be on hormones, there's good intention to try to figure that out. What gives someone a competitive advantage? How do you safeguard that without excluding people from being able to compete when this is what they have trained to do?
They're good at this, and you want to allow them to do this. There have been controversies at every level of competition; this is not going to be resolved quickly. There hasn't been enough work done on clarifying what those standards would need to be across the board. Maybe they need to be applied more on a case-by-case basis than having one length of time that's applied to everybody. I wonder if it's more complicated than it's been made out to be.
How should we understand stories of people who have transitioned, then transitioned back? What kind of attention should they get?
Mark Yarhouse: Sometimes it's referred to as de-transitioning. I haven't seen a very well-designed study that would show us how common that is. In the Netherlands, they recently published a report on 30 years of people using different interventions, including surgical procedures.
The rate of regret continues to be low. I don't think that you're seeing a dramatic rise in regret that would typically correspond with de-transitioning. You could have regrets about surgery and elect not to be transitioned. We need to study that more to see how common that is, but based on the rates of regret that were published more recently, I don't see a rise in that.
I am concerned that we could see a rise in that for the reasons that I've talked about: atypical presentations, late onset, the gender ratio flip towards more cases of female adolescents with later onset. Where will they be in five or 10 years? We don't know yet.
Most actually don't make medical transitions at this point, but if they were to, would we see a rise in regret? I'd be curious.
How do you recommend we pray for people who are experiencing gender dysphoria?
Mark Yarhouse: We pray for God to continue, if He's already been speaking to them, to continue to speak to them; to speak to me, to guide me, to help me know best how to see the person, to love this person, that they would know that they are loved by God. For me and them to have wisdom and discernment moving forward. For wisdom and discernment on how I relate to them as someone that God cares deeply about.
Those are the types of prayers that I pray. I also provide ministry outside of my role as a psychologist. That's been helpful to me in walking with people. I mentioned that most people don't make a medical transition at this point. I think in the last transgender survey, about 44% of something like 26,000 transgender persons had indicated that they were using hormone treatment and only about 25% had used any type of gender confirmation surgery.
That's been a helpful conversation to have in the back of my mind.
See original here:
Why the Transgender Conversation Is Changing - ChristianityToday.com
Recommendation and review posted by Bethany Smith
Diabetes and a Metallic Taste in the Mouth: Causes and Treatments – Healthline
Diabetes is a chronic condition where the body doesnt make enough insulin or use insulin properly. Insulin is a hormone that allows sugar to enter the bodys cells, where its then used for energy.
When the body doesnt make enough or use insulin properly, sugar accumulates in the bloodstream. This leads to high blood sugar.
Uncontrolled diabetes or high blood sugar can cause a range of problems such as nerve damage and kidney damage. But these arent the only side effects of diabetes. Some people with diabetes may also develop a metallic taste in their mouth.
The reasons for taste disturbance vary, but might include medication or poor oral hygiene. Sometimes, a metallic taste in the mouth is also an early sign of diabetes.
Here are a few causes of a metallic taste in the mouth related to diabetes.
Metformin is an oral medication commonly prescribed to treat type 2 diabetes. It reduces the amount of glucose (sugar) produced by the liver. This helps lower blood sugar levels to a safe range.
But although Metformin can stabilize blood sugar thus reducing the risk of serious diabetes complications some people who take this medication complain of a metallic taste in their mouth.
The reason isnt quite clear, but this taste disturbance is likely due to the prescription drug excreting into saliva.
The good news is that this taste problem is often temporary, with taste returning to normal after 1 or 2 weeks.
Parageusia is a taste disorder that can occur alongside diabetes. Its also known to cause a metallic taste in the mouth. But, whats the connection between parageusia and diabetes?
Simply put, your central nervous system (CNS) affects how your brain perceives taste, and its possible that uncontrolled diabetes can affect your nervous system.
Prolonged high blood sugar slowly damages the nerves in your body. This can include the nerves in the:
Parageusia occurs when injury or damage to the CNS distorts taste and smells. Taste disturbances such as a metallic taste in the mouth develop when the nerves that affect taste become damaged.
Oral health issues are another common cause of a metallic taste in the mouth.
Many people think of diabetes only affects blood sugar. But too much sugar in your blood can cause problems with your mouth, too.
High blood sugar also increases the sugar level in your saliva. And if your saliva contains more sugar, youre at a higher risk for cavities, gingivitis, and periodontitis. The latter two can cause a metallic taste in the mouth.
Diabetic tongue is another oral health problem that can cause a metallic taste in the mouth. This occurs when a combination of too much sugar in your saliva and a dry mouth triggers oral thrush.
Thrush develops when a fungus that occurs naturally starts to grow out of control. It can affect the gums, tongue, and the roof of the mouth.
A metallic taste in your mouth due to diabetes might improve over time. It all depends on the underlying issue.
If you take the drug Metformin, a metallic taste should subside after a few weeks once your body adjusts to the medication. If taste disturbance doesnt improve, see a medical professional.
Adjusting your dosage or finding an alternative drug might improve your taste.
If a metallic taste is due to sugar in the saliva, controlling your diabetes can also help improve your taste. Additionally, if you develop an infection due to poor dental hygiene, seeing a dentist and treating the infection might improve taste.
If taste disturbance occurs due to nerve damage, the severity of nerve damage may determine whether your taste returns to normal.
Even if you adjust your medication, improve your oral hygiene, and take steps to control your blood sugar, a metallic taste in your mouth might not improve immediately.
As you wait for your condition to improve, here are a few tips to help your food taste better:
See a doctor if a metallic taste in your mouth does not improve after a couple of weeks. Its important that you dont ignore this taste disturbance, as it can indicate problems with blood sugar control.
If you havent been diagnosed with diabetes, yet you notice a metallic taste in your mouth, see a medical professional. This taste disturbance is sometimes an early sign of diabetes.
A metallic taste in your mouth can distort the taste of foods and beverages, making it difficult to enjoy your favorite foods. Although taste disturbances have different underlying causes, its important to see a doctor for symptoms that dont improve.
This can be an early sign of diabetes, as well as blood sugar that is not in target range.
View original post here:
Diabetes and a Metallic Taste in the Mouth: Causes and Treatments - Healthline
Recommendation and review posted by Bethany Smith
Multimodal Care Is Key Focus at Breast Cancer Conference – Targeted Oncology
As long-awaited results from pivotal trials are revealed during major medical conferences, community oncologists in the clinic look forward to the resulting approvals with much anticipation. That focus continues to be the hallmark of the upcoming 20th Annual International Congress on the Future of Breast Cancer West, hosted by Physicians Education Resource, LLC (PER).1
Cochair Sara A. Hurvitz, MD, said the intensive, 2-day conference provides a multimodal perspective on care that includes medical oncology, radiation oncology, and surgical oncology.
Its a fantastic way for physicians to [learn about] the latest research results that can be translated for use in the clinic, she said in an interview with Targeted Therapies in Oncology. Hurvitz is an associate professor in the Department of Medicine at the David Geffen School of Medicine, codirector of the Santa Monica-UCLA Outpatient Hematology/Oncology Practice, and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit at UCLA in Los Angeles, California.
Hurvitz is moderating the morning session on July 30, which will cover breast cancer management with curative intent. One of the presentations during her session is being made by Joyce OShaughnessy, MD, cochair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and The US Oncology Network in Dallas, Texas, and cochair of the conference. Hurvitz expects OShaughnessys presentation, Neo/Adjuvant CDK4/6 Inhibitors: Ready for Prime Time? to address updated results from the monarchE trial (NCT03155997) and the MONALEESA-7 trial (NCT02278120), both of which evaluated various CDK4/6 inhibitors combined with estrogen therapy.
In monarchE, investigators demonstrated that adding abemaciclib (Verzenio) to standard adjuvant endocrine therapy continued to improve invasive diseasefree survival among patients with high-risk, node-positive, early-stage, hormone receptorpositive, HER2-negative breast cancer.2
In the phase 3 MONALEESA-7 trial, patients with hormone receptorpositive, HER2-negative breast cancer had a significant improvement in overall survival (OS) and chemotherapy delay when treated with ribociclib (Kisqali) plus endocrine therapy compared with placebo.3
At a median follow-up of 53.5 months (range, 46.9- 66.4), the median OS with ribociclib plus endocrine treatment was 58.7 months vs 48.0 months with placebo/endocrine therapy (HR, 0.763; 95% CI, 0.608-0.956), translating to a 24% relative reduction in the risk of death with the CDK4/6 inhibitor.
Moreover, data from a subgroup analysis examining survival in relation to endocrine partner, results showed that patients who received a nonsteroidal aromatase inhibitor (NSAI) experienced a median OS of 58.7 months with ribociclib/endocrine therapy versus 47.7 months with placebo/endocrine therapy (HR, 0.798; 95% CI, 0.615-1.04).
Turning to immunotherapy in breast cancer, Hurvitz acknowledged that it is an exciting strategy for certain tumor types but that in breast cancer, results have been somewhat limited.
Immunotherapy in breast cancer has been shown to be somewhat beneficial, but those benefits are limited to tumors that are PD-L1 positive in the frontline setting, rather than in later lines, Hurvitz said.
For example, updated efficacy results from the IMpassion130 trial (NCT02425891) evaluated 902 patients; 451 were randomly assigned to receive atezolizumab (Tecentriq) plus nab-paclitaxel, and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population).4
Median overall survival in the intention-to-treat patients was 21.0 months (95% CI, 19.0-22.6) with atezolizumab and 18.7 months (95% CI, 16.9- 20.3) with placebo (stratified HR, 0.86; 95% CI, 0.72-1.02; P = .078). In the exploratory OS analysis in patients with PD-L1 immune cell positive tumors, median OS was 25.0 months (95% CI, 19.6-30.7) with atezolizumab versus 18.0 months (95% CI, 13.6-20.1) with placebo (stratified HR, 0.71, 95% CI, 0.54-0.94).
Somewhat limited benefits have also been reported for other immune checkpoint inhibitors. Improved progression-free survival (PFS) was observed with pembrolizumab (Keytruda) and chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer in the KEYNOTE-355 trial (NCT02819518).5
At the second interim analysis for KEYNOTE-355, median follow-up was 25.9 months for patients in the pembrolizumab-chemotherapy group and 26.3 months in the placebo-chemotherapy group. Among patients with a combined positive score (CPS) of 10 or more, median PFS was 9.7 months with pembrolizumab-chemotherapy and 5.6 months with placebo-chemotherapy (HR, 0.65; 95% CI, 0.49-0.86; P = .0012). Median PFS was 7.6 and 5.6 months (HR, 0.74; 95% CI, 0.61-0.90; P = .0014), respectively, among patients with a CPS of 1 or more and 7.5 and 5.6 months (HR, 0.82; 95% CI, 0.69- 0.97) among the intention-to-treat population.
The benefits of pembrolizumab were restricted to those patients with a CPS of 10 or greater, which is not the majority of patients with triple-negative breast cancer, Hurvitz said.
Turning to CDK4/6 inhibitors, Hurvitz noted that despite the benefits observed in PFS and OS for this particular class of drugs, resistance continues to be a challenge, prompting investigators to evaluate next-generation CDK4/6 inhibitors.
The success of CDK4/6 inhibitors in drug development has been outstanding, she said. My hope for the future is that were going to have better agents for triple-negative breast cancer and [that] well see an improvement in survival with this disease subtype in the future, Hurvitz said.
References:
1. 20th Annual International Congress on the Future of Breast Cancer West. Physicians Education Resource, LLC (PER). Accessed March 16, 2021. https://bit.ly/2OwiDPA
2. OShaughnessy J, Johnston S, Harbeck, N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract GS1-01.
3. Tripathy D, Im S-A, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy (ET) +/- ribociclib. Presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD2-04. https://bit. ly/3cGIzQq
4. Schmid P, Rugo HS, Adams S, et al; IMpassion130 Investigators Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;21(1):44-59. doi:10.1016/S1470- 2045(19)30689-8
5. Cortes J, Cescon DW, Rugo HS, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9
Read the original here:
Multimodal Care Is Key Focus at Breast Cancer Conference - Targeted Oncology
Recommendation and review posted by Bethany Smith
Freezing Sperm: Cost, Effectiveness, and More – Healthline
Sperm donors arent the only ones who bank their sperm. People with no plans to donate do it too, especially if theyre not ready to have a baby just yet but know they want to one day.
The process of sperm banking, otherwise known as sperm freezing or cryopreservation, is a great way for couples (or single folks) to preserve their chances of conceiving a biological baby in the future especially if the partner with testes is in a high-risk profession or about to undergo certain medical procedures or treatments.
If you think this might be something youre interested in, were here to break down everything you need to know about the procedure.
If youve been diagnosed with testicular or prostate cancer, you may have been told that treatment can involve surgeries that remove one or both testicles.
And actually, anyone with testicles who has cancer including adolescents might want to freeze their sperm if theyre about to undergo treatment. Cancer treatments, including chemotherapy or radiation, can cause a decline in sperm quality or cause infertility.
Unfortunately, in an older 2002 study of oncology staff physicians and fellows, 48 percent of respondents reported that they never brought up the option of sperm banking or mentioned it to less than a quarter of eligible people.
Even though sperm freezing is more widely recognized as an option today, its still important to advocate for yourself if youre interested in it.
If youre approaching older adulthood, you might choose to freeze your sperm to preserve your chances of having children. Semen quality decreases with age because sperm concentration, morphology (size and shape), and mobility all decline, per a 2011 review.
Not only do the risks for autism, schizophrenia, and other conditions increase with age, theres also evidence that seminal volume declines. In fact, some people simply become infertile.
If you work at hazardous worksites or are deployed in the military, you may opt to bank your sperm, just in case of accidents or chemical exposures that could damage sperm or fertility.
Some people freeze their sperm if theyre going to be traveling to areas of the world with Zika, a virus that can be passed to someone else via semen.
If youre undergoing certain surgeries such as gender confirmation you might decide to do this to preserve your chances of having a biological child.
In addition, you may decide to bank your sperm if youre getting a vasectomy in case you change your mind about having children in the future.
Some medical procedures can also impact the ability to ejaculate, so sperm banking is often offered before those procedures are scheduled.
Other people who might consider freezing their sperm include:
The best place to freeze sperm is at a sperm bank or fertility clinic, says Dr. Juan Alvarez, board certified reproductive endocrinologist with Fertility Centers of Illinois.
This is because, he explains, sperm should be processed within 1 to 2 hours of collecting a sample.
You can also use an at-home banking kit, such as Legacy or Dadi. These kits allow you to collect your sperm at home and ship it in special containers to a lab for testing and freezing.
However, Alvarez says, he only advises using those if there are no sperm banks or fertility clinics nearby. This is because he thinks its important to talk with a fertility doctor if youre deciding to freeze sperm.
Based on the reason for pursuing a sperm freeze, a physician can help you determine how much and when to complete a freeze, he explains.
Before banking your sperm, youll give blood so you can be screened for sexually transmitted infections (STIs). Youll also fill out a lot of paperwork, including a questionnaire, contract, and legal forms.
Before depositing a sample, youll be asked to abstain from sex for 2 to 3 days.
If you feel comfortable, youll give your sample in a private room at the fertility clinic or sperm bank.
This allows the sperm to be frozen when its freshest. (Within minutes of ejaculation, the number of living sperm cells and activity begins to drop off.)
Youll deposit your sample in a sterile cup after masturbation. Some places allow your partner to assist.
If you dont feel comfortable doing this at a clinic or bank, you can collect your sample at home. Just know that the sample will need to be brought to the clinic within an hour.
Samples are analyzed for sperm quantity, shape, and movement, which will help determine how many more samples are needed. In general, about three to six specimens are collected for each desired pregnancy, but itll depend on the quality of your sperm.
The samples are then separated into multiple vials and frozen by a lab technician who specializes in cryoprotectant agents to protect the sperm cells.
If sperm arent present in the sample or if you arent able to ejaculate, its possible to have a surgical retrieval. In this case, a healthcare professional will remove sperm directly from the testicle.
Sometimes, sperm freezing is covered by insurance if youre doing it for a medical reason.
Otherwise, the cost is usually less than $1,000 and that includes all required testing and freezing for the first year, says Alvarez. Afterward, he says, annual cryopreservation costs for sperm are roughly $150 to $300.
Sperm freezing has been done successfully since 1953. Its a highly effective process for people looking to preserve their fertility.
Of course, some sperm dont survive the freezing process.
The thaw survival of sperm is over 50 percent, Alvarez says.
If the sample is of high quality, this reduction isnt an issue for successfully conceiving a healthy baby. This is because the average sperm count ranges from 15 million to more than 200 million sperm per milliliter of semen.
In terms of sperm quantity, we only need 10 million motile sperm for inseminations and one sperm for each egg in IVF [in vitro fertilization], Alvarez explains.
Plus, he says, sperm does not lose its effectiveness with a freeze/thaw and it has the same fertilization capacity as fresh sperm [and] there is no difference in fertilization between frozen and fresh sperm.
Theres also no evidence that using frozen sperm increases the risk of health issues in babies.
In theory, sperm could probably be frozen indefinitely as long as its stored correctly inside liquid nitrogen and it was a high-quality sample to begin with.
Frozen sperm doesnt have a definitive end date, Alvarez explains. Due to modern cryopreservation techniques being so advanced, the health and integrity of sperm is maintained in the process.
There has been success with sperm that has been frozen for over 20 years, he adds.
The short answer is yes.
When you sign up to freeze your sperm, youll sign legal paperwork that will determine what happens to your sperm if you dont pay your storage fees, for example. Youll also set up the rules for how you or your partner can use (or discard) the sample, including in the event of your death.
For example, you can sign an agreement that either terminates your agreement if you die or allows a legally authorized representative (like your spouse) to use or terminate it.
Some clinics may require you to get a witness or have a notary public watch you sign the form.
Sperm freezing if you have the financial means to do it can be a great option if youre looking to preserve your chances of having a biological child.
This is especially true if youre:
The process is highly effective and carries few risks. Talk with a fertility expert if you think it might be a good option for you or your family.
Read this article:
Freezing Sperm: Cost, Effectiveness, and More - Healthline
Recommendation and review posted by Bethany Smith
Recognizing the importance of energy availability in the young athlete – Contemporary Pediatrics
Case A
A female high school rower, aged 17 years, presents to your clinic for upper back pain. She is preparing for her senior year and would like to row competitively in college. Her back pain has been present for 2 months. Initially pain was only with rowing, but it has been progressively worsening and now she has pain at rest. Reviewing her medical record, you notice that she has lost 33 pounds since her last visit about 9 months ago. Her body mass index (BMI) was 24.3 kg/m2 (75.6% percentile) 9 months ago and today it is 18.6 kg/m2 (11.7%). On review of systems, you learn that she has not had a menstrual period in the last 6 months. Menarche occurred when she was aged 12 years. She endorses feelings of depression, but no suicidal ideation. Academically, she is a straight-A student.
Case B
A male cross-country runner with right lower leg pain for 2.5 weeks, aged 15 years, presents to your clinic. He was previously running about 30 miles per week but recently increased his mileage to 60 miles per week. He has a history of shin splints but his current pain feels like it is in the bone of [his] lower leg. The pain is focal to his midtibia. Pain is present with weight-bearing and he has a limp with walking due to pain. He stopped running a week prior, but he likes to be physically active and has been cross-training with core and upper-body resistance training. He has a history of a right tibial stress fracture from the past year. On review of systems, you learn that the patients BMI has decreased from 19.3 kg/m2 (29% percentile) to 18.0 kg/m2 (3%) over the past 2 years. He is a vegetarian. X-ray today demonstrates a stress fracture (Figure 1).
What is the female athlete triad?
The female athlete triad was first described in 1997 as the interrelationship among amenorrhea, osteoporosis, and disordered eating. In 2007, the triad was revised to better identify athletes at risk, recognizing that presentation can be on a spectrum, ranging from optimal health to subclinical and clinical disease (Figure 2). The 3 components are now called menstrual function, bone mineral density (BMD), and EA,1 with low EA being the root cause of the triad. Acknowledging the existence of a spectrum of disease allows athletes to be identified earlier and to receive earlier intervention. If an athlete has any of the 3 components, a more thorough investigation should be performed to evaluate for the other components, which may have subclinical presentations.
Prevalence. Due to the spectrum of disease, it can be difficult to accurately estimate the prevalence of the female athlete triad. An athlete may have 1, 2, or all 3 components. It is estimated that all 3 components are present in 1.0% to 1.2% of high school athletes, 2 components in 4% to 18%, and 1 component in up to 54%.2
Which athletes are most at risk? Any athlete can develop aspects of the triad, but athletes in sports that emphasize endurance, appearance, or weight class are most at risk. Sport specialization at an early age can also increase risk (Table 1). The Female Athlete Triad Coalition Consensus Panel recommends screening during the pre-participation physical exam or if there are concerns that an athlete may have the triad (Table 2).
Components of the triad
ENERGY AVAILABILITY
EA is the amount of dietary energy (calories) remaining for physiologic function after exercise. Low EA is the root cause of the triad as it may affect bone health and lead to hormonal disturbances in the athlete.
Many athletes low EA is not intentional and they do not display pathologic eating or weight control behaviors. When this is the case, simply increasing caloric intake will treat the patient. However, restriction of caloric intake can be intentional in athletes who are trying to maintain a weight class or achieve a certain appearance. Disordered eating is estimated to occur in 6% to 45% of female athletes.3 Athletes who have specialized diets (vegan, vegetarian, pescatarian, etc) may also be at increased risk. In cases where the athlete has intentional disordered eating, psychological intervention and treatment may be required.
According to a study of 1000 female athletes by Ackerman et al, those with low EA were more likely to have negative performance effects, including decreases in coordination, concentration, endurance, and training response. In the clinic setting, it may be helpful to discuss with the athlete how decreased EA can negatively affect performance.4
A low BMI is a strong predictor of low bone mineral density and stress fractures. An adolescent should be screened carefully if they have a BMI that is less than 17.5 kg/m2. An athletes goal weight should be >90% of expected body weight.1 However, it is important to keep in mind that even athletes with a normal BMI may still have low EA.4
If you are able to work with a dietitian, you can calculate fat free mass (FFM) for your athlete patient. In order to have normal menstrual function, 30 kcal/kg of FFM/day are needed, but 45 kcal of FFM/day is ideal.1 Because this calculation can be difficult, it is helpful to have the athlete see a sports dietitian and exercise physiologist, if possible.
Even in the absence of amenorrhea, disordered eating can be associated with lower BMD in athletes.
BONE MINERAL DENSITY
Adolescence is the most crucial time for bone mass accumulation, so the presence of the athlete triad can be particularly harmful during this time. Maximum rate of bone formation usually occurs between the ages of 10 and 14 years, and 90% of peak bone mass is attained by 18 years.2 Diet, weight-bearing activities, and genetic makeup all contribute to an individuals bone mass accrual. Achieving sufficient bone mass is important to decrease the risk of fracture and to prevent osteoporosis in adulthood. Lower estrogen and lower EA increase bone resorption and suppress bone formation and remodeling.
Stress fractures are often the initial presenting symptom in patients with the triad. Stress fractures usually occur due to chronic, repetitive micro-trauma that cause tiny cracks in the bone. Athletes with menstrual irregularities are more likely to have bone stress injuries. As with the other aspects of the triad, a spectrum of stress injury exists, ranging from stress reaction (intermediate injury; bone marrow edema) to fracture (when enough trauma has occurred to cause a break in the cortex).
A dual-energy radiograph absorptiometry (DXA) can be used to assess bone density and should be considered in athletes with a history of stress fractures, and/or menstrual dysfunction, and/or low EA for at least 6 months. Notably, DXAs are usually ordered on postmenopausal women, and separate standards exist for performing DXAs on children or adolescents. Therefore, DXA should ideally be done at a facility whose staff is familiar with interpreting results based on the patients age and gender. In adults, BMD is interpreted using the T-score, which compares the patients BMD with the maximum expected BMD achieved aged between 25 and 30 years. Pediatric bone density, however, is assessed using the Z-score, which compares the patients BMD with those of others of similar age and race. Further details are available in the guidelines provided by DeSouza et al.1 It may be helpful to discuss these with the performing radiologist.
Athletes who participate in high-impact and resistance activities would be expected to have a BMD that is 10% to 15% higher than those of athletes participating in nonimpact sports. This should be taken into consideration when interpreting DXA scans. Z-scores of less than 1.0 may be abnormal in an athlete, alerting concern for low BMD, but that score may be normal in a nonathlete. An athlete who has a Z-score of less than 1 should undergo further evaluation.
MENSTRUAL FUNCTION
It is not normal for female athletes to have menstrual dysfunction; they should not lose their period during their sport season (a phenomenon most classically seen in cross-country runners). Functional hypothalamic amenorrhea (ie, amenorrhea with the female athlete triad) is a diagnosis of exclusion, so if an athlete is experiencing amenorrhea or oligomenorrhea, it is crucial to rule out other causes (Table 2).5,6 Primary amenorrhea is absence of menarche by age 15 years. Secondary amenorrhea is defined as absence of menses for 3 months or longer, while oligomenorrhea is defined as cycles lasting longer than 35 days.2 Maintaining normal menstrual function is important for the athletes bone health.1 As such, exogenous hormones (ie, birth control pills) may be perceived as beneficial. However, many studies have shown that oral contraception is not an effective way to restore bone health. An athlete with menstrual dysfunction may use oral birth control pills to prevent pregnancy, but it is important to let her know that having a period on birth control does not mean her bone health is improving.
Menstrual dysfunction can also negatively affect cardiovascular health in athletes. The results of some studies in ballet dancers and endurance athletes have shown that athletes with oligomenorrhea and amenorrhea had increased risk for high cholesterol and other vascular findings that correlate with the development of atherosclerotic disease.5,6
It may take up to 1 year or longer to resume menses after EA restoration. Decreased bone density, the result of female athlete triad, may be irreversible, although it can improve with increasing EA. Early intervention is key, so it is crucial to screen for those at risk.
Relative energy deficiency in sport (RED-S)
The term RED-S was introduced in 2014 by the International Olympic Committee to encompass males and to acknowledge that energy deficiency can affect other aspects of an athletes health. These may include issues involving the endocrine, metabolic, hematologic, cardiovascular, gastrointestinal, and immunologic systems as well as growth and development. Research done by Ackerman et al demonstrated that athletes with low EA were more likely to have many of the ill effects of RED-S than those with appropriate EA.4
The male athlete triad
The male athlete triad is a term used in males to describe the interrelationship of low EA, impaired bone health, and reproductive suppression. Low EA has been associated with decreased testosterone in male athletes due to a suppressed hypothalamicpituitarygonadal axis. True prevalence of low testosterone from hypogonadotropic hypogonadism is unknown.7 Low testosterone can have numerous effects on the male athlete, including decreased physical performance, sleep disturbances, fatigue, decreased motivation, sexual dysfunction, loss of muscle mass, sperm abnormalities, lower BMD, and depression.
Male athletes with recurrent bone stress injuries or with initial injury in a trabecular region (pelvis, sacrum, femoral neck) should be evaluated for nutrition and hormone function, especially if the athlete has other risk factors such as low BMI. Tenforde et al recommend screening for low BMD with DXA, nutritional evaluation (including a 25-hydroxy vitamin D test), and endocrine work-up (including free and total testosterone) in athletes with high-risk stress fracture in areas such as the pelvis or femoral neck, although more evidence-based guidelines are needed.7
Treatment
Restoring EA is the mainstay of treatment of both male and female athlete triad. This can be accomplished if the athlete increases caloric intake and decreases physical activity/energy expenditure. Working with a sports dietitian to increase EA to >45 kcal/kg FFM per day is ideal, but increasing calories by 300 to 600 per day and decreasing exercise by 1 day per week can be a productive starting point. This should be done on an individual basis depending on the athletes training regimen and expenditure. The goal is to increase BMI to >18.5 kg/m2 and to restore normal menstrual function. Working with a multidisciplinary team that includes a PCP, dietitian, psychologist, athletic trainer, and sports medicine specialist is helpful.
In the past, oral contraceptive pills were commonly used to restore menses; however, as mentioned above, this may offer a false sense of security and should be avoided unless they are necessary for other indications. Bisphosphonates are also generally not recommended in the pediatric/adolescent population. No evidence exists for their effectiveness and they may be teratogenic if an athlete were to become pregnant.2
Calcium and vitamin D are important for bone health. The recommended daily amount of calcium is 1300 mg; if this is not achieved with diet alone, it should be supplemented. The recommendation for vitamin D for patients aged between 1 and 18 years is 600 IU, although higher doses may be considered depending on climate and deficiency. A recent systematic review of military submariners determined that the combination of vitamin D and calcium has a synergistic effect, and that vitamin D levels were most effectively increased with supplementation levels of 2000 IU/day.8 Weight-bearing exercise is also important for enhancing the accrual of bone mass.2
Because the consequences of the athlete triad can be irreversible, affecting long-term bone, reproductive, and possibly cardiovascular health, a PCP must have a high index of suspicion for the triad in an athlete presenting with any of the above components. The annual well-child exam or sports physical is an opportunity for the PCP to screen patients for the athlete triad.
ACKNOWLEDGMENTS: We would like to thank Amanda Weiss Kelly, MD, for her mentorship and expertise on this topic.
References
1. De Souza MJ, Nattiv A, Joy E, et al. 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(4):289. doi:10.1136/bjsports-2013-093218
2. Weiss Kelly AK, Hecht S; Council On Sports Medicine and Fitness. The female athlete triad. Pediatrics. 2016;138(2):e20160922. doi:10.1542/peds.2016-0922
3. Bratland-Sanda S, Sundgot-Borgen J. Eating disorders in athletes: overview of prevalence, risk factors and recommendations for prevention and treatment. Eur J Sport Sci. 2013;13(5):499-508. doi:10.1080/17461391.2012.740504
4. Ackerman KE, Holtzman B, Cooper KM, et al. Low energy availability surrogates correlate with health and performance consequences of Relative Energy Deficiency in Sport. Br J Sports Med. 2019;53(10):628-633. doi:101136/bjsports-2017-098958
5. Hoch AZ, Papanek P, Szabo A, Widlansky ME, Schimke JE, Gutterman DD. Association between the female athlete triad and endothelial dysfunction in dancers. Clin J Sport Med. 2011;21(2):119-125. doi:10.1097/JSM.0b013e3182042a9a
6. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Lindn Hirschberg A. Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid profile. J Clin Endocrinol Metab. 2005;90(3):1354-1359. doi:10.1210/jc.2004-1286
7. Tenforde AS, Barrack MT, Nattiv A, Fredericson M. Parallels with the female athlete triad in male athletes. Sports Med. 2016;46(2):171-182. doi:10.1007/s40279-015-0411-y
8. Sivakumar G, Koziarz A, Farrokhyar F. Vitamin D supplementation in military personnel: a systematic review of randomized controlled trials. Sports Health. 2019;11(5):425-431. doi:10.1177/1941738119857717
More:
Recognizing the importance of energy availability in the young athlete - Contemporary Pediatrics
Recommendation and review posted by Bethany Smith
EP. 3: Defining PSA Nadir After Definitive Therapy in Prostate Cancer – Urology Times
Raoul S. Concepcion, MD, FACS: Brian, how do you define PSA [prostate-specific antigen] nadirs, because I think this is an important point, in the surgical patient and in the radiotherapy patient?
Brian Helfand, MD, PhD: Ultimately after surgery, when we take out the entire prostate, were really expecting that PSA to go to a value of undetectable, 0 [ng/mL]. There are certain definitions, because we use ultrasensitive assays, etc. For the most part, we want to see that at what an equivalent value is of 0 [ng/mL]. At our institution, that is less than 0.02, or less than 0.001 [ng/mL], which I have seen depending on the assay. If after surgery that level rises to a value of 0.2 [ng/mL], I think everyone would agree this is a common definition that would be considered a recurrence. There has been some evolution, especially for men with higher-risk disease, that if youre using an ultrasensitive assay and you are seeing consecutive rises of that PSA before theyre actually getting to a value of 0.2 [ng/mL], most people would agree that thats a recurrence as well. There is some devil in the details there, but certainly, I think if youre going to walk away with this, the value of 0.2 [ng/mL] after a surgery would be considered a recurrence.
For radiation, it becomes a little trickier because we still have the prostate gland thats in situ, and there is some benign tissue there, so there is for many patients, a level of PSA that exists. Your PSA will get down to some lowest value, or that nadir value. There have been various definitions that have been used throughout the years. I typically use whats referred to as the Phoenix definition, which is a value of 2 ng/mL greater than their lowest value. Again, if you see consecutive rises at least a month apart, consistently rising more than would be expected, I also have some suspicion there that earlier intervention or recurrence may be warranted.
Raoul S. Concepcion, MD, FACS: Judd, we know that in the surgical patient, that nadir happens quickly, usually within 6 months, if its going to get to the level that Brian was discussing. What about with the radiation? When do you start to say, OK, Im at 6 months, Im at 12 months, or Im at 18 months? When do you feel comfortable? Ithink as Brian pointed out, its not going to go to less than .001 or less than .02 [ng/mL]. What does that time frame look like in the radiation patient?
Judd W. Moul, MD: Thats a great question. In the classic teaching, in the era before androgen deprivation therapy [ADT] was used with radiation, the radiation therapy itself would sometimes take up to 18 months to clear the prostate cancer. Therefore, weve been always taught that you need to sometimes wait up to 18 months if its a patient whos just receiving radiation, and you wouldnt necessarily want to do a biopsy. You also have a PSA bounce phenomenon that sometimes can occur. Now, all the high-risk patients and many of the intermediate-risk patients are also receiving ADT with the radiotherapy. With the ADT, their PSA should go down generally more quickly, especially if youre using an antagonist like Degarelix, or now the new oral option, relugolix. In general, the PSA typically nadirs, I see it nadir usually within 3 to 6 months in men who are getting hormone therapy with radiation.
The only additional point that I would make is that sometimes in guys who had low-risk or intermediate-risk disease and had a modern-era radical prostatectomy [RP] with aggressive nerve sparing, bladder neck sparing, and urethra sparing, we see low levels of PSA that are not cancer-related. Therefore, I agree with Brian that in the high-risk patients, you can jump on a PSA recurrence quickly, but I would caution the oncologists in our audience tonight that you must look at the RP pathology. Moreover, if it was not so bad pathology, and if the guy has a PSA of 0.13, or even 0.2 [ng/mL] a couple of years out, I tend to follow those patients because there is this phenomenon of benign glands at the margin. We know from the Mayo Clinics series and our work at Duke [Cancer Center], that honestly, sometimes up to 30% of patients can have this in long-term follow-up, a little bit of PSA in the system thats not cancer-related.
Transcript edited for clarity.
Continued here:
EP. 3: Defining PSA Nadir After Definitive Therapy in Prostate Cancer - Urology Times
Recommendation and review posted by Bethany Smith
[Full text] A Review of Modifiable Risk Factors in Young Women for the Prevention | BCTT – Dove Medical Press
Introduction
Globally, breast cancer (BC) is currently the most common cancer diagnosed in women below the age of 40, accounting for 244,000 cases per year.1 It is also the second highest cause of cancer-related mortality in women aged 039 worldwide with 44,800 deaths per year.1 Women under the age of 45 account for 11% of all BC diagnoses in the United States (US)2 and 9% in the United Kingdom (UK).3 Furthermore, there has been a 16% increase in the incidence of BC in women aged 2549 years since the 1990s.3
Geographically, the cumulative risk of developing BC varies between countries: the highest cumulative risk for women aged less than 40 years is seen in Italy and France (0.9%), and lowest in India (0.26%) with the UK and US having a moderate level of risk (0.77% and 0.61%, respectively).1
Most young women are not eligible for asymptomatic breast screening and therefore present to clinicians with either personal breast symptoms or family-related concerns. Although young women with breast cancer have a higher frequency of underlying pathogenic mutations in high penetrance breast cancer susceptibility genes (CSGs) than older women, the vast majority of young breast cancer patients are not found to have a germline CSG mutation.4 Therefore, modifiable risk factors for breast cancer should also receive attention in this age group.
Clinicianpatient interactions during a breast clinic consultation may provide unique opportunities to educate patients about modifiable cancer risk factors,: so-called teachable moments5 These opportunities occur regardless of whether or not the patient receives a cancer diagnosis6 and consultations pertaining to potential cancer diagnoses are regarded as underused moments for the provision of encouraging cancer risk-reducing behaviours.7 When employing these moments to encourage behaviours that can reduce BC risk, the advice given should be based on a comprehensive understanding of the current evidence on modifiable lifestyle risk factors and how younger patients can most effectively influence their risk of disease.
This review presents current understanding of factors in young women associated with the development of primary BC, the direction of risk and the magnitude of effect. Whilst previous publications in this area have focussed on life-style associated risk factors, this article also includes a discussion of the categorisation of risk factors and the inclusion of reproductive and iatrogenic factors as well as those factors that can be most influenced by an individuals behaviour. The interaction between modifiable and genetic factors is also considered.
An electronic literature review using PubMed (NLM) was performed. Search terms included young or early onset, and breast cancer and modifiable risk. All identified articles published in English language between 1960 and 2020 were assessed for suitability. Abstracts and reports from meetings not published in peer-reviewed journals were excluded. Additional references known to the authors or cited within reference lists of relevant papers were also investigated. Articles were excluded from this review if they contained solely post-menopausal data or if they contained data for risk factors that were non-modifiable such as age, sex and past history of breast cancer or proliferative breast disease, apart from genetic risk factors which were included. The last search was performed in October 2020.
The European consensus treatment guidelines for BC in young women define young as aged 40 years or below8 partially based on the observation that women in this age group have poorer BC outcomes than older age groups.9 However, most epidemiological studies of BC risk, including the World Cancer Research Fund (WCRF) continuous update project, stratify patients according to menopausal status (pre- or post-menopausal).10 Although in some datasets this categorisation is based on biological indicators of ovarian function, age ranges of 050 or 055 years are frequently used as surrogate indicators of premenopausal status. It is therefore evident that premenopausal groups will contain data for young women (40 years), but will additionally include variable numbers of older women dependant on the data source. The biological differences in BC between age groups exist on a continuum so that a specific age threshold, such as below 40 years, alludes to trends in BC biology as opposed to definitive unique differences.1113
Many factors have been implicated as factors that influence BC risk in a younger female population,14 with variable effect sizes as well as variable degrees of modifiability.
Some factors associated with BC development are clearly inherent risk factors whereby an individuals choices cannot influence the risk factor, such as the germline genome or pre-natal development. Other risk factors are potentially modifiable such as: physical activity, body weight/habitus, alcohol consumption, which are influenced by personal choice.15
Some factors discussed in this review are more nuanced. For example, increased parity appears to decrease risk of developing BC but problems such as infertility may confound ones degree of personal choice over this factor. Iatrogenic risk factors are similarly more limited in terms of self-adjustment. These factors are referred to here as less modifiable.
Women below the age of 40 with BC are more likely to die from the disease than older women.9,16,17 This can be explained in part by the biological characteristics of tumours in this cohort.
BCs in young women have a higher frequency of more aggressive phenotypes than older women. Young patients are more likely to present with more advanced disease stage with larger tumour size, lymph node involvement, and less differentiated tumours.1821 Tumour biology also reflects more aggressive disease in younger women with increased frequency of oestrogen receptor (ER) negative and triple negative tumours,11 and increased Ki-67 expression than in those over the age of 50 years.20,21
Women under 40 years at first breast cancer diagnosis have a higher frequency of a family history of BC and a higher chance of an underlying pathogenic mutation in a BC susceptibility gene than women diagnosed with breast cancer aged over 40 years.22 BRCA gene mutations (either BRCA1 or BRCA2) are found in approximately 12% of BC patients aged <40 years.4 TP53 germline mutations are found in 5% of diagnoses of BC aged 35 years23 and PALB2 mutations in approximately 1% in early-onset BC.24 Mutation penetrance seems to be higher in younger than older women for some breast cancer susceptibility genes (CSGs); the relative risk of developing BC was 89 in PALB2 mutation carriers below 40 years compared to 58 in women over 40 years.25
American studies have reported some notable racial variations in breast cancer age of onset, with black women experiencing significantly higher breast cancer incidence before the age of 40 years and lower incidence after age 50 compared with white women of the same ages.26 Differences in breast cancer incidence rates between most racial/ethnic groups have been largely explained by risk factor distribution except in African Americans27 where the higher incidence in the younger age group is not yet fully explained. Population-based studies in the UK have concluded that the younger age of Black Caribbean and Black African breast cancer patients in South East England reflects the younger age of these populations, rather than an increased risk of disease at younger ages28. Several non-age selected studies have reported increased incidence of adverse biological features in black women compared to white women. The POSH prospective study of 2915 breast cancer patients aged <41 years has confirmed this finding in young onset breast cancer with higher median tumour diameter and higher frequency of ER/PR/HER2-negative tumours in Blacks (26.1%) than Whites (18.6%, P=0.04).29
In the past, there had been a general acceptance that physical activity has no effect on premenopausal BC risk following large-scale prospective cohort studies such as Rockhill et al (104 468 participants) which reported no association.30 However, more recent data seem to contradict these findings. Since 2013, three independent meta-analyses3133 investigating the effect of physical activity on premenopausal BC have concurred that physical activity significantly reduces the risk of premenopausal BC development. Physical activity led to a 23% reduction in BC cases (RR 0.77; 95% CI 0.720.84) when comparing women in the highest versus the lowest categories of amounts and types of physical activity in a meta-analysis of 6 studies (2258 cases).31 Hardefeldt et als 2018 meta-analysis of 48 cohort studies found that physical activitys ignificantly reduced overall risk (OR 0.79, 95% CI 0.730.87)32 and finally Chen et al in 2019 reported an overall relative risk of 0.83 (95% CI 0.790.87) over 14,968 cases, of developing premenopausal BC associated with physical activity.33 Therefore, it seems there is a recent body of evidence suggesting that physical activity may be key in reducing premenopausal BC risk.
Although evidence in premenopausal women is limited, it indicates a significant downward trend between increasing intensity (in metabolic equivalent task hours per week) and/or longer duration (hours per week) of physical activity in relation to BC risk.34 For studies considering combined pre- and post-menopausal BC risk, for which there are significantly more data, the intensity of the exercise played a modest role in reducing risk. Engaging in higher-intensity activities (activity that causes you to sweat, ie, running and competitive sports) had a slightly greater risk reduction (OR 0.73; 95% CI 0.650.81; P<0.001) than in those who did low-intensity activities (such as walking and gardening) (OR, 0.79; 95% CI, 0.720.86; P<0.001).32 A meta-analysis of 11 studies reporting amount of exercise and 11 studies reporting metabolic equivalent task hours per week (MET-h/week) demonstrated a significant dose-response relationship (p<0.0001) between increasing intensity and/or duration of exercise per week and reductions in BC risk.35 This method for reducing risk is especially important for a younger population, who tend to have an increased capacity for exercise; considering engaging in higher intensity exercises may be an effective way of significantly reducing their BC risk.
Chen et als pooled analysis reported that overall relative risk reductions are associated with all types of physical activity (recreational, occupational and non-occupational) and the differences in risk between types of activity were modest. It remains unclear whether recreational physical activity specifically reduces risk in young women any more than occupational.36,37
It seems that physiological differences between pre- and post-menopause alter the effect of body mass index (BMI) on risk of developing BC.38 Younger adult women have a modest inverse correlation for BC risk with increasing BMI, according to many studies and meta-analyses (Table 1).3946 This is contrary to the positive correlation between BMI and BC risk in post-menopausal women.
Table 1 Summary and Details of Meta-Analyses Investigating the Relationship Between BMI and Relative Risk (RR) of Developing Premenopausal BC
This relationship is comprehensively summarised in Renehan et als meta-analysis of 20 prospective cohort studies, which reported that for every 5kg/m2 increase in BMI there was a significant decrease in relative risk of developing premenopausal BC (RR 0.92; 95% CI 0.880.97), highlighting a dose-response effect of BMI on premenopausal BC.39 The mechanism underpinning this effect is unclear and evidence limited, although it has been suggested that obesity causes ovarian suppression leading to decreasing levels of circulating oestradiol.47
BMI however is simply a marker of overall adiposity at a population level and does not inform us about the distribution of weight in the body in an individual. Waist-to-hip ratio (WHR) describes a pattern of adiposity (comparison of abdominal to gluteal fat), and increases in WHR are associated with increased risk of premenopausal BC. This was explored in a meta-analysis by Amadou et al42 that used 9 case-control and 3 cohort studies to demonstrate a significant dose-response premenopausal BC relative risk increase of 1.08 (95% CI 1.011.16) per 0.1 unit increase in WHR, despite acknowledging that BMI was still associated with a significant dose-response decreased relative risk of premenopausal BC per 5kg/m2 increase (RR 0.95;95% CI 0.940.97).42 This suggests that although increases in BMI (as a marker of general adiposity) decrease risk, central adiposity (deposited around the abdomen) is associated with increased risk of premenopausal BC.
Furthermore, although a higher BMI is protective in premenopausal women, the magnitude of risk reduction in premenopausal BC is less than the increased BC risk witnessed post-menopause.39 Many studies agree that weight change during adulthood increases the risk of BC at an older age (post-menopausal).4851 Although true that a higher BMI can reduce BC risk in premenopausal women, the cumulative risk of developing BC across a persons lifetime will be increased in those with a high BMI.38 Obesity is also associated with increased risk of other malignancies and other serious health issues. Therefore, gaining weight should not be recommended as a suitable method to reduce BC risk long term. Interestingly, in the Carolina Breast Study, higher adult body mass index was inversely associated with premenopausal breast cancer for Whites but not for Blacks;52 Higher waist/hip ratio, adjusted for body mass index, increased risk for both black and white premenopausal women.53
Swanson et al investigated the effect of alcohol consumption in young women (<45 years) in 1997, and found that those who drank more than 14 alcoholic drinks per week had the highest risk of developing BC (RR 1.73, 95% CI 1.22.6) compared with non-drinkers.54
Since then, many studies have investigated the effect of alcohol consumption on BC and most have found that alcohol increases risk of BC in young or premenopausal women.5557
In their evaluation of evidence in 2018, the WCRF concluded that there was strong probable evidence that alcohol consumption increases the risk of premenopausal BC. A pooled multivariate analysis of 3730 cases of premenopausal women found that a 10g per day increment of alcohol consumption was associated with a BC RR of 1.03 (95% CI: 0.991.08), thus supporting the idea that a dose-response effect exists between alcohol and risk of premenopausal BC.58 This supports the WCRF meta-analysis which found statistically significant evidence of dose-response relationship between alcohol and premenopausal BC risk, whereby an increase of 10g of ethanol per day led to a 5% increased risk of developing BC in premenopausal women.10
Type of alcohol beverage also appears to be significant when considering premenopausal BC risk. The WCRFs 2018 report concluded that consuming 10g of ethanol per day as beer had a RR of 1.32 (95% CI: 1.061.64) whereas from wine this was less (RR 1.17, 95% CI: 0.791.73) and from spirits the lowest (RR 1.10, 95% CI: 0.921.30).10
The impact of active smoking on BC risk in young women has been unclear since it was first discussed by MacMahon in 1982.5961 The Collaborative Group on Hormonal Factors in BCs meta-analysis showed that the effect of smoking on BC risk is confounded by its known association with alcohol.61,62 However, most research concurs that if there is a risk associated with smoking, that it is more influential in premenopausal (than post-menopausal) BC risk.6365 Women who commence smoking at a young age seem to have a higher lifetime BC risk than those who take up smoking in later life. A cohort study of 1815 women with invasive BC found that the hazard ratio for all ever smokers (compared to never smokers) was 1.14 (95% CI 1.031.25; p=0.010) rising to 1.24 (95% CI 1.081.43; p=0.002) for starting smoking at ages <17 years.66
Interestingly, passive smoking may be a greater risk factor for BC than active smoking. It has been postulated that active smoking is associated with an anti-oestrogenic effect which may to some extent counteract exposure to smoking-related carcinogens. Passive smoking does not benefit from the anti-oestrogenic effect but results in continued exposure to carcinogenic compounds (ie, N-nitrosamines, benzenes, carbon monoxide and carbon dioxide) which persist in side stream smoke and therefore, a relatively increased risk of breast oncogenesis.64,67,68 A meta-analysis including 14 studies of smoking and premenopausal BC risk found that passive smoking was associated with an increased risk (pooled RR 1.68, 95% CI 1.882.12) increasing to a pooled summary risk estimate of 2.19 (95% CI 1.682.84) when the analysis was limited to the 5 studies with more complete exposure data.63
Individual studies place emphasis on genetic susceptibility and how this, compounded with exposure to secondary smoke, greatly increases BC risk64,69 For example, one study found that passive smoke exposure increased premenopausal BC risk in PARP1 or ESR1 genetically susceptible individuals (OR 1.54 95% CI 1.142.07).69
Long-term rotating night shift work in young adulthood is particularly associated with increased risk of ever developing BC according to an analysis of two large-scale prospective cohort studies (n=9541 total invasive BCs) in the United States: The Nurses Health study (NHS) and Nurses Health study II (NHS-II).70 This analysis found that in the NHS, women who had done 30 years or more of shift work did not have a higher risk of breast cancer (HR 0.95; 95% CI 0.771.17) compared with those who had never done shift work. However, participants of the NHS-II, who were a younger cohort (by approximately 20 years) than those in NHS had a significantly higher risk of breast cancer with 20 years or more of shift work (HR=2.15, 95% CI 1.233.73), and a significantly higher risk for women with 20 years or more of cumulative shift work (HR=1.40; 95% CI 1.001.97) compared to those who had never done shift work.70 This conclusion is supported by a Spanish case-control study (OR 1.08; 95% CI 0.981.79)71 which found that night shift work was a higher risk factor in premenopausal than post-menopausal BC.
Shernhammer et al found that there was a non-significant increase in premenopausal BC relative risk with number of years on rotating night shift work, and that the risk of developing premenopausal breast cancer appeared to increase with increasing years on a rotating night shift (Never worked a night shift age adjusted RR: 1.0; 114 years RR 1.23, 95% CI 0.981.56); 15 years RR: 1.30, 95% CI 0.752.26).72
A recent pooled analysis by Coridina-Duverger et al73 using studies from 5 different western countries: Australia, Canada, France, Germany and Spain found that there was a pooled odds ratio of developing premenopausal BC of 1.26 (95% CI 1.061.51) associated with having ever worked a night shift for 3 or more hours between midnight and 5am. This risk increased to 2.55 (95% CI 1.036.30) for those who had been working the most night shifts per week (3 or more per week) and for a longer period of time (>10 years).
Working at night causes disruptions in circadian rhythm, whereby the light-at-night causes a suppression of pineal gland production of the hormone melatonin.74 Pre-clinical trials suggest that melatonin exerts tumour-suppressive effects through a variety of mechanisms, including modulation of the oestrogen pathway, producing an anti-oestrogenic effect. Therefore, it is hypothesised that the absence of melatonin can lead to breast tumour growth.75
Globally in 2020, the highest incidence rates for premenopausal BC occur in high human development index (HDI) regions (such as Western Europe, Australia and New Zealand and North America), however low human development index regions (such as North and West Africa) had higher new cases and mortality with premenopausal BC in proportion to those of higher income.76
There is a lack of data for the impact of SES within a young US population. However, Akinyemiju et al77 looked at SES across different ethnicities in a US population and found that combined early and late BC risk increased with increasing socioeconomic status. This shows concordance with current understanding of this relationship whereby women of higher socioeconomic status are at the highest risk of developing BC but have better survival outcomes from their diagnoses than lower-income areas in the US.78
An analysis of data from the Wisconsin longitudinal study (4275 women) found that having a higher socioeconomic status (SES) in early life/childhood and being born of a mother of a higher educational level increased BC incidence.79 The underlying reasons may be that higher SES individuals tend to be older at the age of their first pregnancy and have decreased parity compared with lower SES.79,80
The evidence suggests that physical activity reduces the risk of premenopausal and early onset breast cancer with a dose-dependent effect and for all types of activity and so should be recommended. In contrast, although there is a slight risk reduction seen for premenopausal breast cancer with increased BMI this is offset both by the larger increased risk for post-menopausal breast cancer and the more general and cardiovascular risks of obesity and so maintaining a healthy weight, BMI and body composition should be recommended. Alcohol is perhaps one of the more easily modifiable risk factors and there is a dose-dependent relationship with breast cancer risk so should be reduced wherever possible. The effects of smoking may be confounded by alcohol intake but should be avoided regardless due to the overall harm to health beyond that of breast cancer alone. Socioeconomic status and shift working patterns are less easily modifiable and are perhaps more easily addressed at a public health and population rather than individual level.
Within high-income countries, there has been a shift in reproductive behaviours, favouring fewer children per household and at a later stage in a womans reproductive timeframe. Simultaneously, there has been an increased uptake in the use of exogenous hormonal medications, in the form of the oral contraceptive pill (OCP), intrauterine hormonal devices and menopausal hormone therapy (MHT), as cultural shifts have occurred within society.81 Epidemiological evidence associates both exogenous and endogenous hormone exposure with an increased risk of BC82 with exogenous hormone use being amenable to risk modification. There are two types of oestrogen (conjugated equine oestrogen and oestradiol) and four types of progestogen (norethisterone acetate, levonorgestrel, medroxyprogesterone, and dydrogesterone) commonly prescribed in the UK.83
In 2018, the OCP was the main method for contraception for 28% of women in the UK and was the most common method used by women aged between 15 and 49 years.84
In 1996, a large collaborative dataset confirmed the association of an increased risk of BC with OCP use. This analysis compared OCP use in 53,297 women with BC and 100,239 women without a BC diagnosis and concluded an overall relative risk (RR) of BC in OCP users of 1.24 (95% CI 1.151.33).85 On stopping the OCP the modest increased risk disappeared after 10 years (RR 1.01 95% CI 0.961.05). In real terms, this equates to one additional BC case with OCP use among 20,000 women aged 2025 years using this form of contraception.82 For women with a higher background risk, such as strong family history or high risk genetic mutation carriers, the data are limited but suggest the same effect in BC risk as for the overall population.82 A more recent Danish paper has shown that the duration of contraceptive pill use to be important, with 13 years use associated with the highest increase of relative risk at 18% compared to a 5% RR increase for five years use.86 Mrch et al calculated an overall BC risk with users of any hormonal contraceptive to be one extra BC case for every 7690 women using hormonal contraception for 1 year. Long-term hormonal contraceptive use has not been found to be associated with increased total cancer risk however.87 As the overall population risk for BC in women in their 20s is low, the absolute risk for BC with OCP use is therefore small (1:20,000). In an older cohort of women (over 35 years old), with increased overall risk including family history, the additional increased RR with age with the OCP use is an important consideration. Long-term follow-up data on women using the OCP have shown a considerable protection against cancer of the ovary (RR= 0.67), endometrium (RR= 0.66), or colorectum (RR= 0.81).88 Physicians need to establish a risk-benefit ratio on an individual basis to enable a joint decision between the physician and patient on the use of hormonal contraception. For example, patients with BRCA1 mutations will be at potentially increased risk of BC with OCP use, versus a protective effect for ovarian cancer risk should they not be planning a risk-reducing oophorectomy.89
An increased risk has also been noted with the progestin-only intrauterine system (levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena)) compared to women who had not used hormonal contraceptives (RR 1.21; 95% CI 1.11 to 1.33).86
The use of a LNG-IUS is often informed by the need to control heavy menstrual bleeding and avoidance of gynaecological procedures. A recent systematic review and meta-analysis on LNG-IUS users concluded an overall increased risk of BC for all users (odds ratio OR = 1.16; 95% CI 1.061.28) with an increased risk in women over 50 years (OR = 1.52 (95% CI 1.341.72)).90 A riskbenefit discussion between gynaecologist and patient, taking into account personal BC risk factors, is recommended prior to commencement of this long-term hormonal treatment.
Premature menopause before the age of 40 (in the absence of treatment for cancer) is rare affecting 1% of women.91 However, the adverse impact of menopausal symptoms on quality of life in women with premature menopause is well documented and exogenous hormonal replacement therapy (HRT; or menopausal hormonal therapy MHT) is frequently recommended for their relief and also sometimes for bone protection purposes. There are predominately two main forms of preparations: unopposed oestrogen therapy and combined oestrogen and progestin preparations.82
A large meta-analysis of worldwide epidemiological evidence for type and timing of MHT and BC risk was published in the Lancet in 2019.92 This study did include women aged 3039 but there were insufficient data to analyse the impact on breast cancer risk associated with use of MHT for <5 years in this age group. Current use of MHT for 515 years starting between ages of 3039 was not overall found to be associated with a statistically significant increased risk (RR 1.07; 95% CI 0.881.31) associated with a RR of 1.07 (95% CI 0.881.31).
The UK National Institute for health and Care Excellence (NICE) guidelines for patients with a familial BC risk recommend tailoring of MHT to individual needs and seeking alternatives to MHT where possible. MHT should generally be prescribed at the lowest dose required to control symptoms and for as short a duration as possible.89 However, when women with no personal history of breast cancer have either a BRCA1 or BRCA2 mutation or a family history of breast cancer and they have had a bilateral salpingo-oophorectomy before their natural menopause, they can be offered either combined HRT if their uterus remains or oestrogen-only HRT if their uterus has been removed, up until the time they would have expected natural menopause (average age for natural menopause is 5152 years).89
Women who decide to have children later in life may undergo fertility techniques for oocyte harvesting, oocyte cryopreservation and embryo transfer techniques and fertilisation (In vitro fertilisation (IVF)). Follicle-stimulating hormone (FSH) injections are often used daily for 2 weeks to stimulate follicle development and assist harvesting. No association has been reported between use of fertility preservation techniques and BC development,82 including for BRCA 1/2 mutation carriers. IVF exposure was not associated with risk of BC (HR: 0.79, 95% CI: 0.461.36).93 A recent systematic review has highlighted however there is limited evidence on the association between IVF and premenopausal breast cancer risk.94
The age at which a woman gives birth to a child has been shown to influence her BC risk.81 Arguably, timing of pregnancy and child-bearing is not always planned, however a woman with an increased BC risk may wish to actively start a family earlier to reduce her BC risk. The age at first pregnancy is especially important, with parity under 20 years of age associated with the longest term risk reduction of 50% compared to nulliparous women.95 Having a child over 35 years of age conferred an increased BC risk compared to a nulliparous woman.96 Recent data suggest that the age of first pregnancy and parity affects the risk of specific BC subtype development, with young age of first pregnancy and parity being associated with a reduction in luminal oestrogen receptor positive BCs but not other subtypes.97
Post-partum there is a transient observed increase in BC risk which is attributed to the post-partum involution process within the breast.81 It is hypothesised that the breast remodelling following lactational changes takes up to ten years on average and the increased risk may be due to immune microenvironment changes.81 The reduction in BC risk following this period may be due to a reduction in ER sensitive epithelial cells within the breast.98 Compared to nulliparous women, parous women have an increased BC risk peaking 5 years after birth before decreasing up to 34 years later (HR, 1.80 [95% CI, 1.63 to 1.99]) and 0.77 (CI, 0.67 to 0.88, respectively).99
Data from the 19932001 Carolina Breast Cancer Study which included 1505 African-American and 1809 White women identified some important racial differences in breast cancer risk factors amongst younger women (aged 2049). Multiparity was associated with increased risk of breast cancer among younger African-American women (for three or four pregnancies: adjusted odds ratio (OR) = 1.5, 95% confidence interval (CI): 0.9, 2.6; for five or more pregnancies: OR = 1.4, 95% CI: 0.6, 3.1) but not among younger White women (for three or four pregnancies: OR = 0.7, 95% CI: 0.4, 1.2; for five or more pregnancies: OR = 0.8, 95% CI: 0.2, 3.0). The relationship with age at first full-term pregnancy and nulliparity also varied by race.100 Thus, the higher incidence of breast cancer among younger African-American women may result from both higher prevalence of risk factors and higher relative risks associated with these.
Breastfeeding has been shown to reduce a womans risk of BC.101 The mechanism of risk reduction is not clear; however, for every 12 months of breast feeding, the RR reduction is 4% for all women with an increased RR reduction of 5.1% for premenopausal BC.81,102
Interestingly, the protective effect of breast feeding is not limited to only hormone receptor positive breast cancer subtypes.103 A reduction in risk has also been demonstrated in hormone receptor negative breast cancers which are more common in younger women.104
The World Health Organisation recommends at least six months of breast feeding post-partum prior to weaning for a protective effect.105 Young mothers should be supported to breastfeed to reduce their BC risk in addition to promoted benefits to the developing baby.
Anti-oestrogen medications may be offered in specialist clinics to women with high and moderate personal risk for BC.106 These medications are referred to as chemoprevention however risk-reducing medication is a more favourable term to encourage uptake.81
In premenopausal women, use of tamoxifen for 5 years reduced BC risk by 33% and the reduction persisted for at least 15 years after cessation of the anti-hormonal medication.107,108 Of note, there was no benefit shown for overall BC mortality with this treatment. They may be a useful option for women with high to moderate risk of BC who wish to reduce their risk as an alternative or bridge to risk-reducing surgery.106 Caveats to the use of tamoxifen are an increased risk of venous thromboembolism and endometrial cancer (risk 4:1000). A short trial of tamoxifen for six to eight weeks may feel more acceptable to a patient prior to a five-year course to test for medication induced side effects.81 Although raloxifene and aromatase inhibitors have been shown to reduce breast cancer occurrence in high risk post-menopausal women, these drugs are not recommended in premenopausal women.89 Non-hormonal forms of chemoprophylaxis for breast cancer remain under investigation. Several meta-analyses of observational studies have reported reduced risk of breast cancer in aspirin users compared to non-users.109,110 However, in their sub-group analysis, Cao et al found a significant risk reduction of breast cancer associated with aspirin use in postmenopausal women (RR=0.89, 95% CI: 0.830.96, P=.002), but not in premenopausal women (RR=0.88, 95% CI: 0.721.08, P=.223).110
In younger women less than the age of 35 the absolute increased breast cancer risk with the combined oral contraceptive is very small and so this can be prescribed with appropriate information. Between the age of 35 and 50 women with a breast cancer family history should be aware that the increased breast cancer risk increases with age as their absolute familial breast cancer risk increases and this should be weighed within the overall risks and benefits of the combined oral contraceptive. For those with BRCA1 or BRCA2 gene alterations considering the combined oral contraceptive the situation is more complex and specialist genetic service input may be beneficial to judge the competing impacts of increased breast cancer risk against reduced ovarian cancer risk within the specific circumstances of the individual.111 For those with an early menopause no increased risk is seen with HRT up to the natural age of menopause for a general population, but in those with increased familial risk more specialist input may again be helpful.
Worldwide it is estimated that over 1.8 million breast augmentation procedures are performed annually, of which 2.8% are in those aged 18 years or younger, 53.9% in those aged 1934 and 35.0% in those aged 3550. The UK independent review group on Silicone Gel Breast Implants concluded that BC incidence is not raised in women with breast implants,112 however, in those with cosmetic breast augmentation breast cancer diagnosis appears to occur at a later stage and possibly impacts negatively on survival.113 More recently an association has been identified between silicone breast implants and a form of non-Hodgkin lymphoma known as Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). This typically occurs 710 years following implantation,114 and so given the demographics of cosmetic breast augmentation surgery will be relevant to younger women considering such surgery. The MHRA estimates that the incidence of the BIA-ALCL is 1 per 20,000 implants sold,115 and since cosmetic augmentation is usually a bilateral procedure, the rate may be 1 per 10,000 in women undergoing cosmetic implant breast augmentation.
It has been recognised since the 1980s that treatment for Hodgkins Lymphoma (HL) is associated with a subsequent increased risk of BC amongst other secondary malignancies, with an increasing risk over time for over three decades after HL diagnosis. A recent study of 200945 survivors of teenage and young adult cancer survivors reporting cumulative risk of BC of 0.3%, 1.3%, 3.8%, 6.7%, 10.8% and 14.4% at 10, 15, 20, 25, 30 and 35 years after HL diagnosis.116 Risk of BC in HL survivors is closely associated with use of mantle irradiation with both total dose and field size/site of irradiation influencing risk levels.117 A significantly lower risk of BC has been reported among patients who received supradiaphragmatic field radiotherapy not including the axilla than among those who received complete mantle-field radiotherapy (HR, 0.37; 95% CI 0.19 to 0.72).118 Recognition of these risk factors led to adoption of potentially less toxic treatment regimes in the late 1980s incorporating smaller and less intense radiation fields. However, recent cohort studies comparing second malignancy rates in patients treated for HL during different time periods have not indicated the anticipated fall in treatment-related BC rates with newer treatment regimens.118,119 It is postulated that this is due to the simultaneous adoption of less toxic chemotherapy regimens with a lower incidence of premature menopause with associated reduction in oestrogen exposure.
Age at time of HL diagnosis is an important modifier of risk. Studies of childhood cancer survivors however indicate that radiation treatment at age 10 16 years carries more risk than treatment at age <10 (RR 1.9).117 In the teenage and young adult (TYA) population RR is significantly higher for those treated for HL at age <19 than those treated at 2029 years with no increased BC risk for HL patients diagnosed at 30 years.120
For women who received radiotherapy for HL between the ages of 1029, current UK guidelines recommend that breast screening in the form of an annual magnetic resonance imaging (MRI) scan should start 8 years after radiotherapy to breast tissue or at age 25 or 30 (whichever occurs later). Women treated between the ages of 3039 should commence annual breast MRIs at age 30.121
Female HL patients with a family history of BC are significantly more likely to develop BC, compared to HL patients with no history of BC among relatives.119,122 However, there is currently no evidence that there is a role for mutations in the known high penetrance BC susceptibility genes TP53, BRCA1, BRCA2, and ATM as a cause of subsequent cancer risk in HL survivors.123
Some studies report that there are important interactions between an individuals genetics (their background risk) with lifestyle risk factors that can alter the effect size or direction of risk. Niehoff et al demonstrated that recreational physical activity does not reduce risk in premenopausal women with a family history of BC,124 contrary to the effect seen in young women without familial history.
Tryggvadottir et al125 investigated the changes in risk of developing any BC associated with BRCA2 mutations in an Icelandic population, reporting that there was a four-fold increase of incidence of BC in BRCA2 mutation carriers in 2000 (compared to 1920), ultimately concluding that BRCA2 mutation penetrance has increased with time. This work concluded that this increase in penetrance was proportional to increases in the Icelandic population of modifiable BC risk factors which have increased over time. Additionally, a case-control study by Jernstrm et al showed that young women (below age 40 years) who carried BRCA1 and BRCA2 mutations would be at higher risk of developing BC with increasing number of pregnancies. Therefore, the direction of a partially modifiable risk factor such as parity is dependent on whether they have wild type or mutant BRCA1 and 2 genes.126 Tobacco smoking in BRCA1 and 2 mutation carriers increases risk of developing BC by 17% compared to mutant non-smokers, and women with the highest pack years (4.39.8) having a 33% increase of BC (HR=1.33 9% CI 1.021.75).127 More research is needed the investigate the interactions between genetic effects and other factors.
Counselling and health education for premenopausal women with a family history of BC is complex. Communicating DNA-based disease risk estimates for conditions where risk could be reduced by behaviour change produced no significant effects on smoking, diet, physical activity or alcohol use behaviours.128 An interview study of premenopausal women with a family history of BC who were overweight/obese found that they had feelings of guilt and anxiety when unable to lose weight. Therefore, credible rationales for weight loss that address these feelings of anxiety and doubt are required to reduce this significant risk factor in this high risk population, as well as appropriate support.129 In a feasibility study of 79 overweight premenopausal women at increased risk of breast cancer, 55% of those enrolled in a 12-month diet and exercise weight loss programme (n = 40) achieved target weight loss of 5% baseline weight, compared to 15% of those receiving usual care in the form of a healthy lifestyle advice leaflet.130
BC is the most common cancer diagnosis in women aged under 40 and associated with poorer survival outcomes than in older women. As incidence of young onset BC increases globally there is an urgent need to address risk factors that are modifiable by individual behaviour change.
Overall risk is however determined by both modifiable and non-modifiable risk factors and the most significant non-modifiable risk factor is often familial risk. Health care professionals should therefore assess BC inherent and familial risk through a careful medical and family history and aim to discuss modifiable factors in relation to this background risk. Modifiable risk factors (Table 2) including physical activity and alcohol habits should be considered whenever presented with a teachable moment applicable to breast health. Discussions regarding personal risks and benefits should also accompany conversations regarding reproductive health and hormonal preparations, and take into consideration other modifiable risks and the background individual non-modifiable and iatrogenic BC risk factors. Increasing understanding of the interactions between genomic and modifiable factors will be vital in providing individualised advice to young women who wish to minimise their personal BC risk.
Table 2 Summary of the Key Evidence Regarding Specific Risk Factors in Relation to the Risk of Developing Breast Cancer at a Premenopausal Age/Stage
Prof. Ramsey I Cutress reports non-financial support from SECA, outside the submitted work. Dr Ellen R Copson reports grants, personal fees from World Cancer Research Fund, non-financial support from SECA, personal fees from AstraZeneca, personal fees from Roche, personal fees from Lilly, personal fees from Pfizer, personal feesfrom Nanostring, personal fees from Novartis, outside the submitted work. Prof. Cutress and Dr Copson report research funding from World Cancer Research Fund (WCRF UK) as part of the WCRF International grant programme . The authors report no other conflicts of interest in this work.
1. Global Cancer Observatory (GLOBOCAN). Global cancer observatory. Cancer Today- International Agency for Research on Cancer: World Health Organisation; 2018. Available from: https://gco.iarc.fr/today/home. Accessed November 3, 2020.
2. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. U.S. Cancer Statistics Working Group. U.S. cancer statistics data visualizations tool; June, 2020. Available from: https://gis.cdc.gov/Cancer/USCS/DataViz.html. Accessed November 3, 2020.
3. Cancer Research UK. Breast cancer statistics UK: cancer research UK; 2016. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive#heading-One. Accessed November 3, 2020.
4. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169180. doi:10.1016/S1470-2045(17)30891-4
5. Lawson PJ, Flocke SA. Teachable moments for health behavior change: a concept analysis. Patient Educ Couns. 2009;76(1):2530. doi:10.1016/j.pec.2008.11.002
6. Senore C, Giordano L, Bellisario C, Di Stefano F, Segnan N. Population based cancer screening programmes as a teachable moment for primary prevention interventions. A review of the literature. Front Oncol. 2012;2:45. doi:10.3389/fonc.2012.00045
7. Gritz ER, Fingeret MC, Vidrine DJ, Lazev AB, Mehta NV, Reece GP. Successes and failures of the teachable moment. Cancer. 2006;106(1):1727. doi:10.1002/cncr.21598
8. Paluch-Shimon S, Cardoso F, Partridge AH, et al. ESO-ESMO 4th international consensus guidelines for breast cancer in young women (BCY4). Ann Oncol. 2020;31(6):674696. doi:10.1016/j.annonc.2020.03.284
9. Gnerlich JL, Deshpande AD, Jeffe DB, Sweet A, White N, Margenthaler JA. Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. J Am Coll Surg. 2009;208(3):341347. doi:10.1016/j.jamcollsurg.2008.12.001
10. World Cancer Research Fund. Diet, nutrition, physical activity and breast cancer: a global perspective. World Cancer Research Fund/American Institute for Cancer Research; 2017 (Revised 2018). Available from: dietandcancerreport.org. Accessed November 3, 2020.
11. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. JNCI. 2014;106(5):dju055dju. doi:10.1093/jnci/dju055
12. Thomas GA, Leonard RCF. How age affects the biology of breast cancer. Clin Oncol. 2009;21(2):8185. doi:10.1016/j.clon.2008.11.006
13. Narod SA. Breast cancer in young women. Nat Rev Clin Oncol. 2012;9(8):460470. doi:10.1038/nrclinonc.2012.102
14. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009;36(3):237249. doi:10.1053/j.seminoncol.2009.03.001
15. Maas P, Barrdahl M, Joshi AD, et al. Breast cancer risk from modifiable and nonmodifiable risk factors among white women in the United States. JAMA Oncol. 2016;2(10):12951302. doi:10.1001/jamaoncol.2016.1025
16. Brandt J, Garne JP, Tengrup I, Manjer J. Age at diagnosis in relation to survival following breast cancer: a cohort study. World J Surg Oncol. 2015;13(1):33. doi:10.1186/s12957-014-0429-x
17. Collins LC, Marotti JD, Gelber S, et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat. 2012;131(3):10611066. doi:10.1007/s10549-011-1872-9
18. Lee H-B, Han W. Unique features of young age breast cancer and its management. J Breast Cancer. 2014;17(4):301. doi:10.4048/jbc.2014.17.4.301
19. Seidler S, Huber D. Breast cancer in young women: implications for clinical practice. Rev Med Suisse. 2020;16(695):11061113.
20. Morrison DH, Rahardja D, King E, Peng Y, Sarode VR. Tumour biomarker expression relative to age and molecular subtypes of invasive breast cancer. Br J Cancer. 2012;107(2):382387. doi:10.1038/bjc.2012.219
21. Walker R, Lees E, Webb M, Dearing S. Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer. 1996;74(11):17961800. doi:10.1038/bjc.1996.632
22. Lynch HT, Watson P, Conway T, Fitzsimmons ML, Lynch J. Breast cancer family history as a risk factor for early onset breast cancer. Breast Cancer Res Treat. 1988;11(3):263267. doi:10.1007/BF01807285
23. Lee DS, Yoon S-Y, Looi LM, et al. Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res. 2012;14(2):R66. doi:10.1186/bcr3172
24. Gmez-Flores-Ramos L, lvarez-gmez RM, Villarreal-Garza C, Wegman-Ostrosky T, Mohar A. Breast cancer genetics in young women: what do we know? Mutat Res. 2017;774:3345. doi:10.1016/j.mrrev.2017.08.001
25. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497506. doi:10.1056/NEJMoa1400382
26. Joslyn SA, Foote ML, Nasseri K, Coughlin SS, Howe HL. Racial and ethnic disparities in breast cancer rates by age: NAACCR breast cancer project. Breast Cancer Res Treat. 2005;92(2):97105. doi:10.1007/s10549-005-2112-y
27. Chlebowski RT, Chen Z, Anderson GL, et al. Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst. 2005;97(6):439448. doi:10.1093/jnci/dji064
28. Jack RH, Davies EA, Mller H. Breast cancer and age in black and white women in South East England. Int J Cancer. 2012;130(5):12271229. doi:10.1002/ijc.26088
29. Copson E, Maishman T, Gerty S, et al. Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study. Br J Cancer. 2014;110(1):230241. doi:10.1038/bjc.2013.650
30. Rockhill B, Willett WC, Hunter DJ, et al. Physical activity and breast cancer risk in a cohort of young women. J Natl Cancer Inst. 1998;90(15):11551160. doi:10.1093/jnci/90.15.1155
31. Wu Y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2013;137(3):869882. doi:10.1007/s10549-012-2396-7
32. Hardefeldt PJ, Penninkilampi R, Edirimanne S, Eslick GD. Physical activity and weight loss reduce the risk of breast cancer: a meta-analysis of 139 prospective and retrospective studies. Clin Breast Cancer. 2018;18(4):e601e12. doi:10.1016/j.clbc.2017.10.010
Here is the original post:
[Full text] A Review of Modifiable Risk Factors in Young Women for the Prevention | BCTT - Dove Medical Press
Recommendation and review posted by Bethany Smith
[Full text] Prognostic value of TP53 mutation location in breast cancer | CMAR – Dove Medical Press
Introduction
As a tumor suppressor and DNA binding transcription factor, TP53 is actively involved in the regulation of the cell cycle, apoptosis, and genomic stability.1,2 TP53 is one of the most frequently mutated genes in human cancers, including breast cancer,3 and numerous studies have reported it as a biomarker for predicting an aggressive and metastatic phenotype in breast cancer.47 Most of these studies used first-generation sequencing or automated DNA extraction from formalin-fixed and paraffin-embedded tissue (FFPE). However, real-time (RT)-PCR results and first-generation sequencing could not be used to detect all TP53 mutations to further investigate TP53 status more accurately and reliably.
TP53 is located on chromosome 17p13.1 and contains 11 exons and 10 introns. Most TP53 mutations map to exons 58, which encodes the DNA binding domain (DBD), and most are missense mutations.810 Hotspot codons 175, 213, 245, 248, 273, and 282 account for at least 2% of all mutations within the DBD.2 Patients with acute myeloid leukemia carrying TP53 mutations in the DBD had a worse prognosis than those with wild-type TP53.11 Furthermore, another clinical trial showed that truncating mutations in the DBD had a significant independent prognostic value in breast cancer, being associated with increased recurrence compared with patients with non-modified p53 proteins.12
Early studies using first-generation sequencing or automated DNA extraction from FFPE found that TP53 mutations were associated with poor prognosis in hormone receptor-positive (HR+) breast cancer patients.1315 Moreover, in an HR+ cohort, TP53 signaling was enriched in resistant tumors (38% in the aromatase inhibitor-resistant group vs 17% in the sensitive group) such that HR+ tumors with TP53 mutations were mostly aromatase inhibitor-resistant.5 No significant result was obtained from human epidermal growth factor receptor 2 positive (HER2+) or triple-negative breast cancer (TNBC) cohorts.16 Other studies found that TP53 mutations were associated with tumor recurrence and apoptosis, which were more common in HER2-positive and TNBC cohorts.17,18
While the significance of TP53 mutations has been shown by RT-PCR and first-generation sequencing, most clinical laboratories do not use next-generation sequencing (NGS) to determine the p53 mutational status because of high costs and complex interpretation. Therefore, it is difficult to understand the clinical applications of TP53.19 In the present study, we collected peripheral blood samples from Chinese patients with freshly diagnosed metastatic breast cancer (MBC) and examined the whole exons and introns of TP53 by NGS to further investigate the relationship between TP53 mutations, prognosis, and therapy.
From January 2013 to March 2020, patients past first-line treatment and those for whom blood samples were not available were excluded, leaving a total of 194 at the stage of first-line treatment at the Department of Breast Oncology, Peking University Cancer Hospital. Of these, 187 consented with enrollment and had complete clinic-pathological information (Figure 1).
Figure 1 Flowchart of patient inclusion.
We defined estrogen receptor (ER), progesterone receptor (PR), and HER2 status according to recommended guidelines,20,21 which identified three subtypes: the HER2+ cohort, HR+/HER2- cohort, and TNBC cohort.
HR+/HER2- patients who accepted adjuvant endocrine therapy were divided into two groups: endocrine-resistant patients were defined as patients relapsing during adjuvant endocrine therapy, or <12 months after its completion. Endocrine-sensitive patients were defined as patients relapsing 12 months after completing adjuvant endocrine therapy in the early breast cancer stage.22
Peripheral blood samples before first-line therapy were collected in EDTA Vacutainer tubes and centrifuged at 2000 g for 10 min at 4C. The supernatant was then removed, and each sample of 3 mL plasma was stored at 80C.
Circulating free (cf)DNA was extracted using a QIAamp Circulating Nucleic Acid Kit (QIAamp, Venlo, the Netherlands) from EDTA and citrate anticoagulant plasma. The average volume of plasma used for extraction was 2.6 mL (range, 0.73.9 mL). The quantity and quality of the purified cfDNA were checked using a Qubit 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) and Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA). For samples with severe genomic contamination from peripheral blood cells, size selection was performed to remove large genomic fragments with AMPure XP beads (Beckman Coulter, Brea, CA, USA). Samples with a total yield <5 ng were considered inadequate for NGS and were removed from any further sequencing methods.
cfDNA was end-repaired before the dA-tailing process, and then ligated with proprietary UMI adapters. The library yield was measured after PCR amplification using a Qubit and Bioanalyzer 2100. Samples yielding >700 ng proceeded to the hybridization step. Library capture was conducted using biotin-labeled DNA probes (Thermo Fisher Scientific). In brief, the library was hybridized using PredicineCARE panel (Huidu Shanghai Medical Sciences, Inc.) overnight and captured on Dynabeads M-270 Streptavidin (Thermo Fisher Scientific).23,24 Unbound fragments were washed away, and the enriched fragments were amplified via PCR. For library preparation, the purified product was checked using Bioanalyzer 2100 and loaded into the HiSeq X Ten system (Illumina, San Diego, CA, USA) for NGS with paired-end 150 bp sequencing kits.
Consensus binary alignment map (BAM) files were derived by merging paired-end reads that originated from the same molecules (based on mapping location and unique molecular identifiers) as single-strand fragments. Single-strand fragments from the same double-strand DNA molecules were merged to be double-stranded for suppressing sequencing and PCR errors during this process. NGS quality-checking was performed by examining the percentage of targeted regions with >1500x unique consensus coverage. Samples with <80% regions having >1500x unique coverage were deemed to be QC failed and excluded. Candidate variants, consisting of point mutations, small insertions and deletions, were identified using Huidu proprietary bioinformatics pipeline. Candidate variants with low base quality, mapping scores, and other quality metrics were filtered. Candidate variants in repeat regions were also excluded.
A variant identified in cfDNA was considered to be a candidate somatic mutation-based if all of the following pre-defined criteria were present. These criteria were 1) the presence of at least 4 distinct paired reads in the mutation in the plasma; 2) the number of distinct paired reads containing a particular mutation in the plasma is at least 0.1% of the total distinct read pairs (if the nucleotide change and amino acid change are identical to an alteration observed in 20 cancer cases reported in the COSMIC database or previously reported as a cancer hotspot [http://www.cancerhotspots.org]) or the number of distinct paired reads containing a particular mutation in the plasma was at least 0.25% of the total distinct read pairs (if the nucleotide change and amino acid change are not a frequent alteration in COSMIC database or reported as a cancer hotspot previously); 3) the variant is not present in public databases of common germline variants, including 1000 genomes, ExAC, gnomAD, and KAVIAR, with population allele frequency >0.5%; 4) the variant is not present in matched PBMC samples (unpublished data, manuscript in preparation).
Candidate somatic mutations were further filtered based on gene annotation to identify those occurring in protein-coding regions. Intronic and silent changes were excluded, and mutations resulting in missense mutations, nonsense mutations, frameshifts, or splice site alterations were retained. Mutations annotated as benign or likely benign in ClinVar database were also filtered.
Clinical outcome was evaluated as disease-free survival (DFS) and overall survival (OS). Disease-free survival (DFS) was defined as the interval between surgery and time of recurrence for relapsed patients so that patients with stage IV were not included. OS was defined as the time from diagnosis to the date of death or last follow-up. According to Response Evaluation Criteria in Solid Tumors version 1.1 guidelines,25 we evaluated the response assessment by a computed tomography scan or magnetic resonance imaging every 612 weeks or as the patients condition deteriorated.
SPSS software version 20 was used to analyze the TP53 status and categorical patient characteristics. DFS and OS were estimated by the KaplanMeier method and comparisons between groups were conducted by the log rank test. P values <0.05 were considered significant. For multivariable analysis, Cox proportional hazards method was used to evaluate clinical outcome. The association between the TP53 status and clinical characteristics was examined using the Chi-square test.
Of 187 patients, 79 carried TP53 mutations and 108 had wild-type TP53. Detailed baseline clinical information of all patients is shown in Table 1. The median age in the TP53 mutated group was 48 years (range: 2769 years old) versus 46 years of age in the TP53 wild-type group (range: 2680 years old) (P = 0.702). We also found that 73.4% (58/79) of TP53-mutated patients and 86.1% (93/108) of TP53 wild-type patients were HER2 negative (P=0.030).
Table 1 Baseline Clinical Characteristics of TP53 Wild-Type and -Mutated Metastatic Breast Cancer Patients (n=187)
In univariate analysis of DFS (Table 2), HER2 status (P=0.024) and HR status (P=0.000) were significant predictors in TP53 wild-type patients and TP53-mutated patients, respectively, and Ki67 status was also a significant predictor for TP53 wild-type patients (P=0.001) and TP53-mutated patients (P=0.022). After multivariable analysis of DFS (Table 2), Ki67 status (P=0.003) and HR status (P=0.000) in TP53 mutated group remained significant predictors and patients with stage III had a higher risk of relapse after surgery than stage III (p=0.030) in TP53 wild-type cohort.
A total of 87 somatic TP53 mutations were identified in the 79 TP53-mutated patients. Sixty-seven of these (77.0%) were located in exons 58, which span the DBD of the protein (Supplementary Table S1). Codons 175, 220, and 248 within the DBD were the locations of 4.6% of all mutations, respectively, which were all missense mutations (Figure 2). Of the 87 mutations, there were 46 missense mutations (43 was in DBD, 1 was in TD, 1 was in TAD, and 1 was outside the p53 protein domain) and 41 non-missense mutations (18 nonsense mutations, 3 splicing mutations, 16 frameshift mutations, 4 in-frame mutations).
We found that the median DFS of TP53-mutated patients was significantly shorter at 33.0 months (95% confidence interval [CI]=21.444.6) than that of TP53 wild-type patients at 51.0 months (95% CI=39.160.9) (hazard ratio=1.89, 95% CI=1.312.71, P=0.001) (Figure 3A). Similarly, the median OS of TP53-mutated patients was significantly shorter at 67.0 months (95% CI=44.489.6) than that of TP53 wild-type patients at 140.0 months (95% CI=119.5160.5) (hazard ratio=1.99, 95% CI=1.213.26, P=0.006) (Figure 3B).
Figure 3 Survival analyses by KaplanMeier according to TP53 status in MBC patients. (A and B) TP53 wild-type patients had a significantly better clinical outcome than TP53-mutated patients. (C and D) there were no significant differences between TP53 wild-type and -mutated patients in the HER2-positive cohort. (E and F) TP53 wild-type patients had a significantly longer median DFS and OS than TP53-mutated patients in the HR+/HER2 cohort. (G and H) TP53 wild-type patients had a significantly longer median DFS than TP53-mutated patients in the TNBC cohort.
In the HER2+ cohort (n=36, 21 of whom were TP53-mutated patients), there was no significant difference regarding TP53 status with respect to DFS (34.0 vs 21.0 months, P=0.822) (Figure 3C) or OS (91.0 vs 65.0 months, P=0.080) (Figure 3D).
In the HR+/HER2- cohort (n=113, 40 of whom were TP53-mutated patients), the median DFS of TP53 mutated patients of 44.0 months (95% CI=35.952.1) was significantly shorter than the 58.0 months (95% CI=46.269.8) of TP53 wild-type patients (hazard ratio=1.57, 95% CI=0.972.54, P=0.038) (Figure 3E). No significant difference was observed for OS (P=0.606) (Figure 3F).
In the TNBC cohort (n=38, 18 of whom were TP53-mutated patients), the median DFS of TP53-mutated patients of 16.0 months (95% CI=7.824.2) was significantly shorter than the 26.0 months (95% CI=16.635.4) of TP53 wild-type patients (hazard ratio=2.17, 95% CI=0.964.90, P=0.023) (Figure 3G). There was no significant difference regarding TP53 status with respect to OS (137.0 vs 54.0 months, P=0.117) (Figure 3H).
We next classified the 187 patients into three groups by mutation domain: TP53 mutations in the DBD, TP53 mutations in the non-DBD, and TP53 wild-type groups. The median DFS for these patients was 36.6 (95% CI=25.342.7), 22 (95% CI=16.125.9), and 51 (95% CI=39.160.9) months, respectively, while the median OS was 80 (95% CI=46.3113.7), 51 (95% CI=41.260.8), and 140 (95% CI=119.5160.5) months, respectively.
TP53 wild-type patients had a significantly better clinical outcome than those with TP53 mutations in the DBD with respect to DFS (P=0.008, Figure 4A) and OS (P=0.003, Figure 4B). Similarly, TP53 wild-type patients had a significantly better clinical outcome than those with TP53 mutations in the non-DBD with respect to DFS (P<0.001, Figure 4A) and OS (P=0.001, Figure 4B). There were no significant differences in DFS or OS between patients with TP53 mutations in the DBD compared with those in the non-DBD.
Figure 4 Survival analyses by KaplanMeier according to TP53 mutation sites in MBC patients. (A) Patients with a mutation in the non-DNA binding domain had a significantly shorter median DFS than TP53 wild-type patients and those with mutations in the DNA-binding domain. (B) Patients with a mutation in the non-DNA binding domain had shorter median OS than TP53 wild-type patients and those with mutations in the DNA-binding domain. (C) Patients with protein non-stable mutation had shortest median DFS than patients with protein stable mutation and TP53 wild-type patients. (D) Patients with protein non-stable mutation had shortest median OS than patients with protein stable mutation and TP53 wild-type patients.
Notes: Protein stable mutations would include non-truncating and non-frame altering mutations outside of the p53 tetramerization domain, and protein non-stable mutations would include all truncating and frame-altering mutations, as well as mutations in the tetramerization domain.
And then, we divided patients into three groups: TP53 wild-type group; protein stable mutations group (non-truncating and non-frame altering mutations outside of the p53 tetramerization domain); protein non-stable mutations group (all truncating and frame-altering mutations, and mutations in the tetramerization domain).
Patients with protein non-stable mutations had significantly shorter DFS (21.0 months vs 49.0 months, respectively, hazard ratio=2.82, 95% CI=1.634.87, P<0.001, Figure 4C) and OS (57.0 months vs 140.0 months, respectively, hazard ratio=4.05, 95% CI=1.958.40, P<0.001, Figure 4D) than TP53 wild-type patients. Moreover, the median DFS of protein stable mutations was 43.5 months, longer than protein non-stable mutations (hazard ratio=0.54, 95% CI=0.310.93, P=0.025, Figure 4C). There were no significant differences in DFS or OS between patients with protein stable mutations and TP53 wild type.
Furthermore, we wanted to study mutations in DBD so that we classified them into missense (n=43) and non-missense mutations (n=24, including nonsense mutations, splicing mutations, frameshift mutations and in-frame mutations). Patients with non-missense mutations in the DBD had significantly shorter DFS (20.0 months vs 51.0 months, respectively, hazard ratio=3.26, 95% CI=1.586.71, P=0.001, Figure 5A) and OS (57.0 months vs 140.0 months, respectively, hazard ratio=10.45, 95% CI=3.7928.8, P<0.001, Figure 5B) than TP53 wild-type patients. Moreover, the median OS of patients with non-missense mutations in the DBD was significantly shorter than those with missense mutations in the DBD (hazard ratio=2.45, 95% CI=1.055.09, P=0.015, Figure 5B). There were no significant differences in DFS or OS between patients with missense mutations in the DBD and wild-type TP53 patients.
Figure 5 Survival analyses by KaplanMeier according to TP53 mutation type in the DNA binding domain. (A and B) Patients with non-missense mutations in the DNA binding domain had a significantly shorter median DFS and OS than TP53 wild-type patients and those with missense mutations in the DNA binding domain.
A total of 96 patients who received adjuvant endocrine therapy were selected to evaluate the relationship between TP53 mutation status and the response to endocrine therapy. As shown in Table 3, we found that 84.7% (50/59) of patients accepted adjuvant chemotherapy in TP53 wild-type group, whereas 78.4% (29/37) of patients accepted adjuvant chemotherapy treatment in TP53 mutant patients. There was no significant difference between TP53 status and adjuvant chemotherapy (P=0.467). As well known, ESR1 mutations are associated with acquired endocrine resistance in breast cancer so that we took ESR1 mutation rate into consideration in Table 3, but there were no significant differences in ESR1 mutation rate (p=0.558) between the two groups.
Table 2 Univariate and Multivariate Cox Regression Analysis of DFS in TP53 Wild-Type and -Mutated Patients
Table 3 Clinical Characteristics of Patients Receiving Adjuvant Endocrine Therapy (n=96)
To further explore the relationship between TP53 status and treatment response, we classified patients into the adjuvant endocrine therapy-resistant group and the adjuvant endocrine therapy sensitive group. Interestingly, we found that in the adjuvant endocrine therapy sensitive group, patients with TP53 mutations had a significantly shorter DFS than TP53 wild-type patients (69.0 months vs 108.0 months, respectively, hazard ratio=3.22, 95% CI=0.7014.77, P=0.008) (Figure 6B). No significant DFS differences between TP53-mutated and TP53 wild-type patients were seen in the endocrine therapy-resistant group (34.0 months vs 40.0 months, respectively, P=0.903) (Figure 6A).
Figure 6 Survival analyses by KaplanMeier according to TP53 status in MBC receiving adjuvant endocrine therapy. (A) There was no significant difference in TP53 status in the endocrine therapy-resistant cohort. (B) TP53 wild-type patients had a significantly better clinical outcome than TP53-mutated patients in the endocrine therapy sensitive cohort.
In our study, we used NGS to detect TP53 mutations in the cfDNA, which might affect tumor temporal and spatial heterogeneity, of 187 Chinese MBC patients. Our results indicated that TP53 mutations could be used as a prognostic marker for worse outcome in MBC and for the response of adjuvant endocrine therapy.
We established genomic profiles of patients which revealed a TP53 mutation frequency of 42.2%, similar to that seen in the Guangdong Provincial Peoples Hospital cohort (45.0%) but higher than in the TCGA breast cancer cohort (30.0%).26 Another recent study on cfDNA molecular profiling in Chinese patients with MBC reported a TP53 mutation rate of 64.1% compared with 52% in Caucasian patients.27,28 These discrepancies could reflect differences between patient ethnicities, such as in the median age of breast cancer patients with TP53 mutations in our study of 48 years compared with 55.2 years in Caucasians.29
The p53 pathway was previously shown to rank top in the basal-like breast cancer subtype, but not in the HER2-enriched type; therefore, TP53 mutations were not associated with poor prognosis in the HER2-enriched group.6 In support of this, our data indicated that the TP53 mutation status was an independent predictive factor of survival especially in HR+/HER2 and TNBC cohorts, but not in the HER2-positive cohort.
Several studies have shown that the DBD is the most frequently mutated TP53 region in breast cancer. In line with this, codons 175, 220, and 248 located within the DBD were the site of many TP53 mutations in our study, of which most were missense mutations. DBD mutations were previously reported to have prognostic value,30,31 while non-missense mutations were associated with a worse outcome in MBC.32 A recent study showed that missense mutation in the DNA-binding domain had dominant-negative effects (DNE).33 There was no difference in survival between patients with dominant-negative p53 mutant tumors and those with TP53 mutations that are predicted to be non-dominant negative.34,35 In our study, TP53 missense mutations in the DBD were associated with improved survival. Further analysis showed that patients with TP53 mutations in the non-DBD had a significantly shorter DFS than those in the TP53 non-mutation cohort.36 In order to investigate the prognostic value of p53 protein further, we divided them into TP53 wild-type group; protein stable mutations group and protein non-stable mutations group. In our study, patients with protein non-stable mutations had significantly shorter DFS and OS than TP53 wild-type patients. Moreover, protein non-stable mutations included all truncating and frame-altering mutations, and mutations in the tetramerization domain so that mutations in TD had a worse clinical outcome. The reasons were that mutations in TD could either abolish or reduce binding of p53 protein to DNA and transcriptional activation, and TP53 mutation in TD domain had dominant-negative effects (DNE) that inactivate TP53 wild type in some cases.37 Other researchers also found mutations in TD domain were associated with cancer-associated development.38 Not all missense mutations cause protein accumulation, while non-missense mutations are true loss-of-function mutations. Thus, missense mutations have generally been associated with higher protein expression compared with non-missense mutations.16
Some clinical trials showed us TP53 might be the potential to be a therapeutic biomarker. Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting.3942 Data on the association between TP53 mutations and endocrine therapy response were also controversial.4345 When it came to the association between hormone therapy and chemotherapy, some researchers found that adding hormone therapy to chemotherapy could improve the survival for TP53 wild-type patients not for TP53 mutation patients.46,47 While in our research, 84.7% of patients in TP53 wild-type group and 78.4% patients in TP53 mutant group all accepted adjuvant chemotherapy and endocrine therapy treatment in Table 3, and the distribution of patients with adjuvant chemotherapy was balanced in two groups, which did not exert an influence on the analysis of endocrine therapy and TP53 status. In our study, we also found TP53 mutations were associated with endocrine resistance. TP53-mutated patients had a shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group. Previously, increased expression of estrogen-related receptor (ERR) was associated with increased levels of p53 in ER-positive cases. ER and ERR share only 33% homology in their ligand-binding domains, resulting in the insensitivity of ERR to tamoxifen.48 Additionally, TP53 wild-type tumors might be more responsive to endocrine therapy because this disrupts the ERp53 interaction and reactivates p53.49
The retrospective nature of our study resulted in a number of limitations. DFS might have influenced the survival analysis, which was retrospectively calculated. Additionally, we lacked matched primary and recurrence samples for analysis. Finally, we did not analyze p53 protein expression to verify our results.
In conclusion, TP53 wild-type MBC patients showed better survival than TP53-mutated patients in HR+/HER2 and TNBC cohorts. Missense mutations in the DBD of p53 appeared to be an independent prognostic marker for short DFS, while TP53 mutations were associated with endocrine resistance. This indicates that alternative therapies for HR-positive patients with TP53 mutations should be considered. Large-scale prospective studies are needed to verify our findings.
We can provide the original data in this manuscript upon request.
The written informed consent of this research had been provided by the patients, and this study was approved by the Medical Ethics Committee of Peking University Cancer Hospital & Institute (Approval No.2016KT47) according to the Declaration of Helsinki.
We thank Sarah Williams, PhD, from Liwen Bianji, Edanz Editing China, for editing the English text of a draft of this manuscript.
There were no funding sources for this work.
Jianjun Yu and Shidong Jia are employees and stockholders of Huidu Shanghai Medical Sciences, Ltd. The authors declare that they have no other competing interests.
1. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170(6):10621078. doi:10.1016/j.cell.2017.08.028
2. Hainaut P, Pfeifer GP. Somatic TP53 mutations in the era of genome sequencing. Cold Spring Harb Perspect Med. 2016;6(11):a026179. doi:10.1101/cshperspect.a026179
3. Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400404. doi:10.1038/nature11017
4. Basho RK, de Melo Gagliato D, Ueno NT, et al. Clinical outcomes based on multigene profiling in metastatic breast cancer patients. Oncotarget. 2016;7(47):7636276373. doi:10.18632/oncotarget.12987
5. Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353360. doi:10.1038/nature11143
6. Ren J, Wang B, Li J. Integrating proteomic and phosphoproteomic data for pathway analysis in breast cancer. BMC Syst Biol. 2018;12(Suppl S8):130. doi:10.1186/s12918-018-0646-y
7. Koak A, Heselmeyer-Haddad K, Lischka A, et al. High levels of chromosomal copy number alterations and TP53 mutations correlate with poor outcome in younger breast cancer patients. Am J Pathol. 2020;190(8):16431656. doi:10.1016/j.ajpath.2020.04.015
8. Wang D, Kon N, Lasso G, et al. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature. 2016;538(7623):118122. doi:10.1038/nature19759
9. Sullivan KD, Galbraith MD, Andrysik Z, et al. Mechanisms of transcriptional regulation by p53. Cell Death Differ. 2018;25(1):133143. doi:10.1038/cdd.2017.174
10. Marchenko ND, Hanel W, Li D, et al. Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ. 2010;17(2):255267. doi:10.1038/cdd.2009.173
11. Parry TE. Mutagenic mechanisms in leukemia and cancer: a new concept cytosine lack could be as mutagenic as cytosine deamination. Leuk Res. 2006;30(9):10791083. doi:10.1016/j.leukres.2005.12.019
12. Fernndez-Cuesta L, Oakman C, Falagan-Lotsch P, et al. Prognostic and predictive value of TP53mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 0298 Phase III trial. Breast Cancer Res. 2012;14(3):R70. doi:10.1186/bcr3179
13. Meric-Bernstam F, Zheng X, Shariati M, et al. Survival outcomes by TP53 mutation status in metastatic breast cancer. JCO Precis Oncol. 2018;2:15. doi:10.1200/PO.17.00245
14. Lopez G, Costanza J, Colleoni M, et al. Molecular insights into the classification of luminal breast cancers: the genomic heterogeneity of progesterone-negative tumors. Int J Mol Sci. 2019;20(3):510. doi:10.3390/ijms20030510
15. Silwal-Pandit L, Vollan HKM, Chin S-F, et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res. 2014;20(13):35693580. doi:10.1158/1078-0432.CCR-13-2943
16. Darb-Esfahani S, Denkert C, Stenzinger A, et al. Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy. Oncotarget. 2016;7(42):6768667698. doi:10.18632/oncotarget.11891
17. Luo Y, Huang W, Zhang H, et al. Prognostic significance of CD117 expression and TP53 missense mutations in triple-negative breast cancer. Oncol Lett. 2018;15(5):61616170. doi:10.3892/ol.2018.8104
18. Pileczki V, Pop L, Braicu C, et al. Double gene siRNA knockdown of mutant p53 and TNF induces apoptosis in triple-negative breast cancer cells. Onco Targets Ther. 2016;9:69216933. doi:10.2147/OTT.S110719
19. Li J-P, Zhang X-M, Zhang Z, et al. Association of p53 expression with poor prognosis in patients with triple-negative breast invasive ductal carcinoma. Medicine. 2019;98(18):e15449. doi:10.1097/MD.0000000000015449
20. Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med. 2014;138(2):241256. doi:10.5858/arpa.2013-0953-SA
21. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):27842795. doi:10.1200/JCO.2009.25.6529
22. Brando M, Maurer C, Ziegelmann PK, et al. Endocrine therapy-based treatments in hormone receptor-positive/HER2-negative advanced breast cancer: systematic review and network meta-analysis. ESMO Open. 2020;5(4):e000842. doi:10.1136/esmoopen-2020-000842
23. Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5):547555. doi:10.1038/nbt.3520
24. Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213219. doi:10.1038/nbt.2514
25. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228247. doi:10.1016/j.ejca.2008.10.026
26. Zhang G, Wang Y, Chen B, et al. Characterization of frequently mutated cancer genes in Chinese breast tumors: a comparison of Chinese and TCGA cohorts. Ann Transl Med. 2019;7(8):179. doi:10.21037/atm.2019.04.23
27. Rossi G, Mu Z, Rademaker AW, et al. Cell-free DNA and circulating tumor cells: comprehensive liquid biopsy analysis in advanced breast cancer. Clin Cancer Res. 2018;24(3):560568. doi:10.1158/1078-0432.CCR-17-2092
28. Tao Z, Li T, Feng Z, et al. Characterizations of cancer gene mutations in Chinese metastatic breast cancer patients. Front Oncol. 2020;10:1023. doi:10.3389/fonc.2020.01023
29. Warner ET, Tamimi RM, Hughes ME, et al. Racial and ethnic differences in breast cancer survival: mediating effect of tumor characteristics and sociodemographic and treatment factors. J Clin Oncol. 2015;33(20):22542261. doi:10.1200/JCO.2014.57.1349
30. Olivier M, Langer A, Carrieri P, et al. The clinical value of somatic TP53 gene mutations in 1794 patients with breast cancer. Clin Cancer Res. 2006;12(4):11571167. doi:10.1158/1078-0432.CCR-05-1029
31. Liu Y, Xu F, Wang Y, et al. Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer. Oncol Lett. 2019;18(3):31593169. doi:10.3892/ol.2019.10625
32. Petitjean A, Achatz MIW, Borresen-Dale AL, et al. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26(15):21572165. doi:10.1038/sj.onc.1210302
33. Boettcher S, Miller PG, Sharma R, et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019;365(6453):599604. doi:10.1126/science.aax3649
34. Shahbandi A, Jackson JG. Analysis across multiple tumor types provides no evidence that mutant p53 exerts dominant negative activity. NPJ Precis Oncol. 2019;3(1):1. doi:10.1038/s41698-018-0074-x
35. Giacomelli AO, Yang X, Lintner RE, et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018;50(10):13811387. doi:10.1038/s41588-018-0204-y
36. Terada K, Yamaguchi H, Ueki T, et al. Full-length mutation search of the TP53 gene in acute myeloid leukemia has increased significance as a prognostic factor. Ann Hematol. 2018;97(1):5161. doi:10.1007/s00277-017-3143-2
37. Gencel-Augusto J, Lozano G. p53 tetramerization: at the center of the dominant-negative effect of mutant p53. Genes Dev. 2020;34(1718):11281146. doi:10.1101/gad.340976.120
38. Muscolini M, Montagni E, Caristi S, et al. Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain. Cell Cycle. 2009;8(20):33963405. doi:10.4161/cc.8.20.9910
39. Jackson JG, Pant V, Li Q, et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell. 2012;21(6):793806. doi:10.1016/j.ccr.2012.04.027
40. Bertheau P, Turpin E, Rickman DS, et al. Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicincyclophosphamide regimen. PLoS Med. 2007;4(3):e90. doi:10.1371/journal.pmed.0040090
41. Bertheau P, Espié M, Turpin E, et al. TP53 status and response to chemotherapy in breast cancer. Pathobiology. 2008;75(2):132139. doi:10.1159/000123851
42. Bonnefoi H, Piccart M, Bogaerts J, et al. TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised Phase 3 trial. Lancet Oncol. 2011;12(6):527539. doi:10.1016/S1470-2045(11)70094-8
43. Kai K, Nishimura R, Arima N, et al. p53 expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study. Int J Clin Oncol. 2006;11(6):426433. doi:10.1007/s10147-006-0601-6
44. Yamashita H, Toyama T, Nishio M, et al. p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer. Breast Cancer Res. 2006;8(4):R48. doi:10.1186/bcr1536
45. Bailey ST, Shin H, Westerling T, et al. Estrogen receptor prevents p53-dependent apoptosis in breast cancer. Proc Natl Acad Sci U S A. 2012;109(44):1806018065. doi:10.1073/pnas.1018858109
46. Ungerleider NA, Rao SG, Shahbandi A, et al. Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment. Breast Cancer Res. 2018;20(1):115. doi:10.1186/s13058-018-1044-5
47. Shahbandi A, Nguyen HD, Jackson JG. TP53 mutations and outcomes in breast cancer: reading beyond the headlines. Trends Cancer. 2020;6(2):98110. doi:10.1016/j.trecan.2020.01.007
48. Thewes V, Simon R, Schroeter P, et al. Reprogramming of the ERR and ER target gene landscape triggers tamoxifen resistance in breast cancer. Cancer Res. 2015;75(4):720731. doi:10.1158/0008-5472.CAN-14-0652
49. Konduri SD, Medisetty R, Liu W, et al. Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci U S A. 2010;107(34):1508115086. doi:10.1073/pnas.1009575107
View original post here:
[Full text] Prognostic value of TP53 mutation location in breast cancer | CMAR - Dove Medical Press
Recommendation and review posted by Bethany Smith
Dale Toney: A ‘wake up call’ for diabetes talk to your doctor about prevention and treatment – User-generated content
An estimated 88 million Americans have prediabetes, and just over 1 in 10 have been diagnosed with type 2 diabetes. In Kentucky, nearly 12 percent of the adult population is affected by this disease. Week after week, Kentucky physicians care for patients with type 2 diabetes and the potentially debilitating complications it can cause. Unfortunately, it is also well-documented that pre-existing conditions such as diabetes can put patients at high-risk for complications should they contract COVID-19.
March 23, is American Diabetes Alert Day, and the Kentucky Medical Association (KMA) and its thousands of physician members are encouraging Kentuckians to learn more about their risk factors and family history of the disease, and to talk to their doctor about prevention and treatment options.
Dr. Dale Toomey
Diabetes is the condition in which the body does not properly process food for use as energy. Most of the food we eat is turned into glucose, or sugar, for our bodies to use for energy. The pancreas makes a hormone called insulin to help glucose get into the cells of our bodies. When you have diabetes, your body either doesnt make enough insulin or cant use its own insulin as well as it should. This causes too much sugar to build up in your blood. In those with type 1 diabetes, the body completely stops producing insulin, and this usually occurs in childhood or early adulthood. With type 2 diabetes, the body produces insulin, but the cells dont respond to insulin the way they should.
Prediabetes occurs when a patient has a higher-than-normal blood sugar level. Its not high enough to be considered type 2 diabetes yet, but without lifestyle changes, adults with prediabetes are more likely to develop type 2 diabetes. More than 8 in 10 American adults with prediabetes dont know they have it. These patients are also at risk for developing other serious health problems like heart disease and stroke.
The first step in preventing or delaying type 2 diabetes and related health problems is to screen and test for prediabetes. Patients are encouraged to talk to their physician during their annual well-visits about being screened for type 2 diabetes. Your physician can order a simple blood test for patients with risk factors for prediabetes and type 2 diabetes, which include anyone 45 years of age or older, those who are overweight or obese, people with a family history of type 2 or gestational diabetes, and those who are physically active less than three times per week.
Patients diagnosed with prediabetes can be referred to the National Diabetes Prevention Program (DPP) lifestyle change program to prevent or delay type 2 diabetes. Programs are conducted by lifestyle coaches who are trained on an evidence-based curriculum. The coach can engage and guide you through makingand sticking withlifestyle changes. When patients join the program, they get a full year of support to make their new, healthy habits stick and keep them from slipping back into old habits. Kentucky also offers diabetesself-management education and support (DSME) groups, which can help you learnto manage your diabetes as part of your daily life. More information on these programs is available here.
Type 2 diabetes prevention is a priority of Kentucky physicians. As a focus of its AIM for Better Care: Administrative Improvements in Medicine initiative, KMA seeks to eliminate barriers to care for diabetes and to provide patients with the most updated resources and education to help prevent and manage this disease.
On American Diabetes Alert Day, consider this a wake up call to talk to your physician about diabetes prevention and treatment and get on the right path to a healthier tomorrow.
Dale Toney, M.D. is President of the Kentucky Medical Association. He is a board-certified internist in Lexington and is employed by the University of Kentucky Albert B. Chandler Hospital, is an Associate Professor at the University of Kentucky College of Medicine and serves as the Division Chief of General Internal Medicine and Womens Health.
Recommendation and review posted by Bethany Smith
Milford OB/GYN to close womens health care practice after over 30 years – Milford Daily News
MILFORD Pelvic exams, in vitro fertilization and childbirth typically aren't comfortable procedures for any woman, but Dr.Mitchell Bellucci seeks toensure that patients are secure and that he is positive but especially calm.
So calm thatpatients sometimes askhim if he'sabout to head out for vacation after work.
Everyone would always say, Well, geez, you look like youre going on vacation, said Bellucci during an interview in his office on Friday afternoon, wearing a loose-fitting button-up shirt withthe top fourbuttons undone. For me, it was convincing myself that everything was cool, even if sometimes it wasnt.
Hes been the doctor to more than 10,000 patients and has helped deliver more than 3,500 babies in his career, he said.Known for his cowboy boots, Bellucci, 66, also frequently wore flip flops and casual Hawaiian shirts.
He has a faded 1988 newspaper clipping from the Daily Newsof himself wearinga pair offull-quill ostrich boots. Those cost him around $400, he said. He wore cowboy boots so much, he ended up developing plantar fasciitis, which causes a lot of pain in the heel.
Thecowboy boots have been retired, and Bellucci is poised to do the same.
More: U.S. Rep. Clark aims to build child care into infrastructure debate
Bellucci is retiring next month after 40 years as an OB/GYN. He'splanning to close hiswomens health care practice at 192 West St. after opening it 33 years ago. He's selling the space, which is part of the Westview Professional Building.
Over four decades, Bellucci has made his mark in advancingwomens health care, including setting up the first bone density unit at Milford Regional Medical Center, bringing womens health innovations to local television, patenting medical devices for newborns, training medical doctors on advanced laparoscopyand establishing scholarships for nurses and pre-med students.
He's gone from the swimming pool into the delivery room a few times, too.
Ive delivered no less than two dozen kids in my Speedos... well, they were swim trunks, said Bellucci, who moved to Milford to be close to the hospital (and his practice) if he was needed immediately. He has a pool athome, and has raced from there to Milford Regional several timeswith just enough time to towel off.
It's a career field he never intended to enter, but he's glad he did, he said.
Training as a medical studentwas a pivotal time for Bellucci. While growing up onLong Island, New York, knew he wanted to be surgeon, but didn't want to docancer surgery, which he thought was depressing.
From there, it was process of elimination. He thought he would be an orthopedist performing bone surgery, but found most of his time would be spentdoing hip surgery for elderly patients who stayed at the hospital for weeks, he said. Hand surgery was too long to train forand general surgery seemed too boring, he said. He considered urology, but "didnt want to look at penises and prostates all day."
Then he tried obstetrics and gynecology.
Reproduction and bringing new life into the world especially intrigued Bellucci, who has a daughter, Laura, who's 33 and a bartender in New Orleans. But on abulletin board in the hallway of his office, she's a child, peeringinto the lensof anunderwater camera. Surrounding her are photos of dozens of other babies Belluccihas helped deliver, some also now in their 30s.
Youre there at the most important timeof their lives, man. And youre part of it, he said. What other doctor gets to be with a woman in pain for eight hours, she pushes for two hours, you catch the baby, and youre the hero?Its such a neat thing to experience.
Plus, most if not all of the patients he sees are healthy and have insurance.
I like explaining things, and you have to be direct and have to not overreact, he said about making patients feel comfortable and reassured. The office even has a therapy dog "Charlie," a cockapoo who comes in occasionallyand is adored by patients, said Bellucci.
He also has aletter froma patient, written in 1994, that still makes him smile.
Hehelped a woman deliver her first baby, but she moved and delivered her second baby elsewhere. That experiencewas very upsetting, she wrote him, and said her doctor lacked a sympathetic bedside manner.
But her experience with Bellucci in Milford,by contrast, was wonderful, she wrote.She said he remained positive throughout the ordeal and joked with her to make her feel more relaxed. She wrote that she and her husbandstill laugh years later recalling when a nurse in the delivery room strapped a maxi pad to Belluccis forehead to soak up some of his sweat.
Opinion: 2020 saw great strides for women, but it also exposed inequities we should fix in 2021
When I went into it, there were five guys to one woman. Now theres five women and no guys, said Bellucci.
In the 1970s, about 7% of American gynecologists were female, according to the American College ofObstetricians and Gynecologists.Today, about 82%of OB/GYN residents throughout the nation are women.
About a decade ago, Bellucci wasapproached by Bryant University in Rhode Island to teach male physician assistant students who weredenied access to learn inside other women's health care practices. For about nine years, he taught one student a month.
Moremen are turning away fromobstetrics and gynecology, said Bellucci, and its still difficult for them togain accessinto that space. The upside is that physician assistants aren't going into delivery rooms anymore with positions like midwives and nurse practitioners. Rather, male physician assistants today are going into settings like emergency rooms or family practices, he said.
More healthcare news: Dr. Dennis Plante, who grew up in Worcester, dies of COVID-19 in Texas
When most women hit age 50 many of his patients are about thatage their estrogen drops, he said. He realized bone density was an important component to womens health, because while estrogenis the key regulator ofbonemetabolism in both men and women, menopause leads to decreased estrogen, which is associated with decliningbonemineraldensity.
Milford Regional Medical Center didnt have a bone density unit at that time, so he helped create one, he said, and he taught primary care doctors the value of testing for it.
He also helped developthe CO2 Surgical Laser,designed to treat pre-cancerous conditions like warts and lesions, and is known for his Mona Lisa Touch.
That machine, created inItaly, is a laser treatment for symptoms somewomen experience after menopause, such as painful sex. It's an alternative to hormone treatment, which can be risky for some.
A lot of women who have these problems have had breast cancer, and what do (many doctors)do? They put you on anti-estrogen and they save your life, he said. But then you say, 'Well, what about my sex life?' I think we should address that.
If you didn't see "Dr. B" at his medical practice, you might have seen him on "Pasta Playoffs," a cooking show that aired on community access television.
I used to say, If you think you can cook good food, you should go one-on-one against Grandma," said Bellucci, who enjoys cooking Italian food. "And that was the premise of the show."
Various "grandmas" competed against Bellucci in making a pasta sauce, which was thenjudged by three randomly selected customers at Caff Sorrento in Milford, said Bellucci. The showlasted five episodes, and eventually morphed into "Cooking Against Cancer," specificallybreast cancer.
Opinion: We need to help women during the pandemic and beyond
Bellucci isexcited aboutretirement and has had a rewarding career, but said itll be a tough goodbye to his practice. After closing and selling it, he's moving toRhode Island to be with his girlfriend Mary, where hell spend most of his time boating, fishing, possibly offering consulting services in the medical device industry and writing screenplays drawing from his medical knowledge.
And finally, the next time he wears a Hawaiian shirt and pair of flip flops, he really will be on vacation an extended one.
Lauren Young writes about business and pop culture. Reach her at 774-804-1499 orlyoung@wickedlocal.com. Follow her on Twitter @laurenwhy__.
Continue reading here:
Milford OB/GYN to close womens health care practice after over 30 years - Milford Daily News
Recommendation and review posted by Bethany Smith
Beshear ceremonially signs 13 health bills, including one that caps price of insulin – Hoptown Chronicle
Gov. Andy Beshear signed 13 health bills into law Monday, highlighting one that caps insulin costs for about 30% of Kentuckians who need the life-preserving hormone.
The limit is $30 for a 30-day supply. This is the right thing to do and its a game-changer for those who rely on insulin to live, Beshear said. Until now, a single dose of insulin which cost between $2 and $7 to manufacture could sell for an average wholesale price of around $300 per vial.
Beshear noted that in a lawsuit he filed against insulin companies while attorney general over their unconscionable overpricing,revealed that over 10 years, the price of one insulin product went up 311%, and another rose 285%, including a rise from $325 per package in 2011 to $530 in 2017.
While these companies work to increase bottom lines and sustain market shares, he said. Kentucky families hit hardest by this price gouging can be paying more than $1,000 a month on insulin just to stay alive.
House Bill 95, co-sponsored by Reps. Danny Bentley, R-Russell, and Patti Minter, D-Bowling Green, will cap the monthly out-of-pocket cost for a 30-day supply of insulin at $30 for Kentuckians covered by state-regulated employer health plans or plans purchased on the marketplace exchange.
Minter, whose son has Type 1 diabetes,has saidthe bill will cover about 30% of insulin-dependent Kentuckians. It doesnt cover Medicare, Medicaid or self-funded employer plans except the one for state employees.
I want to be very clear, this is only a first step, Minter said. There is much more work to do but today is a very big deal. It will save lives and it will give people hope. She said that for many families, it will make the difference between bankruptcy and keeping a child alive.
In a video, Angela Lautner,Kentucky #insulin4alllegislative lead, expressed her gratitude to the lawmakers for the bill, but she too warned that more work needs to be done, saying it will help about 22,000 people.
Much more has to be done, butHB 95is a step forward, said Lautner, My chapter is here for insulin for all and thats why we must continue this momentum into the next session with urgency, with priority.
More than half a million Kentuckians have diabetes, and Kentucky ranks seventh-highest in the U.S. for diabetes prevalence. Lautner said more than one in four insulin-dependent people ration insulin due to cost.
The price cap will apply regardless of the amount or type of insulin the person with diabetes needs.
In addition to capping the price, HB 95requires health plans to provide the equipment, supplies and outpatient training and education needed to help diabetics stay healthy, and forbids any reductions from this coverage by others involved in coverage.
Thefiscal impact statementattached to the bill says it will increase premiums for health benefit plans, not including the state employee plan, by about 80 cents a month.
Bentley said thats a small price to pay to make sure diabetics keep getting their insulin because without it they can suffer amputations, loss of vision, neuropathy, ketoacidosis and even death. The costs on the medical side is much more than the cost that were going to have by helping people with insulin, he said.
Beshear also signed bills addressing these health topics:
HB 140, sponsored by Rep. Deanna Frazier, R-Richmond, will permittelehealth servicesthat were allowed to expand due to the pandemic to remain in place. The bill requires reimbursement for telehealth to be equivalent to reimbursement for the same service provided in person. I think its one of the most important bills that have been passed, Beshear said.
HB 219, sponsored by Bentley, allows pharmacies to sell hypodermic syringes and needles without a prescription. The aim is to increase access to clean supplies for people who inject drugs, which will help to decrease the risk of blood-borne diseases such as hepatitis C and HIV/AIDS.
SB 55, sponsored by Sen. Stephen Meredith, R-Leitchfield, abolishes co-payments required by Medicaid.
HB 183, sponsored by Rep. Brandon Reed, R- Hodgenville,will allowKentucky hospitals to get more money from Medicaid, based on an average commercial rate instead of the current Medicaid rate, which is often below that amount. The program would not cost the state anything, because Kentuckys hospitals have agreed to cover the cost. To get the money, hospitals will have to abide by higher quality standards that are still being decided by theKentucky Hospital Associationand theCabinet for Health and Family Services.The bill is expected to help many of the states rural hospitals; arecent reportshows that 16 of them are at risk of closing.
HB 108, sponsored by Melinda Gibbons Prunty, R-Belton (Muhlenberg County), codifies current Medicaid coverage of colorectal cancer, including screenings starting at 45 for most people and genetic cancer-risk testing, to align Medicaid and commercial coverage.
HB 50, sponsored by Rep. Kim Moser, R-Taylor Mill, will make health-insurance plans comply with a 2008 federal law that requires them to treat mental health conditions and substance use disorders the same as physical health. It also requires health insurers to file annual reports with the state to show how they are complying with federal law.
HB 276, sponsored by Moser, allows Kentuckians trained as temporary COVID-19 personal-care attendants under an executive order to apply their supervised training toward their Registered Nurse Aide certification. About 300 personal-care attendants work in Kentucky long-term care facilities, Moser said while presenting the bill to the House in February.
SB 154, by Sen. Tom Buford, R-Nicholasville, lets advanced practice registered nurses and physician assistants prescribe and supervise home-health services, as federal law has allowed them to do in the pandemic. An emergency clause ensures there would be no gap in care if the federal rule ended.
HB 448, sponsored by Rep. Bill Wesley, R-Ravenna, expands the definition of qualified mental-health professional so that it fits the states juvenile code, allowing those who work in private agencies to testify in child-welfare hearings, especially around issues of emotional injury.
SB 74, by Sen. Ralph Alvarado, R-Winchester,createsbut does not fund a dementia services coordinator in the heath cabinet to manage theAlzheimers Disease and Related Disorders Council, the state plan to address Alzheimers in Kentucky, and apply for federal funding.
HB 75, sponsored by Rep. Shawn McPherson, R-Scottsville, prohibits insurance companies from increasing rates on organ donors or dropping their coverage. It would also encourage the cabinet to develop educational materials relating to organ donation.
SB 163, sponsored by Sen. Alice Forgy Kerr, R-Lexington, expands the definition of charitable health care provider to include those that provide invasive or surgical procedures. This change was needed to allow the non-profit surgery program Surgery on Sunday in Lexington to be reimbursed for liability insurance premiums.
Beshear alsovetoed five billsthat would strip power from the governor or the executive branch. None were related to health.
(Kentucky Health Newsis an independent news service of the Institute for Rural Journalism and Community Issues, based in the School of Journalism and Media at the University of Kentucky, with support from the Foundation for a Healthy Kentucky.)
See more here:
Beshear ceremonially signs 13 health bills, including one that caps price of insulin - Hoptown Chronicle
Recommendation and review posted by Bethany Smith
A potential role for insulin treatment during pregnancy in reducing postpartum psychological distress in maternal obesity: an administrative…
Statistics Canada. Table 13-10-0096-01 Health characteristics, annual estimates. 2019. https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310009601. Accessed 27 Nov 2019.
Vinturache A, Moledina N, McDonald S, Slater D, Tough S. Pre-pregnancy Body Mass Index (BMI) and delivery outcomes in a Canadian population. BMC Pregnancy Childbirth. 2014;14:110.
Article Google Scholar
Wei YM, Yang HX, Zhu WW, Liu XY, Meng WY, Wang YQ, et al. Risk of adverse pregnancy outcomes stratified for pre-pregnancy body mass index. J Matern Neonatal Med. 2015;29:22059.
Article Google Scholar
Kulie T, Slattengren A, Redmer J, Counts H, Eglash A, Schrager S. Obesity and womens health: an evidence-based review. J Am Board Fam Med. 2011;24:7585.
PubMed Article PubMed Central Google Scholar
Steinig J, Nagl M, Linde K, Zietlow G, Kersting A. Antenatal and postnatal depression in women with obesity: a systematic review. Arch Womens Ment Health. 2017;20:56985.
PubMed Article PubMed Central Google Scholar
Cunningham SD, Mokshagundam S, Chai H, Lewis JB, Levine J, Tobin JN, et al. Postpartum depressive symptoms: gestational weight gain as a risk factor for adolescents who are overweight or obese. J Midwifery Womens Heal. 2018;63:17884.
Article Google Scholar
LaCoursiere DY, Barrett-Connor E, OHara MW, Hutton A, Varner MW. The association between prepregnancy obesity and screening positive for postpartum depression. BJOG. 2010;117:10118.
CAS PubMed Article PubMed Central Google Scholar
Schofield Z, Kapoor D. Pre-existing mental health disorders and pregnancy. Obstet Gynaecol Reprod Med. 2019;29:749.
Article Google Scholar
Binder EB, Newport DJ, Zach EB, Smith AK, Deveau TC, Altshuler LL, et al. A serotonin transporter gene polymorphism predicts peripartum depressive symptoms in an at-risk psychiatric cohort. J Psychiatr Res. 2010;44:6406.
PubMed Article PubMed Central Google Scholar
Galea LAM, Frokjaer VG. Perinatal depression: embracing variability toward better treatment and outcomes. Neuron. 2019;102:136.
CAS PubMed Article PubMed Central Google Scholar
Guille C, Newman R, Fryml LD, Lifton CK, Epperson CN. Management of postpartum depression. J Midwifery Womens Health. 2013;58:64353.
PubMed PubMed Central Article Google Scholar
Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res. 2004;114:397407.
CAS PubMed Article PubMed Central Google Scholar
Napso T, Yong HEJ, Lopez-Tello J, Sferruzzi-Perri AN. The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation. Front Physiol. 2018;9(AUG):139.
Google Scholar
Bridges RS. Neuroendocrine regulation of maternal behavior. Front Neuroendocrinol. 2015;36:17896.
CAS PubMed Article PubMed Central Google Scholar
Freemark M. Placental hormones and the control of fetal growth. J Clin Endocrinol Metab. 2010;95:20547.
CAS PubMed Article PubMed Central Google Scholar
Sonagra AD, Biradar SM, Murthy J. Normal pregnancya state of insulin resistance. J Clin Diagnostic Res. 2014;8:CC01-3.
Google Scholar
Kampmann U, Knorr S, Fuglsang J, Ovesen P. Determinants of maternal insulin resistance during pregnancy: an updated overview. J Diabetes Res. 2019;2019:19.
Article CAS Google Scholar
Sumption LA, Garay SM, John RM. Low serum placental lactogen at term is associated with postnatal symptoms of depression and anxiety in women delivering female infants. Psychoneuroendocrinology. 2020;116:104655.
CAS PubMed Article PubMed Central Google Scholar
Janssen AB, Capron LE, ODonnell K, Tunster SJ, Ramchandani PG, Heazell AEP, et al. Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3. Psychol Med. 2016;46:29993011.
CAS PubMed PubMed Central Article Google Scholar
Vakili H, Jin Y, Menticoglou S, Cattini PA. CCAAT-enhancer-binding protein (C/EBP) and downstream human placental growth hormone genes are targets for dysregulation in pregnancies complicated by maternal obesity. J Biol Chem. 2013;288:2284961.
CAS PubMed PubMed Central Article Google Scholar
Jin Y, Vakili H, Liu SY, Menticoglou S, Bock ME, Cattini PA. Chromosomal architecture and placental expression of the human growth hormone gene family are targeted by pre-pregnancy maternal obesity. Am J Physiol Endocrinol Metab. 2018;315:E43545.
CAS PubMed Article PubMed Central Google Scholar
Muralimanoharan S, Maloyan A, Myatt L. Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143. Clin Sci (Lond). 2016;130:93141.
CAS Article Google Scholar
Sibiak R, Jankowski M, Gutaj P, Mozdziak P, Kempisty B, Wender-Oegowska E. Placental lactogen as a marker of maternal obesity, diabetes, and fetal growth abnormalities: current knowledge and clinical perspectives. J Clin Med. 2020;9:1142.
CAS PubMed Central Article Google Scholar
Dam P, Cherubini K, Goveia P, Pena G, Galliano L, Faanha C, et al. Depressive symptoms in women with gestational diabetes mellitus: the LINDA-Brazil Study. J Diabetes Res. 2017;2017:7341893.
PubMed PubMed Central Article Google Scholar
Molyneaux E, Poston L, Ashurst-Williams S, Howard LM. Obesity and mental disorders during pregnancy and postpartum: a systematic review and meta-analysis. Obstet Gynecol. 2014;123:85767.
PubMed PubMed Central Article Google Scholar
Rogan SC, Payne JL, Meltzer-Brody S. Relationship between depressive mood and maternal obesity: implications for postpartum depression. In: Nicholson W, Baptiste-Roberts K, editors. Obesity during pregnancy in clinical practice. London: Springer; 2014. p. 99120.
Google Scholar
Azami M, Badfar G, Soleymani A, Rahmati S. The association between gestational diabetes and postpartum depression: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2019;149:14755.
PubMed Article PubMed Central Google Scholar
Roos LL, Brownell M, Lix L, Roos NP, Walld R, MacWilliam L. From health research to social research: privacy, methods, approaches. Soc Sci Med. 2008;66:11729.
PubMed Article PubMed Central Google Scholar
Jutte DP, Roos LL, Brownell MD. Administrative record linkage as a tool for public health research. Annu Rev Public Health. 2011;32:91108.
PubMed Article PubMed Central Google Scholar
Fryar CD, Kruszon-Moran D, Gu Q, Ogden C. Mean Body Weight, Height, Waist Circumference, and Body Mass Index Among Adults: United States, 19992000 Through 20152016. 2018. https://www.cdc.gov/nchs/data/nhsr/nhsr122-508.pdf. Accessed 27 Nov 2019.
Centers for Disease Control and Prevention. 2017 Data Release. National Health Interview Survey. 2017. https://www.cdc.gov/nchs/nhis/nhis_2017_data_release.htm. Accessed 27 Nov 2019.
Ghaedrahmati M, Kazemi A, Kheirabadi G, Ebrahimi A, Bahrami M. Postpartum depression risk factors: a narrative review. J Educ Health Promot. 2017;6:60.
PubMed PubMed Central Google Scholar
Gelaye B, Rondon MB, Araya R, Williams MA. Epidemiology of maternal depression, risk factors, and child outcomes in low-income and middle-income countries. Lancet Psychiatry. 2016;3:97382.
PubMed PubMed Central Article Google Scholar
Silverman ME, Reichenberg A, Savitz DA, Cnattingius S, Lichtenstein P, Hultman CM, et al. The risk factors for postpartum depression:a population-based study. Depress Anxiety. 2017;34:17887.
PubMed PubMed Central Article Google Scholar
Fransoo R, Mahar A, The Need to Know Team, Anderson A, Prior H, Koseva I, et al. The 2019 RHA Indicators Atlas. Winnipeg, Manitoba; 2019. http://mchp-appserv.cpe.umanitoba.ca/reference//RHA_Report_web.pdf. Accessed 27 Nov 2019.
Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science (80-). 2003;299:11720.
CAS Article Google Scholar
Lucas BK, Ormandy CJ, Binart N, Bridges RS, Kelly PA. Null mutation of the prolactin receptor gene produces a defect in maternal behavior. Endocrinology. 1998;139:41027.
CAS PubMed Article PubMed Central Google Scholar
Pawluski JL, Lonstein JS, Fleming AS. The neurobiology of postpartum anxiety and depression. Trends Neurosci. 2017;40:10620.
CAS PubMed Article PubMed Central Google Scholar
Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabetes Obes. 2011;18:40916.
CAS PubMed Article PubMed Central Google Scholar
Nicklas JM, Miller LJ, Zera CA, Davis RB, Levkoff SE, Seely EW. Factors associated with depressive symptoms in the early postpartum period among women with recent gestational diabetes mellitus. Matern Child Health J. 2013;17:166572.
PubMed Article PubMed Central Google Scholar
Putnick DL, Sundaram R, Bell EM, Ghassabian A, Goldstein RB, Robinson SL, et al. Trajectories of maternal postpartum depressive symptoms. Pediatrics. 2020;146:e20200857.
PubMed Article PubMed Central Google Scholar
Hinkle SN, Buck Louis GM, Rawal S, Zhu Y, Albert PS, Zhang C. A longitudinal study of depression and gestational diabetes in pregnancy and the postpartum period. Diabetologia. 2016;59:2594602.
CAS PubMed PubMed Central Article Google Scholar
Nyberg ST, Batty GD, Pentti J, Virtanen M, Alfredsson L, Fransson EI, et al. Obesity and loss of disease-free years owing to major non-communicable diseases: a multicohort study. Lancet Public Heal. 2018;3:4907.
Article Google Scholar
Edqvist J, Rawshani A, Adiels M, Bjrck L, Lind M, Svensson A-M, et al. BMI and mortality in patients with New-Onset Type 2 diabetes: a comparison with age- and sex-matched control subjects from the general population. Diabetes Care. 2018;41:48593.
PubMed Article PubMed Central Google Scholar
Kim SS, Zhu Y, Grantz KL, Hinkle SN, Chen Z, Wallace ME, et al. Obstetric and neonatal risks among obese women without chronic disease. Obstet Gynecol. 2016;128:10412.
PubMed PubMed Central Article Google Scholar
Scott-Pillai R, Spence D, Cardwell CR, Hunter A, Holmes VA. The impact of body mass index on maternal and neonatal outcomes: a retrospective study in a UK obstetric population, 20042011. BJOG. 2013;120:9329.
CAS PubMed Article PubMed Central Google Scholar
Shields M, Connor Gorber S, Tremblay MS. Estimates of obesity based on self-report versus direct measures. Heal Rep. 2008;19:6176.
Google Scholar
Gutin I. In BMI we trust: reframing the body mass index as a measure of health. Soc Theory Health. 2018;16:25671.
PubMed Article PubMed Central Google Scholar
Ortega FB, Sui X, Lavie CJ, Blair SN. Body mass index, the most widely used but also widely criticized index: would a criterion standard measure of total body fat be a better predictor of cardiovascular disease mortality? Mayo Clin Proc. 2016;91:44355.
PubMed PubMed Central Article Google Scholar
Bliddal M, Pottegrd A, Kirkegaard H, Olsen J, Srensen TIA, Nohr EA. Depressive symptoms in womens midlife in relation to their body weight before, during and after childbearing years. Obes Sci Pract. 2016;2:41525.
CAS PubMed PubMed Central Article Google Scholar
See the article here:
A potential role for insulin treatment during pregnancy in reducing postpartum psychological distress in maternal obesity: an administrative...
Recommendation and review posted by Bethany Smith
KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Significantly Improved Progression-Free Survival and Overall Survival Versus Chemotherapy in…
KENILWORTH, N.J. & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced the first presentation of investigational data from the pivotal Phase 3 KEYNOTE-775/Study 309 trial in an oral plenary session (Plenary Session #10191) at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Womens Cancer. The trial evaluated the combination of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for the treatment of certain patients with advanced, metastatic or recurrent endometrial cancer following one prior platinum-based regimen in any setting.
The study met the dual primary endpoints of progression-free survival (PFS), as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and overall survival (OS) as well as the secondary efficacy endpoint of objective response rate (ORR), as assessed by BICR per RECIST v1.1, in the all-comer population (mismatch repair proficient [pMMR] and mismatch repair deficient [dMMR]) and in the pMMR subgroup. Median follow-up was 11.4 months for both the all-comer population and the pMMR subgroup. A statistically significant and clinically meaningful improvement in PFS was seen in the all-comer population, in which KEYTRUDA plus LENVIMA (n=411) reduced the risk of disease progression or death by 44% (HR=0.56 [95% CI: 0.47-0.66]; p<0.0001), with a median PFS of 7.2 months (95% CI: 5.7-7.6; number of events=281) versus 3.8 months (95% CI: 3.6-4.2; number of events=286) for patients who received chemotherapy (treatment of physicians choice [TPC] of doxorubicin or paclitaxel; n=416). Additionally, a statistically significant and clinically meaningful improvement in OS was seen in the all-comer population, in which KEYTRUDA plus LENVIMA reduced the risk of death by 38% (HR=0.62 [95% CI: 0.51-0.75]; p<0.0001), with a median OS of 18.3 months (95% CI: 15.2-20.5; number of events=188) versus 11.4 months (95% CI: 10.5-12.9; number of events=245) for patients who received TPC. The safety profile of KEYTRUDA plus LENVIMA was generally consistent with the established safety profiles of the individual monotherapies.
Patients diagnosed with endometrial cancer, the most common type of gynecologic cancer in the U.S., face low survival rates when diagnosed at an advanced stage or at recurrence, especially once the disease progresses after prior platinum-based therapy and is not amenable to curative surgery or radiation, said Dr. Vicky Makker, Principal Investigator and Medical Oncologist, Memorial Sloan Kettering Cancer Center. With a 38% reduction in risk of death regardless of mismatch repair status, KEYTRUDA plus LENVIMA significantly improved overall survival compared with chemotherapy in the all-comer group of patients with advanced, metastatic or recurrent endometrial carcinoma, which is very encouraging, as this arm included an investigational patient population for which more data have been sought after by the gynecologic oncology community.
In the all-comer population, the secondary efficacy endpoint of ORR was 31.9% (95% CI: 27.4-36.6), with a complete response (CR) rate of 6.6% and a partial response (PR) rate of 25.3%, for patients who received KEYTRUDA plus LENVIMA versus 14.7% (95% CI: 11.4-18.4), with a CR rate of 2.6% and a PR rate of 12.0% for patients who received TPC (ORR difference versus TPC: 17.2 percentage points; p<0.0001). For patients who responded, the median duration of response (DOR) was 14.4 months (range: 1.6-23.7) for patients who received KEYTRUDA plus LENVIMA versus 5.7 months (range: 0.0-24.2) for patients who received TPC.
In this confirmatory Phase 3 study, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements in progression-free survival, overall survival and objective response rate versus chemotherapy, said Dr. Gregory Lubiniecki, Vice President, Oncology Clinical Research, Merck Research Laboratories. We are encouraged by these results that reaffirm Mercks and Eisais commitment to explore the potential of the combination to help more patients with difficult-to-treat types of cancer.
The positive results seen in KEYNOTE-775/Study 309 help confirm the currently approved use of the KEYTRUDA plus LENVIMA combination in certain patients with advanced endometrial carcinoma, said Dr. Takashi Owa, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. As this stage of disease has been notoriously difficult to treat, Eisai and Merck remain committed to addressing the unmet need of advanced endometrial carcinoma. We are grateful to the patients and healthcare providers whose participation and persistence amid a global pandemic have made this milestone possible.
Results were similar across the all-comer population and the pMMR subgroup. In the pMMR subgroup, KEYTRUDA plus LENVIMA reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI: 0.50-0.72]; p<0.0001), with a median PFS of 6.6 months (95% CI: 5.6-7.4; number of events=247) versus 3.8 months (95% CI: 3.6-5.0; number of events=238) for patients who received TPC. KEYTRUDA plus LENVIMA reduced the risk of death by 32% (HR=0.68 [95% CI: 0.56-0.84]; p=0.0001), with a median OS of 17.4 months (95% CI: 14.2-19.9; number of events=165) versus 12.0 months (95% CI: 10.8-13.3; number of events=203) for patients who received TPC. The secondary endpoint of ORR was 30.3% (95% CI: 25.5-35.5), with a CR rate of 5.2% and a PR rate of 25.1%, for patients who received KEYTRUDA plus LENVIMA versus 15.1% (95% CI: 11.5-19.3), with a CR rate of 2.6% and a PR rate of 12.5%, for patients who received TPC (ORR difference versus TPC: 15.2 percentage points; p<0.0001). For patients who responded, the median DOR was 9.2 months (range: 1.6-23.7) for patients who received KEYTRUDA plus LENVIMA versus 5.7 months (range: 0.0-24.2) for patients who received TPC.
In the all-comer population, in the KEYTRUDA plus LENVIMA arm (n=406), treatment-emergent adverse events (TEAEs) of any grade led to discontinuation of KEYTRUDA in 18.7% of patients, of LENVIMA in 30.8% of patients, and of both in 14.0% of patients. In the TPC arm (n=388), TEAEs of any grade led to discontinuation of chemotherapy in 8.0% of patients. Grade 5 TEAEs of any cause occurred in 5.7% of patients in the KEYTRUDA plus LENVIMA arm and in 4.9% of patients in the TPC arm. Grade 3 TEAEs occurred in 88.9% of patients in the KEYTRUDA plus LENVIMA arm and in 72.7% of patients in the TPC arm. In the KEYTRUDA plus LENVIMA arm, the most common TEAEs of any grade occurring in at least 25% of patients were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), decreased appetite (44.8%), vomiting (36.7%), weight decrease (34.0%), fatigue (33.0%), arthralgia (30.5%), proteinuria (28.8%), anemia (26.1%), constipation (25.9%) and urinary tract infection (25.6%). In the TPC arm, the most common TEAEs of any grade occurring in at least 25% of patients were anemia (48.7%), nausea (46.1%), neutropenia (33.8%), alopecia (30.9%), and fatigue (27.6%). Median treatment duration was 231 days (range: 1-817) with KEYTRUDA plus LENVIMA and 104.5 days (range: 1-785) with TPC.
KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the U.S. Food and Drug Administrations (FDA) 2019 accelerated approval of the KEYTRUDA plus LENVIMA combination for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.
KEYNOTE-775/Study 309 Trial Design (Plenary Session #10191)
KEYNOTE-775/Study 309 is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT03517449) evaluating KEYTRUDA in combination with LENVIMA in patients with advanced endometrial cancer following one prior platinum-based regimen in any setting. The dual primary endpoints are PFS, as assessed by BICR per RECIST v1.1, and OS. Select secondary endpoints include ORR, as assessed by BICR per RECIST v1.1, and safety/tolerability. Of the 827 patients enrolled, 697 patients had tumors that were pMMR, and 130 patients had tumors that were dMMR. Patients were randomized 1:1 to receive:
About Endometrial Cancer
Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. In 2020, it was estimated there were more than 417,000 new cases and more than 97,000 deaths from uterine body cancers worldwide (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be more than 66,000 new cases of uterine body cancer and nearly 13,000 deaths from the disease in 2021. The five-year survival rate for metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.
About KEYTRUDA (pembrolizumab) Injection, 100 mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
Tumor Mutational Burden-High
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA with Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.
Immune-Mediated Dermatologic Adverse Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.
See original here:
KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Significantly Improved Progression-Free Survival and Overall Survival Versus Chemotherapy in...
Recommendation and review posted by Bethany Smith
West Virginians considering abortion need good information about the procedure; bill might keep them from getting the facts – Beckley Register-Herald
While some people whove had abortions in West Virginia regret them, and others say those decisions were best for them, they agree on the importance of accurate information.
But a bill working its way through the West Virginia Legislature would require health care professionals to provide them with one piece of information that isnt supported by research and could amount to, in the words of one state medical group, unmonitored experimentation on West Virginians seeking abortions.
Under House Bill 2982, those people would hear that it may be possible to stop a medical abortion after taking the first of two pills required for such an abortion. The bill doesnt require they be told that the assertion isnt supported by research, that its based on taking a medication that isnt approved by the U.S. Food and Drug Administration for the purpose of stopping abortions, or about the potential harm of attempting to stop an abortion.
Supporters of the bill, including some people whove had abortions, say the bill is needed because some women have regrets after beginning the procedure.
Opponents of the bill, also including people whove had abortions, say that its important for people seeking abortions to understand theyre making permanent decisions.
The bill, if it becomes law, would tell people they dont have to make a decision, that they can be wishy-washy about it, said Hunter Starks, who had an abortion while in an abusive relationship.
And you cant, Starks said. You have to make that decision, whether thats easy or hard for you. You have to make that decision.
Starks, a transgender non-binary person, said if they hadnt had that abortion, they would have been tied to that abuser for life.
Opponents of the bill also warn that its based on the unproven idea that taking progesterone after the first pill in a medication abortion can reverse the process. They note the FDA has not approved progesterone for this use, and that limited research suggests patients health and safety could be put at risk.
What does the bill do?
When a patient seeks a medical abortion, health care providers provide them with two pills. Mifepristone, the first pill, blocks the hormone progesterone. This thins the uterine lining, so the embryo wont stay implanted and continue growing. Misoprostol, the second pill, causes the uterus to contract and expel the embryo through the vagina.
The original version of House Bill 2982, sponsored by Delegate Kayla Kessinger, R-Fayette, said that providers had to tell patients that their abortion could be reversed. Lawmakers in the House of Delegates Health and Human Resources Committee changed that wording last week, so the bill now would require health care providers to tell patients that it may be possible to stop an abortion.
Delegate Todd Longanacre, R-Greenbrier and a bill co-sponsor, said the bill would help a young lady [who] realizes the error of her ways, by taking that first pill to terminate a babys life.
Its an opportunity for that young lady who may have, in a knee-jerk, emotional state-of-mind decided to take an RU-486 pill, and then woke up the next morning and thought, Oh, my gosh, what have I done? he said. This is her opportunity to save that babys life.
Its not a perfect bill, Longanacre said. But you know what, an old general from the World War II era once said and that guys name was General Patton he said a less-than-perfect plan violently executed now is better than the perfect plan executed next week. People are dying; babies are dying. This is an opportunity to save lives.
House Bill 2982 is based on the unproven idea that taking progesterone after the first pill will reverse its effects.
Research on progesterone for this use is so weak, according to a statement from the West Virginia American College of Obstetricians and Gynecologists chapter, that administering it to patients in an effort to reverse or stop abortions potentially subjects women to unmonitored experimentation, which is in direct violation of a physicians oath to care.
The bill is supported by West Virginians for Life and the National Right to Life Committee. It is opposed by both the national and West Virginia chapters of the American College of Obstetricians and Gynecologists, Planned Parenthood and the state-level reproductive rights group, WV Free.
Democrats in the House committee last week noted that a study on the effectiveness of progesterone in stopping an abortion mid-procedure was halted early because several women experienced severe bleeding, possibly because they had taken the first pill but not the second.
Researchers aimed to determine whether progesterone could be used to reverse the effects of mifepristone, preventing pregnancy termination, but three patients experienced severe hemorrhaging and had to be taken to the hospital, according to the study, published in a 2019 edition of Obstetrics & Gynecology, the official publication of the American College of Obstetricians and Gynecologists.
Delegate Barbara Fleischauer, D-Monongalia, wanted to amend the bill in committee to warn patients about possible side effects, but that amendment was rejected.
Delegate Ric Griffith, D-Wayne and a pharmacist who said he is anti-abortion, was concerned enough to oppose the bill, saying he worried taking the first pill, but not the second, could lead to birth defects.
In our desire to protect the unborn, we are potentially causing harm to the unborn, he said.
No medical professionals were called to testify during the meeting.
Karen Cross, who is from West Virginia and lobbies for the National Right to Life Committee, was present but did not testify.
Ive had two abortions, and I regret mine, Cross said in an interview following the meeting. I know so many women, who are involved in the pro-life movement even, actively, because of the decision they made to abort their children, so that they can help other women not make that mistake.
Delegate Heather Tully, R-Nicholas and an anti-abortion family nurse practitioner, voted for the bill during that meeting, but said in an interview that she did have concerns.
I would be very concerned about a non-approved FDA medication, but obviously, this procedure has been done in some places, maybe not necessarily within the state of West Virginia, or within the confines of the border, she said.
Tully, who noted that she doesnt work in reproductive medicine, said abortion pills also come with risk. Shes had patients change their minds about other procedures, she said. And patients have a right to withdraw consent, she noted.
I think that this bill, it really quite honestly strengthens the informed consent process for a patient that may change their mind, she said.
Ten states have passed similar legislation, and others are working on their own bills, according to Cross. Courts have blocked implementation in several states. Six states have the law in place, according to a March 1 statement from the pro-abortion rights Guttmacher Institute.
The House of Delegates Judiciary Committee, where delegates would normally discuss the legality of bills, passed the bill with no discussion of those court cases Thursday.
The bill is up for second reading in the House on Tuesday, during which time delegates may offer amendments. Its tentatively scheduled for a final House vote on Wednesday, and would then have to pass the state Senate and get the approval of Gov. Jim Justice to become law.
Lived experiences
While some West Virginians whove had abortions made the right decision for them and others have regrets, several people interviewed agreed on the important of being informed.
But while the bill does require doctors to tell patients about an option, it doesnt tell them anything about the lack of research supporting that option and the potential harmful effects of it.
Suzi Bragg, of Morgantown, still supports the bill. She regrets her two abortions, and would rather anti-abortion lawmakers become involved than rely on doctors.
Im 63 and to this day, I do not trust when doctors tell me things, she said.
Bragg said when she was 16 and in foster care, a young man blackmailed her into sex. She said her social workers took her to Pittsburgh for the abortion when she was about 18 weeks pregnant.
She said they injected saline into her abdomen, which was extremely painful, and held her down when she yelled for them to stop. She said the experience was extremely traumatic, because I wasnt told the truth about what would occur.
She said she was told the experience would be no more painful than menstrual cramps, and the fetus was a clump of cells. She didnt realize until seeing a Newsweek magazine later on that a fetus is more developed than that at about 18 weeks.
I remember just screaming, They lied to me, she said.
Bragg said she went on to develop post-traumatic stress disorder. She didnt want to eat. She didnt want to socialize with friends. She said the trauma was due in part to being coerced into both the act of sex, and the abortion. During a second abortion in her 20s, she declined pain medication. She felt like she deserved the pain.
Back then, information about abortion was less readily available to women, she said.
Hunter Starks, of Charleston, was 19 and in an abusive relationship when they sought their first of two abortions in 2012.
Starks, who was assigned female at birth, took pain pills for the first abortion, which was medical, so pain wasnt significant, they said, and they experienced no pain for the second, which was surgical.
Starks said they were in a fragile mindset at the time and it was mainly their partners decision, but they still dont regret the choice.
While Longanacre, the bill co-sponsor, said some abortions may be knee-jerk reactions, ACOG-WV and some West Virginians whove had abortions say the bill itself would actually encourage people to see abortion as something they dont have to be sure about.
In their statement, leaders of the state OB/GYN group wrote that if the bill becomes law, it would create an environment of confusion and stigma.
Starks already felt confused and scared going into the abortion, without doctors telling them that the decision could be stopped or reversed.
Everyone should have agency over their own decisions with their body, and doctors shouldnt be making that any more confusing or difficult, they said.
Starks does regret one thing going to the clinic alone. Protestors screamed and name-called.
Maggie McCabe, whose mother worked to start the last remaining abortion clinic in West Virginia, the Womens Health Center in Charleston, was 16 when her mother flew her to Washington, D.C., for an abortion in the days before the U.S. Supreme Court legalized abortion in its Roe v. Wade decision in 1973.
A professor at BridgeValley Community and Technical College who worked for a health insurance provider for 28 years, McCabe was just getting ready to start her life.
She said she wouldnt have wanted wishy-washy information when seeking an abortion, and said patients deserve concrete, appropriate information.
My abortion had no negative effect on me, she said. Its made me a stronger woman, because I believe in helping others in any way that I can. Telling my story is my contribution to helping other women in their decisions.
McCabe, of Charleston, criticized lawmakers for involving themselves in health care decisions and called abortion bills a form of sex discrimination.
She noted people with fewer resources and less support couldnt have flown to D.C., like she did.
The right-to-lifers are using a very offensive, very un-Christian campaign to keep women oppressed, and to keep women in a lower class controlled, she said.
Jamie Miller, an abortion rights advocate who lives in South Charleston, was almost 17 when she received an abortion.
She had already gotten approval from a mental health professional for the abortion to avoid telling her family, and saved up money.
Miller said if after all that, she arrived at her appointment and providers told her the process could be stopped or reversed, she would have wondered whether she could trust them and if she needed to attempt a possibly deadly abortion on her own.
I would have felt like they werent on my side, she said.
We are making critical coverage of the coronavirus available for free. Please consider subscribing so we can continue to bring you the latest news and information on this developing story.
Here is the original post:
West Virginians considering abortion need good information about the procedure; bill might keep them from getting the facts - Beckley Register-Herald
Recommendation and review posted by Bethany Smith
BV Isn’t a Sign of Cheating Here’s Why – Healthline
Although many people think otherwise, bacterial vaginosis (BV) isnt a sexually transmitted infection (STI).
Any person who has a vagina can develop it, and there are a number of factors that may lead to such an infection.
Yes, exposure to a new sexual partner is one of them. But the list also includes things like smoking and douching.
So theres no way that anyone can definitively say BV is linked to cheating.
No, BV isnt considered to be an STI even though some people have reported being told this by a clinician.
The confusion likely comes from the fact that BV can be associated with sexual activity.
For example, penetrative sexual activity can affect the natural bacterial balance in your vagina, leading to extra bacterial growth and eventually BV.
But theres little evidence that the infection can be passed between people through sexual contact, so it isnt on the STI list.
However, BV can increase your chances of contracting an STI, as the bacterial changes may lower the vaginas natural defenses.
The exact cause of BV is unknown, but its characterized by an unbalanced bacterial balance in the vagina.
However, experts have found a number of factors that may increase your risk of developing it.
This includes anything that affects the vaginas pH levels, such as douching or using irritating vaginal products.
Youre also more likely to develop BV if:
Unfortunately, there isnt an easy answer to this. Theres still much more for researchers to learn about the infection.
From using an IUD as contraception to taking up smoking or even changing the way you clean your genital area, all of these factors can lead to BV.
Because of this, theres a chance that you may not know why or even when youve suddenly developed it.
BV can go away on its own after a few days.
But if you need medical treatment, youll likely have to take a weeklong course of antibiotics. If the infections persistent, your provider may prescribe a second round.
Half of people with BV dont have any symptoms, so you may have little to deal with.
But strong-smelling vaginal discharge and irritation when urinating are typical symptoms of the infection.
Although you should seek medical advice from a doctor or other healthcare professional, you can try the following at home to lessen symptoms:
If your partner has a penis, its unlikely that theyll need treatment.
But the infection can be passed between people who have vaginas.
So if your partner has a vagina, its worth seeking medical advice for the both of you.
As doctors arent sure how bacterial vaginosis occurs or spreads, its hard to say how to prevent a recurring infection.
But there are a few simple steps you can take to help reduce your risk of developing a second bout of BV. (Most of these steps are similar to the ones you may have taken to relieve symptoms at home.)
First, its advisable to avoid putting anything that may cause irritation in or around your vagina.
This includes douches, deodorants, and perfumed cleansing products.
Instead, use water and plain soap to clean the area, sticking to showers rather than baths where possible.
When it comes to your underwear, stick to breathable, moisture-wicking fabrics, such as cotton, to avoid unwanted bacterial growth.
And wash underwear using a mild detergent, rather than a strong formula.
Finally, when having intercourse or any kind of sexual activity, ensure sex toys are clean before contact and use condoms or dental dams.
Unfortunately, recurrence is quite common, but it wont hurt to follow the above tips.
If youre worried about STIs, its better to book a test to put your mind at rest.
Symptoms to look out for include:
Thinking that your partner has been unfaithful is a little more complex.
Its natural to want to confront them, but try to take some time to think things through.
After all, your worries could be nothing more than a misunderstanding.
If you do want to speak with your partner, its often a good idea to write down the kinds of things you want to say beforehand.
You may also want to think about whether youd like to try and move forward if it turns out they have been unfaithful, or whether the relationship will have to end.
Speaking with a neutral person who has little connection to you or your partner can also help you get things straight.
When youre ready to talk, let your partner know that youd like to discuss something thats concerning you.
Try to set the conversation up in an environment that suits the both of you, whether thats in private or in public.
Start off by talking about how much the relationship means to you, as well as honesty and trust.
You can then say that you feel there might be a problem in the relationship, bringing up specific examples if needed.
Try not to be accusatory and listen to what your partner has to say. But if something doesnt feel right, dont be afraid to press them on it.
If the shoes on the other foot and your partner thinks that youre the guilty party, try to stay calm.
We tend to get defensive when were being confronted with something thats not true.
But try to put yourself in their shoes and realize that theyre likely only acting this way because they care about the relationship.
Let them talk through the issue and then attempt to understand why they think the way they do.
For example, have you been paying them less attention than usual?
Or is there something going on in their life that could be affecting their emotional state?
I hear you is a good way to start off your end of the conversation. It lets them know that youre listening and understanding where theyre coming from.
At the same time, dont be afraid to let them know if theyve upset you with such an accusation. Remember, its important for both of you to be open and honest.
Asking if youre able to move past the issue is often a good way to end things.
Itll leave you both with an understanding of where youre currently at and clear steps to take to improve the relationship if needed.
If their concern is about contracting an STI, explain that BV isnt an STI. And if theyd still like an STI test, be supportive.
Offer to go with them and get one too if youre comfortable doing so.
Most doctors recommend booking an appointment if you think you have BV, even though it can go away on its own.
This is because, if left untreated, BV can lead to pregnancy complications, pelvic inflammatory disease, or an increased risk of STIs.
So any unusual discharge, itching, burning, swelling, or soreness around the genital area warrants a call.
A healthcare professional can test vaginal discharge and fluid for the infection and prescribe the right treatment, if necessary.
Treatment usually involves a course of antibiotics, either in a pill, capsule, or cream form.
Although much more research is needed into BV, the infection is most definitely not a clear-cut sign of cheating.
So if you or a partner do experience it, try not to blame yourself or others. The cause may have nothing to do with your sex life.
Lauren Sharkey is a U.K.-based journalist and author specializing in womens issues. When she isnt trying to discover a way to banish migraines, she can be found uncovering the answers to your lurking health questions. She has also written a book profiling young female activists across the globe and is currently building a community of such resisters. Catch her on Twitter.
Originally posted here:
BV Isn't a Sign of Cheating Here's Why - Healthline
Recommendation and review posted by Bethany Smith
Qualigen Therapeutics, Inc. to present at the Benzinga Biotech Small Cap Conference – GlobeNewswire
CARLSBAD, Calif., March 18, 2021 (GLOBE NEWSWIRE) -- Qualigen Therapeutics, Inc. (NASDAQ: QLGN), a biotechnology company focused on developing novel therapeutics for the treatment of cancer and viral diseases, announced today that Michael Poirier, President, Chief Executive Officer and Chairman of Qualigen, and Amy Broidrick, EVP, Chief Strategy Officer will present on March 24, 2021 at the Benzinga Biotech Small Cap Conference being held March 24-25, 2021.
Qualigen Therapeutics, Inc. Presentation Details are as follows:
Investors and others invited to attend this conference event may request one-on-one meetings with representatives of the Company through the respective conference hosts or via email to Tony Schor, tony@investorawareness.com or David Kugelman, dk@atlcp.com.
About Qualigen Therapeutics, Inc.
Qualigen Therapeutics, Inc. is a biotechnology company focused on developing novel therapeutics for the treatment of cancer and infectious diseases, as well as maintaining and expanding its core FDA-approved FastPack System, which has been used successfully in diagnostics for 20 years. The Company's cancer therapeutics pipeline includes ALAN (AS1411-GNP), RAS-F and STARS. ALAN (AS1411-GNP) is a DNA coated gold nanoparticle cancer drug candidate that has the potential to target various types of cancer with minimal side effects. The foundational nucleolin-targeting DNA aptamer of ALAN, AS1411, is also a drug candidate for use in treating COVID-19 and other viral-based infectious diseases. RAS-F is a family of RAS oncogene protein-protein interaction inhibitor small molecules for preventing mutated RAS genes proteins from binding to their effector proteins; preventing this binding could stop tumor growth, especially in pancreatic, colorectal and lung cancers. STARS is a DNA/RNA-based treatment device candidate for removal from circulating blood of precisely targeted tumor-produced and viral compounds.
Because Qualigen's therapeutic candidates are still in the development stage, Qualigen's only products that are currently commercially available are FastPack System diagnostic instruments and test kits, used in physician offices, clinics and small hospitals around the world. The FastPack System menu includes rapid point-of-care diagnostic tests for cancer, men's health, hormone function, vitamin D status and antibodies against SARS-CoV-2. Qualigen's facility in Carlsbad, California is FDA and ISO Certified and its FastPack product line is sold worldwide by its commercial partner Sekisui Diagnostics, LLC.
For more information on Qualigen Therapeutics, Inc., please visit https://www.qualigeninc.com/.
Forward-Looking Statements
This news release contains forward-looking statements by the Company that involve risks and uncertainties and reflect the Company's judgment as of the date of this release. Actual events or results may differ from the Companys expectations. For example, there can be no assurance that any clinical trials will be approved to begin by or will proceed as contemplated by any projected timeline; that the Company will successfully develop any drugs or therapeutic devices; that preclinical or clinical development of the Company's drugs or therapeutic devices will be successful; that future clinical trial data will be favorable or that such trials will confirm any improvements over other products or lack negative impacts; that any drugs or therapeutic devices will receive required regulatory approvals or that they will be commercially successful; that patents will issue on the Companys owned and in-licensed patent applications; that such patents, if any, and the Companys current owned and in-licensed patents would prevent competition; that the Company will be able to procure or earn sufficient working capital to complete the development, testing and launch of the Companys prospective therapeutic products; that the Company will be able to maintain or expand market demand and/or market share for the Companys diagnostic products generally, particularly in view of COVID-19-related deferral of patients physician-office visits and FastPack reimbursement pricing challenges; that adoption and placement of FastPack PRO System instruments (which are the only FastPack instruments on which the Company's SARS-CoV-2 IgG test kits can be run) will be widespread; that the Company will be able to manufacture the FastPack PRO System instruments and SARS-CoV-2 IgG test kits successfully; that any commercialization of the FastPack PRO System instruments and SARS-CoV-2 IgG test kits will be profitable; or that the FDA will ultimately approve an Emergency Use Authorization for the Companys SARS-CoV-2 IgG test. The Companys stock price could be harmed if any of the events or trends contemplated by the forward-looking statements fails to occur or is delayed or if any actual future event otherwise differs from expectations. Additional information concerning these and other risk factors affecting the Company's business (including events beyond the Company's control, such as epidemics and resulting changes) can be found in the Company's prior filings with the Securities and Exchange Commission, available at http://www.sec.gov. The Company disclaims any intent or obligation to update these forward-looking statements beyond the date of this news release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.
Investor Relations:
David Kugelman, President and CEOAtlanta Capital Partners, LLC(404) 856-9157 Office(866) 692-6847 Toll Free - U.S. & Canadadk@atlcp.com
Tony Schor, PresidentInvestor Awareness, Inc.(847) 971-0922tony@investorawareness.com
See the rest here:
Qualigen Therapeutics, Inc. to present at the Benzinga Biotech Small Cap Conference - GlobeNewswire
Recommendation and review posted by Bethany Smith
Minoxidil and Shedding: Why it Happens and What to Expect – Healthline
Minoxidil (Rogaine) is a popular product for people with thinning hair. The product comes as a gel or a foam, and is meant to be applied topically to your scalp on a daily basis.
When people first start using minoxidil to restore their hair, some notice that they actually start losing more of it at least for a short period of time.
There are plenty of clinical trials and medical evidence that support the use of minoxidil for moderate hair loss caused by alopecia. But how do you know if its actually working, especially if it looks like youre losing more hair than before?
Lets cover hair loss caused by Rogaine so you can understand how common it is, what causes it, and whether you should be concerned.
Minoxidil was a drug originally developed to treat hypertension.
Researchers observed that people who had alopecia and used minoxidil for hypertension experienced hair regrowth, and the worlds most popular over-the-counter treatment for alopecia was born. People have been using minoxidil to treat hair loss since 1986.
The way that minoxidil works isnt completely clear. Whats apparent is that minoxidil decreases hair loss in some people while also increasing hair growth. It doesnt work for everyone.
Minoxidil is also classed as a vasodilator, meaning that it dilates your blood vessels so that blood flows more easily where its applied. An increase in blood circulation to your scalp could be part of why minoxidil increases hair growth.
Your hair follicles go through four phases of growth. Not every follicle is in the same phase at once. Minoxidil is believed to affect two stages of hair growth.
The anagen phase of hair growth is its growing phase. This is when the hair is being pushed out from the root. Applying minoxidil may extend the length of the anagen phase.
The telogen phase of your hair is its resting phase, when its done growing but not yet ready to fall out. In clinical trials on rats, minoxidil shortened the telogen phase of hair from 20 days to 1 to 2 days.
Minoxidils side effects are typically mild. Common side effects include mild itching and burning as well as flaky skin. Minoxidil can also cause your hair to shed, especially when you first start using it.
As minoxidil speeds up the resting phase of your hair, sometimes it falls out more quickly than it normally would.
However, minoxidil also extends the growth phase of your hair. That means that even though some hair shedding is to be expected at first, new hair growth should soon replace the hair that youve lost.
Not everyone will experience shedding as a side effect of minoxidil, while some may experience it severely. There arent statistics currently available that explore how common this particular side effect is.
You cant do much to prevent minoxidil-related shedding or even predict if youll experience it when you first start using the product.
One thing to be aware of is that the higher the concentration of minoxidil you use, the more powerful the side effect is likely to be. Using a foam with 2 percent concentration of minoxidil, for example, could cause fewer side effects than with a 5 percent concentration.
If youre seeing a lot of hair loss, you might want to switch to a less powerful dose of minoxidil. If youre concerned about hair loss and havent started using minoxidil yet, start with a lower concentration and work up to a higher one if you need it.
Results of minoxidil vary from person to person. Generally speaking, it takes about 8 weeks of consistent use to start to see results with minoxidil. After 4 months of use, you should start to see the end of hair loss and start to see hair growth.
If its been 4 months and youre still seeing hair shedding, it may not be related to minoxidil. Its also possible that minoxidil isnt the right product for you. If you see a lot of your hair falling out after 4 months of use, speak with your doctor about alternative treatments.
Minoxidil does have some other side effects in addition to hair shedding. Side effects may include:
If youre experiencing strong side effects as a result of minoxidil, call your doctor and discontinue use.
If youve been using minoxidil for several weeks and youre still seeing more hair loss than growth, see your primary care doctor or a dermatologist. They may be able to determine if hair loss is being caused by another underlying health condition.
You should always seek medical attention if you experience the following:
Some shedding is normal when you start using any topical product that contains minoxidil. If youre concerned about hair loss, this might be alarming, but its typically no cause for concern.
If shedding doesnt stop within 4 months of starting a hair regimen with minoxidil, discontinue use and speak with your doctor about other hair regrowth options.
See more here:
Minoxidil and Shedding: Why it Happens and What to Expect - Healthline
Recommendation and review posted by Bethany Smith