Archive for the ‘Hormone Clinic’ Category

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

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Multimodal Care Is Key Focus at Breast Cancer Conference - Targeted Oncology

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.

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Freezing Sperm: Cost, Effectiveness, and More - Healthline

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

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

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.

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[Full text] A Review of Modifiable Risk Factors in Young Women for the Prevention | BCTT - 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.

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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

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[Full text] Prognostic value of TP53 mutation location in breast cancer | CMAR - Dove Medical Press

How much a penis extends in length while erect varies from person to person. It may also change over time and with age. However, there is no evidence to suggest this affects an individuals health or sex life.

A shower or grower refers to how much a penis expands in length when erect compared with its flaccid state.

This article explores the science behind the terms, how common they are, and whether being a shower or a grower has any significant impact on health and sex life.

According to the popular colloquialism, a shower is a person with a penis that does not expand relatively significantly in length when it becomes erect.

In contrast, a grower is a person with a penis that grows relatively significantly longer when erect.

The erectile tissue of the penis comprises:

All of these allow the penis to become erect.

However, with age, the penis can lose tissue elasticity, which may affect how it stretches.

People may also experience inflammation and less blood flow to the penis as they age, which can affect erection.

A 2018 study involving 274 males found that age played a role in whether participants were a grower or a shower.

The researchers defined a grower as having a flaccid to erect penile length increase of 4 centimeters (cm) or more, while an increase of less than 4 cm indicated that a person was a shower.

All of the participants had previously undergone penile duplex ultrasound (PDDU) for erectile dysfunction.

Researchers measured flaccid penile length and gave participants a vasodilation drug before measuring erect penile length.

Growers had an average length change of 5.3 cm, while showers had an average length change of 3.1 cm. The mean age of the growers was 47.5 years, compared with an average of 55.9 years in the showers.

The research also reported that 37% of males who fell into the grower category were single, compared with 23% in the showers category, although this may also relate to age.

Growers also had a lower dose of the vasodilation drug.

There were no differences in the showers or growers regarding:

The study notes that confirming these findings requires more research, including larger scale, multicultural, and multinational studies.

The research did find an age difference between growers and showers. According to the International Society for Sexual Medicine, the way the penis changes as people age may account for this age differentiation.

The 2018 study found that out of 274 participants, 73 males (26%) were growers, while 205 males (74%) were showers, according to the researchers criteria on flaccid to erect penis length.

This suggests that showers may be more common, but there is not enough evidence to reflect the whole population.

Further studies are needed to confirm the findings.

People may be able to tell if they are a shower or grower without any tests.

If people have a penis that does not significantly change size between a flaccid and erect state, they may be a shower.

In contrast, if an individuals penis size changes drastically between a flaccid and erect state, they may be a grower.

People can measure their penis when flaccid, from the base to the tip. They can then take the same measurement when their penis is erect.

If the difference between the two measurements is greater than 4 cm, people meet the definition of a grower.

However, if the difference is less than 4 cm, people meet the definition of a shower.

The 2018 study found that age was the main factor in whether people were a grower or a shower, which suggests that people may change between a grower and a shower as they age.

When people age, collagen and elastic fibers in the penis decrease, which may affect whether they are a shower or grower.

Other penis changes can also happen as people age. Testosterone levels start to decline after a person reaches 40 years of age, which can cause the penis to shrink slowly.

Health conditions that impair blood flow can also affect penis color and erection.

According to the Kinsey Institute, flaccid penis size is not a reliable indicator for its erect size.

Generally, shorter flaccid penile lengths enlarge by a greater percentage than longer flaccid penile lengths.

The 2018 study found that growers had a larger erect penis size, measuring 15.5 cm compared with 13.1 cm in the showers group.

There is no research to suggest whether being a shower or a grower impacts a persons sex life.

However, concerns about penis appearance may affect sexual activity.

A 2016 survey looked at genital dissatisfaction in 4,198 males aged 1865 years and living in the United States.

Participants reported the lowest satisfaction with flaccid penile length, with 27% reporting dissatisfaction. Different demographics had no bearing on survey answers.

Those who reported dissatisfaction with their genitals reported less sexual activity, including less vaginal sex and less receptive oral sex.

If a person has concerns that their penis appearance is affecting their self-esteem, confidence, or sex life, people may find it helpful to talk with their partner or healthcare professional.

Being a shower or a grower refers to the change in penis length from a flaccid to erect state.

If people have a penis that increases significantly in length from a flaccid to erect state, they may be a grower. If there is no significant change, they may be a shower.

Some research suggests being a shower or a grower relates to age. Therefore a persons category may change over time.

However, there is no evidence to suggest that being a shower or grower affects their health or sex life.

Link:
Shower vs grower: What is the difference and does it really matter? - Medical News Today

The Scottish Medicines Consortium (SMC) has accepted Takedas PROSTAP SR DCS & PROSTAP 3 DCS (leuprorelin acetate) for use in patients with early breast cancer and advanced breast cancer.1,2,*,

Leuprorelin acetate belongs to a family of drugs called gonadotrophin-releasing hormone (GnRH) agonists which is used as adjuvant treatment in combination with tamoxifen or an aromatase inhibitor for endocrine responsive early-stage breast cancer and in advanced breast cancer suitable for hormone manipulation. In patients with breast cancer cells that have oestrogen receptors (ER) about 70% of cases of breast cancer3 it is important to lower the levels of oestrogen in the body to stop the cancer cells from growing.

Leuprorelin acetate works by suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH) and offers an additional treatment choice as its dosing regimen means that suitable patients with early-stage breast cancer require four clinic visits a year, up to 13 visits a year as with other GnRH agonists licenced for breast cancer.

GnRH agonists are an important part of treatment for women with oestrogen receptor positive breast cancer. In patients with early breast cancer, the combination of (GnRH) agonists with the peripheral oestrogen antagonist, tamoxifen results in a significant benefit in recurrence-free survival and overall survival, while the regime in those with advanced breast cancer has been shown to prolong progression-free survival.4

Dr Roger Henderson, GP in Dumfries and Galloway, said: As a GP I find that being able to use PROSTAP 3 DCS in women with early breast cancer helps to reduce both the number of times a woman with early breast cancer needs to visit the hospital and the stress associated with these, while maintaining efficacy of treatment.

References

1 https://www.medicines.org.uk/emc/product/4650/smpc

2 https://www.medicines.org.uk/emc/product/4651/smpc

3 ttps://www.cancerresearchuk.org/about-cancer/breast-cancer/treatment/hormone-therapy

4 https://pubmed.ncbi.nlm.nih.gov/12706354/#:~:text=GnRH%20agonists%20have%20been%20shown,produce%20combined%20oestrogen%20blockade

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Positive decision from SMC on Takeda's breast cancer treatment - Pharmafield

Jim Shanahan from SynDevRx explains why metabo-oncology treatment modalities could be the answer to a rise in metabolic disorders and cancers.

The global pandemic of metabolic disorders such as obesity and diabetes combined with an ageing population is leading to an upcoming tsunami of cancers, according to Jim Shanahan, Co-Founder, Vice President of Business Development and Director of SynDevRx.

Some cancers, such as breast, colon, liver, prostate and certain parts of lung, are sensitive to dysregulated metabolic hormones. In an interview with Drug Target Reviews Victoria Rees, Shanahan highlighted that metabolic hormone signalling pathways could be exploited to treat these cancers, including with SynDevRxs lead molecule, SDX-7320.

Shanahan began by explaining that the metabolic hormones insulin, leptin and adiponectin are the three primary signalling molecules that work through well understood cancer signalling pathways. Insulin primarily signals through the PI3K/AKT/mTOR pathway, leptin through the MAPK and JAK2-STAT3 pathways, while adiponectin is an agonist of the cyclic adenosine monophosphate pathway (cAMP) and protects against the phosphorylation and activation of notch signalling.

While these pathways have been thoroughly researched and described in many peer-reviewed research papers, Shanahan emphasised that how these externalities affect cancer growth and outcomes have been underappreciated.

Cancer looks for external signals that indicate there is sufficient energy for the cell to replicate. That is where the PI3K/AKT/mTOR pathway, the JAK-STAT pathway and other pathways come in, he said, as aberrant signalling by dysregulated hormones stimulates these pathways.

Having developed a lead molecule to fulfil this unmet need for oncology and metabolic disorders, Shanahan explained that SDX-7320 is in the fumagillin class of methionine aminopeptidase 2 (MetAP2) inhibitors. He explained that fumagillin is a naturally occurring biomass from the fungus named Aspergillus fumigatus Fresenius.

This was discovered by accident in the lab of Dr Judah Folkman in the mid-1980s a researcher named Dr Don Ingber had a contamination in one of his angiogenesis experiments that lead to the discovery. When he returned to the lab after the weekend, he found that there was a part of the dish that was clear of blood vessels. He was then able to isolate fumagillin and realised this could be a potential drug.

Working with Takeda in the 1990s, they developed a drug called TNP-470 that went into the clinic as an anticancer agent and demonstrated promising antitumour efficacy. However, while this drug was successful against late-stage tumours across a variety of different solid tumour types, it crossed the blood-brain barrier and induced central neural toxicity.

After several years, Takeda returned the technology to Dr Folkmans lab and the researchers investigated how to change its physical characteristics while maintaining its activity. One strategy they explored was conjugating the drug to a high molecular weight polymer backbone. By attaching TNP-470 to a polymer, the researchers developed a molecule called caplostatin.

Shanahan said that around this time, SynDevRx were exploring ways to improve the risk associated with drug development. Their aim was to identify drug classes that had been explored clinically and had proven human activity but had side effects that could be addressed.

Meeting with Dr Folkman, they began to work on the molecule. Shanahan said that SynDevRx brought in a polymer chemist and spent several years developing a new compound that is their current lead molecule.

the focus on metabo-oncology as a new and complimentary treatment modality could be critical to the improvements in patient outcomes

While the discovery of fumagillin and its potent antiangiogenic effects were reported in the early 1990s, Shanahan said that its mechanism of action was not elucidated until the late 1990s by researchers at MIT. He explained that this fumagillin drug class inhibits the metalloprotease class enzyme MetAP2, also known as protein 67 (p67), referring to its molecular weight.

Shanahan explained that there are two known methionine aminopeptidase isoforms, identified as MetAP1 and MetAP2. Both carry out code translational functions, meaning the enzymes sit on the ribosome and cleave the initiator methionine concurrent with protein synthesis and in preparation for post-translation modifications.

He said that MetAP2 has six identified exclusive AP2 substrates. These are: thioredoxin-1 (TRX-1); cyclophilin A (CypA); GAPDH; eukaryotic elongation factor-2 (eEF2); Rab37; and SH3BGRL.

The fumagillin drug class inhibits methionine aminopeptidase activity. When it is administered, it binds irreversibly to the histidine 231 pocket of MetAP2 and prevents the removal of methionine. Where MetAP1 will remove methionine for most other molecules, the exclusive MetAP2 substrates do not undergo the removal of their methionine; this has some interesting downstream effects, said Shanahan.

By inhibiting MetAP2, the methionine on these proteins is retained and therefore post-translational modifications that would add different fatty acids do not occur. The proteins do not fold properly, causing some to be ubiquitinated, while others are relocated to a different part of the cytosol because of changes to their solubility. Shanahan explained that these cause a cascade effect and have a downstream impact, including on the metabolic hormone signalling pathways.

By inhibiting MetAP2, you affect these six proteins then by impacting these six proteins, you get this pleiotropic set of effects, from very potent antiangiogenic effects, to changes to the cell signalling, to really potent effects on metabolic and lipid processing, said Shanahan.

We see this as a prime modality for treatment in combination with other modalities, highlighted Shanahan. He said that the researchers have so far completed Phase I clinical trials in solid tumours, which included a dose escalation to determine the maximum tolerated dose and schedule for Phase II and subsequent clinical phases.

We have demonstrated pre-clinically that by coming at the tumours with a multimodal attack, we can have a profound effect. Over the last five to 10 years, it has now been demonstrated through the immune system that external factors have a large impact on the fate of the cancer and the patient. With the increase in obesity and diabetes and rise of tumours sensitive to systemic metabolic dysfunction, Shanahan said that the focus on metabo-oncology as a new and complimentary treatment modality could be critical to the improvements in patient outcomes.

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Could metabo-oncology be the treatment modality of the future? - Drug Target Review

A new clinic has launched in Norwich to focus on mens health, including male hormone replacement therapy, anti-aging treatments and erectile dysfunction.

Dr Gary Horn, consultant plastic surgeon and mens health expert, answers some of the questions he is most frequently asked:

Q: What are the benefits of attending a specialist mens clinic?

We are able to focus on mens health as a whole as we have a more comprehensive understanding of how the whole body is working and how we can make it better. If someone comes to me for liposuction, for example, I can ask them about why they think they have so much fat and find out more about their diet and look into their hormone levels. Some products work better for men or for women they are two different types of patient and need specific advice and treatment.

A patient of Dr Gary Horn, pre-reshaping operation and post-operation.- Credit: Dr Gary F. Horn

Q: What is the main cause of erectile dysfunction?

There are different causes. I look into lifestyle, weight and whether someone smokes, for example. As well as conducting a physical examination, I might end up ordering blood tests and checking testosterone levels. The problem might be neurological or vascular, where vessels in the penis have become smaller. This is often is the first sign of having a more general cardiovascular problem, which could go on to affect the heart or other vessels in the body. I may therefore need to refer this person to a cardiologist. Erectile dysfunction can also follow prostate surgery, or it can be a psychological issue.

Q: How can I improve my erectile dysfunction?

There was a time when Viagra was one of our only options, but now we can also treat erectile dysfunction with low-intensity shock waves and that can be used alone or combined with injections of stem cells which is becoming quite popular.

Q: Is male hormone therapy safe?

Yes, absolutely. But you dont give it without carrying out certain checks. It starts with a questionnaire; then a physical examination and then, of course, there is a blood test to assess different things, including testosterone levels, which can then be managed with oral or injectable applications.

Dr Gary Horn, consultant plastic surgeon and mens health expert. - Credit: Dr Gary F. Horn

Q: What are the signs that I might need hormone replacement therapy?

Feeling tired all the time; not being able to complete different activities or do sport; having problems concentrating and not being able to finish tasks can all be signs that you may need hormone replacement therapy. There can be sleeping issues, a reduction in libido or problems maintaining a proper erection. The majority of men requiring hormone replacement therapy will be over 50 but anyone from 20 to 80 can have an assessment.

Q: What is the best anti-aging treatment for men?

Apart from hormone replacement therapy and the other supplements that go along with it, peptides etc, as a plastic surgeon I can offer non-surgical treatments such as facial injections, including fillers and botox, and maybe different types of cream to maintain and restore texture of the skin. On the surgical side, I can offer eyelid surgery, facelifts, rhinoplasty and hair transplants.

Q: What other treatments do you offer?

I have a reshaping clinic for men. Apart from looking at exercise and diet, I also offer surgery such as scar revision or laser liposuction and high definition liposuction for people who want to look more athletic. I can carry out tummy tucks and body lifts, when patients have had massive weight loss and can offer implants, ranging from pectoral implants to calf, buttock and bicep implants.

For more information visit http://www.norwichcosmeticsurgeryandskinclinic.com

Continued here:
Men's health: What is the best anti-ageing treatment? Q&A - Eastern Daily Press

In this study, 16 women with POI, aged from 27 to 46years old, and a POI duration of 125years were interviewed. The age range of women at the time of POI and definitive diagnosis was 13 to 40years. Among the participants, three women had remarried, two of whom had divorced after diagnosis POI due to infertility. The level of education of women was from primary to doctorate. The cause of the POI was mainly unknown, but in 2 participants, POI occurred after cancer treatment and a participant afflicted to POI following an autoimmune disease. The Other demographic characteristics of the participants are presented in Table 1.

After content analysis of the interviews with a focus on the perception and experience of women with POI of reproductive-sexual health, four categories emerged (endangerment of women's health, psychological agitation, disruption of social life disturbance in sexual life), explained as follows.

The results showed that all participants were concerned about the effects of decreased ovarian function and changes in hormone levels on their future health.

This main category consists of four subcategories (irregular menstruation, emergence of menopausal symptoms, infertility, signs of early aging) as follows:

Menstrual cycle changes (irregular menstrual cycle, primary amenorrhea or sudden cessation of menstrual bleeding) are one of the first suspicious signs of POI in women that resulted mostly to consult a physician.

One of the participants, who had POI for 8years, said:

The first time my period became irregular, I went to the doctor and she told me that I should take hormone therapy. Before that, I had regular periods, but after 2-3years, I did not have regular periods, and the doctor said there was a possibility of premature ovarian insufficiency (p. 9, 43 y).

Another participant who had regular periods for 27years, stated:

Suddenly, I did not have another period. I went to the doctor. I had an ultrasound and found that I no longer had an ovum (p. 3, 46 y).

A number of participants did not experience menstruation at puberty and had primary amenorrhea, or spotted only once.

One participant that had a spontaneous POI, said:

I did not menstruate at all from the beginning, like my sister (p. 1, 30 y).

Following changes in hormone levels, participants experienced some degree of menopausal complications.

One of the participants who had POI following treatment of cancer, said:

Dry uterus bothers me a lot, especially during sex (p. 10, 46 y).

Another participant who had POI for 10years, stated:

It was very hard at first. In particular, flushing much annoyed me (p. 11, 44 y).

The other participant had POI with an autoimmune disease origin and had one live child with successful spontaneous pregnancy, said:

Premature ovarian insufficiency reduced libido (p. 8, 35 y).

This issue was the main concern of most participants and one of the main complaints of participants with POI was infertility.

A participant who had underwent chemotherapy for cancer treatment in 2008 and had lost her fertility for 11years, said:

I did not know before, but when I inclined to have a baby, I later realized that POI result to infertility (p.2, 4 y).

Another woman who had divorced due to have a 17-year-old history of infertility and remarried, stated:

When I did ultrasound check for infertility, the report showed that my ovaries are very small like as ovaries in menopause women (p.12, 43 y).

Due to decreased levels of estrogen in afflicted women, some of them reported conditions like loss of beauty, wrinkling of the skin and decreased feeling of youth.

One participant, who had been suffering from premature ovarian failure since the age of 22 and for 10years, said:

My first concern was this: I was no longer beautiful (p.16, 34 y).

The other participant that is pregnant currently with donated egg, said:

Eventually you f1eel the changes in your body. For example, you notice wrinkles on your skin (p.9, 43 y).

One participant that had POI for 13years, stated:

Although I am 37years old, I do not feel young I feel aging and I am old (p.13, 38 y).

POI occur in women is less than 40years old, while the normal age of menopause in women is 4555years. Hence the acceptance of POI for participants was accompanied with psychological reactions.

This main category consists of three subcategories [anxiety reaction, mood reaction, agitation in the selection of childbearing] as following:

Participants experienced an onslaught of negative emotions after being diagnosed with POI by a physician, including feelings of despair, depression, a sense of aging, and shock from menopause.

A participant who had POI since the beginning of her marriage and for 5years said:

When it told me to get menopause, I tried for traditional medicine but, due to that was not successful, I was disappointed (p.7, 37 y).

Another participant expressed:

At that time, when I realized my problem, I became depressed and thought that I was the only one. It had a great effect on my mood (p.1, 30 y).

A participant told in despair:

Because I dont have children, I be early menopause, that is, I got oldThese are other signs of aging (p.4, 46 y).

Another participant, who had POI since the age of 22 and had been struggling with it for 12years, said:

I really didnt expect such a thing at all. I was planning to have a planned pregnancy. But the exact opposite happened. The shock was so great it was the biggest shock of my life I have ever experienced (p.16, 34 y).

Popular reactions in afflicted women with POI were included: feeling of uncertainty of future conditions, fear of disease outcome, feeling eternal problems [eternal infertility] negative effect on mood and weakness of the nerves.

One of the participants expressed with surprise and confusion:

I have no idea about the future. I'm very confused. I dont know what will happen to me (p.4, 42 y).

Also part of the conversation with a participant was as follows:

I think more about the fact that this [pregnancy] may never have happened to me (p.14, 27 y).

Another participant said:

Premature ovarian insufficiency makes me angry quickly. I'll get mad soon (p.10, 46 y).

A participant told:

I am worried that I will not have any problems after the age of 40. I am afraid of the consequences of this disease (p.2, 34 y).

Considering that the options available to solve the problem of infertility in women with POI are currently limited and unfortunately there is no definitive treatment for female infertility in these women and the issue of cell therapy is being researched on animal models and do not use so far on humans, the only options offered to couples are the use of donated egg and adoption. Nevertheless, some participants opposed to accept them. If a participant commented on the issue of donated egg as follow:

I think to myself about the baby Because the egg is not mine, I am afraid I will not feel like a mother when she was born. Also she continue:

I must convince myself about this pregnancy and deal with it (p.15, 43 y).

Spiritual aspects of donated egg were important for some participants.

A participant was concerned about this, saying,

I do not care if I conceive with the donated egg, but its religious issue is important to me. It bothers me a little (p.1, 30y).

Moreover, it was important for a number of participants to know that the donor be a familiar person.

A participant stated:

I'm happy to have an ovum from my sister rather than a stranger (p.2, 34 y).

Most participants expressed POI has disrupted the social aspects of their lives. Social isolation, having privacy, unconscious jealousy and seeking support are four subcategories that related to this main category and be explain as follows:

Patients stated that they were reluctant to be in public because of impatience, a tendency to be alone, and to become nervous about social relationships.

A participant said:

I'm not bored totally. I like to be at home, to be alone (p.13, 38y).

Most afflicted women tended to maintain their privacy for fear of being judged by others, the importance of hiding the problem of infertility and believing in the privacy of the subject.

Some of the statements of the participants are as follows:

It is important for us that the donated egg is kept secret. Because if I get a donated egg, I will not be my own child and I will not judge (p.6, 34 y).

This is a personal matter and has nothing to do with anyone (p.13, 38 y).

Some participants expressed a reluctance to associate with families that have children and they are jealous of pregnancies in others or seeing children.

If a participant that had POI for 26years, said:

I was upset when I saw that others had children and became pregnant. Because I have a problem getting pregnant myself (p.12, 43 y).

This issue was the most important item that as a motivation factor helped afflicted women not only to accept complicated condition but also to pursue infertility treatment seriously. According to participants, the support of husbands, family and friends helped to increase hope and reduce psychological threat to women. In the meantime, the supportive role of the husbands was very prominent for women, as one of the participants that had POI for 18years, said:

I am most supported by my husband. If he did not help me, I wouldn't be able to control the situation and control myself. He encourages me to continue my treatment and does not let me Disappointed. (p.5, 30 y).

Another participant stated:

My sister, like me, had an early menopause. He tells me you are young now. Get treated sooner. You get the result. She is very hopeful and encourages me (p.7, 37 y).

In most patients, POI had a negative effect on the couple's sexual relationship.

Due to changes in hormone levels, women experienced sexual function disorders such as dyspareunia, reduced libido, and anorgasmia. These factors caused women to worry about the stability of their married life and the instability in marriage that they formed two subcategories from three.

In contrast, a number of other patients reported that POI had no effect on their sexuality.

The third subcategory was the ambivalence sensations that all of them explained as follows:

The disease had a negative effect on sexual intercourse and sexual pleasure of affected women and on the other hand, sexual intercourse was important for the husband. As a result, a number of participants were concerned about the stability of married life.

A participant stated:

Before my problem, I had sexual desire, but now I do not have it at all, and this causes us to have sex more often with fights, and it has disrupted our relationship (p.10, 46 y).

Beside to decreased sexual satisfaction in couple, infertility also, leaded to some women felt insecure and worried about divorce. A few others threated to divorce from the spouse's family, and some be feared from their husband remarriage.

A participant said:

From the beginning of my marriage, I was stressed until now because I did not have children. My concern is to have children and that our marriage will fall apart (p.1, 30 y).

Another participant stated:

Now my mother-in-law can easily divorce me. She says either bring a child or we will divorce you (p.4, 42 y).

The cessation of menstrual bleeding on the one hand created negative feelings for the participants and caused a kind of psychological pressure on them, but on the other hand had different effects on the participants spouses such as sexual satisfaction and helping to improve sexuality. Moreover, in the context of Iran religiously, having sex during a woman's period is against the Sharia, some patients even said that their partners were delighted with stopping in their menstruation to have sex freely. Therefore, these conditions caused women had been had a dual feeling about the negative impact of POI on their sexuality.

One of the participants said:

My husband says how good I am. I am comfortable without a condom. No man is happier than me (p.5, 31y).

Another participant, who has been suffering from POI since the age of 22 and for 12years, said:

We are trying to cope with and we are trying to control and improve the condition ourselves. For example, we use lubricant for dyspareunia (p.16, 34 y).

Or another participant said:

My husband thought POI meant we could no longer have sex. But when he saw that we had no problem with sex, he said it didn't matter. The important thing is that we can have sex without any limitation (p.11, 44 y).

View post:
Perceptions and experiences of women with premature ovarian insufficiency about sexual health and reproductive health - BMC Blogs Network

Dr Miriam Mutebi, Consultant Breast Cancer Surgeon.

What started as a lump in her left breast early last year would mark the beginning of Sylvia Sandagis fight for survival against cancer.

The 40-year-old was having a bath when she noticed the swelling. And there was some pain.

I thought Id probably been hit by something. I went to hospital and an ultrasound was done. The doctor said blood was not flowing in the lump and recommended a biopsy, Sandagi says.

Five days later, the biopsy results were out and the swelling was found to be cancerous. I remember that day, on August 31. I didnt want to believe what Id just heard. But I didnt cry. All I could think of was when I would start treatment and who would take care of my daughter should I get weak, especially because her father does not live in Kenya."

The mother of one is among patients under the care of various clinicians at Aga Khan University Hospitals Multidisciplinary Breast Cancer Clinic, which is touted as the hope for those in need of cancer treatment.

Sandagi says an oncologist referred her to Aga Khan where she was admitted to the centre and started her treatment. What I love about multidisciplinary clinic is a patient is not attended to by one doctor, or one medical professional," she says.

I found several experts when I came. That is when I learnt my cancer was in Stage Four. They told me the rate of survival for breast cancer is high. The doctors said the drugs they would give me were effective and that I would survive.

Horror stories

Sandagi is currently taking the drugs which will also ensure her oestrogen levels are reduced as breast cancer feeds on it. After six months, the doctors will decide whether she will need chemotherapy or radiotherapy.

Many patients have interpreted Stage Four cancer to mean death. However, Sandagi says the treatment she has been receiving has reduced the pain and shes living a near-normal life.

What people share about cancer are more of horror stories. It is true I have cancer and it is in Stage Four. But there is no pain. Im not bedridden. The only time I remember I have cancer is when someone mentions it or when Im taking my medicine, Sandagi says.

She has never told her eight-year-old daughter she is suffering from cancer because of the stigma attached to the disease by some communities.

All that I told her was Im unwell and that Ill be going to the hospital more often. I fear talking to her about cancer because when she tells people about it, the horror stories they will tell her will scare her. Shell think Im dying. I dont want that to happen, she says. I will fight. I dont want to die. I want to see my daughter grow up.

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Aga Khan launched the Multidisciplinary Breast Cancer Clinic to improve treatment. At any given time, a patient is able to be attended to by a breast surgeon, a medical and a radiation oncologist in one sitting.

It takes a village to care for a cancer patient. But here, we have decided to bring the village to the patient with our multi-disciplinary treatment, says Dr Mansoor Saleh, the founding chair of the Department of Hematology-Oncology at Aga Khan University.

He adds: Here, we have a breast cancer surgeon, a pathologist who helps with diagnosis, a radiologist who helps with imaging, a medical oncologist who does chemotherapy, and a radiation oncologist who gives radiation therapy, all in one place, at the same time. This enables the patient to get a unanimous report. When each doctor attends to a patient by themselves, they work in silence and the patient may not get the full picture.

Dr Miriam Mutebi, a breast surgical oncologist at Aga Khan, notes there are many types of breast cancers with the distinguishing factor being either hormone-positive breast cancers or hormone-negative breast cancers.

Think of a breast cancer cell as having three little spikes or receptors on its surface. These receptors act like doors to the cell and can influence how the cancer cell behaves. Different hormones act like keys that sit in the doors to the cell causing activity to increase or reduce, Dr Mutebi says.

The receptors we see on the surface of a breast cancer cell are ER-estrogen receptor, PR-progesterone receptor and HER-2 receptor (a special molecule on the cell). Its the presence or absence of these three doors or receptors that determines the type of breast cancer one has.

Mutebi says this is important information that must be established before treatment starts as it has implications on how the cancers behave and determines the treatment options.

The most common are the hormone-positive breast cancers (ER positive, PR positive) that account for between 60-70 per cent of cancers. When we say a breast cancer is hormone-positive, we mean female hormones in the body will act as keys to these cancer doors and encourage the cancer to grow.

"Therefore, as part of treatment after surgery, chemotherapy or radiotherapy, a patient may need medicine for five to ten years to minimise chances of the cancer recurring.

Original post:
How multi-disciplinary treatment of cancer is giving hope to patients - The Standard

The Endometriosis Treatment market report provides a detailed analysis of global market size, regional and country-level market size, segmentation market growth, market share, development, competitive Landscape, sales analysis, impact of domestic and global market players, value chain optimization, trade regulations, recent developments, opportunities analysis, strategic market growth analysis, product launches, area marketplace expanding, and technological innovations.

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The information for each competitor includes:

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The report comprises a broad overview of the major retailers operating in the target market. The research forecasts the market development in the established year and prediction time frame from 2020 to 2026. The report encompasses key factors related to market share detained by each region along with development chances expected major geographies. The global Endometriosis Treatment market division by product, type, application, and areas has been explained. Comprehensive particulars on market opportunities, restrictions, and probabilities are provided further in this report. The report also helps companies in marketing for tasks like identifying their prospective customers, building relationships with them.

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Table of Contents

1 Study Coverage

2 Executive Summary

3 Breakdown Data by Manufacturers

4 Breakdown Data by Type

4.1 Global Endometriosis Treatment Sales by Type

4.2 Global Micro Server IC

System Revenue by Type

4.3 Endometriosis Treatment Price by Type

5 Breakdown Data by Application

5.1 Overview

5.2 Global Endometriosis Treatment Breakdown Data by Application

6 North America

7 Europe

8 Asia Pacific

9 Central & South America

10 Middle East and Africa

11 Company Profiles

12 Future Forecast

13 Market Opportunities, Challenges, Risks and Influences Factors Analysis

14 Value Chain and Sales Channels Analysis

15 Research Findings and Conclusion

16 Appendix

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Global Endometriosis Treatment Market Share Global Growth, Trends, Industry Analysis, Key Players and Forecast 2020 2028 KSU | The Sentinel...

In a split second, your body might go from oooh to ow! Sex shouldnt be painful. So what gives? Why is your penis sore afterward?

First things first: If you have a sore penis after sex, youre not alone. This malady can be traced to anything from friction (ooh, sound familiar?) to an STI.

Should I be worried about a sore penis after sex?

That depends. A sore penis after sex doesnt always indicate a bigger problem. Maybe you a little too jiggy with it.

However, if you have accompanying symptoms that indicate infection or allergic reaction, call your doctor to rule out serious illness.

So, put on your cotton boxers, take a seat, and scroll down to figure out whats going on with your nether regions and how to fix it.

If your junks a little tender, dont sweat it. Heres a list of possible culprits and what to do about them.

Your penis is a pretty sensitive organ. Thats a *good* thing. But it also means you can injure it by going too hard or for too long.

Specifically:

Solution: Give it time.

Rough sex? Check in

Rough sex can potentially cause injuries to all parties. If its yours and your partner or partners thing, thats fine. But make sure youre on the same page before getting into rough sex.

If youre in pain after getting it on vigorously with someone else, check on them too. And dont forget to have a safe word in place or communicate when enoughs enough.

Communicating in the bedroom is central to safe, consensual, and enjoyable sex.

Hello, friction, my old friend

Chafing happens. On your thighs, glutes, armpits, and yep your peen.

Lack of lubrication during sex can rub or wear away at the top layer of skin. That leads to sensitivity and soreness.

If lack of lube is your issue, you might also notice:

Solution: Time. Avoid sex or masturbation until your penis is back to normal. (Also, use lube, condoms with lube, or even coconut oil next time.)

A range of lubes is available for purchase online.

In general, taking longer than 30 minutes to ejaculate is considered delayed ejaculation (DE).

DE is one of several types of ejaculatory dysfunction erectile dysfunction being the most common.

What causes delayed ejaculation?

Any combo of these factors can lead to DE:

DE can make your penis feel swollen (and not in a good way), but the tenderness should go away within a few hours of ejaculation.

Solution: Wait it out. But also, if this was your first time experiencing DE, call your doctor. DE can be a sign of other health problems.

Are you allergic to latex? The chemicals in certain lubes? Or the material of your newest sex toy?

If you have sensitive skin, an allergic reaction mightve happened, aka contact dermatitis. Allergic reactions usually cause some of these other symptoms too:

Contact dermatitis can last a few days to a few weeks. Avoid sex (and irritating products) until your skin has cleared up.

Solution: Your course of action will depend on the severity of your allergy. If its extreme, call a doc. Otherwise, try an over-the-counter (OTC) allergy med or topical treatment.

Allergic medications and OTC topical creams are available to buy online.

Yep, sometimes a sore penis is a sign of an STI. And if you think you have an STI, youre not in uncharted waters.

According to the Centers for Disease Control and Prevention (CDC), people reported a record-breaking 2,457,118 STI cases in the U.S. during 2018.

TBH, some folks with STIs never experience symptoms. But if an STI is causing pain, its probably one of these:

Other signs of an STI include:

Solution: Visit a healthcare clinic or call your doctor. Your sore penis requires medical treatment. Its always best to be open with sexual partners about current STIs and you should expect the same in return.

Whether you have acute or chronic prostatitis, the swelling can cause pain and soreness in your junk. That includes your penis.

What exactly is prostatitis?

A little Latin lesson: The suffix -itis means inflammation.

Prostatitis = an inflamed prostate.

#TheMoreYouKnow

Prostatitis can occur due to an underlying infection, so sit up and listen if you notice these other symptoms:

Solution: If you feel fever, chills, and UTI symptoms alongside a painful peen, seek medical treatment immediately.

Phimosis = when you cant pull your foreskin back from around the tip of your penis. (Its like that time you found it really hard to get your swimming hat on, but for your wang.)

An infection or skin condition causes the head of your penis to swell, restricting blood flow and mobility.

If you have phimosis, youll notice soreness when you pee, get a boner, and have sex. Other signs include:

Solution: Talk to your doctor. This requires medical treatment and analysis of the underlying cause.

Yep, folks with penises get yeast infections too.

A yeast infection is an overgrowth of a fungus called Candida albicans (wow, catchy).

Youre more likely to experience a yeast infection if you have a weak immune system, dont wash your junk often enough, or your partner has a yeast infection. Certain meds can also make you more prone to yeast infections.

Other signs of a penile yeasty:

The good news? Yeast infections are totally treatable. Youll want to start an antifungal cream or ointment pronto to get it under control.

Solution: Treat your yeast infection to soothe your sore penis. If youve never had a yeast infection, its best to confirm your diagnosis and any recommended treatments with a doctor.

Topical antifungal creams are available for purchase online.

Urinary tract infections (UTIs) are no joke. Youll probably have a painful, burning sensation when you pee and you might even feel the sting in your anus or rectum.

Other symptoms of UTIs include:

If your sore penis is the first sign of a UTI, youre in luck! You can nip that infection in the bud. As a UTI progresses, it can cause kidney, bladder, and urethra problems.

Solution: Call your doctor. UTIs dont always go away and might even cause complications without treatment.

According to the U.S. Department of Health and Human Services, up to 10 percent of folks with penises could have Peyronies disease a buildup of scar tissue that causes your penis to curve.

For obvious reasons, Peyronies disease can lead to a sore penis. Depending on the severity of the curve, penetrative sex might be painful. Or you might just feel tender and sore after the act.

Folks with autoimmune disorders seem more likely to develop Peyronies. Diabetes, prostate cancer, and age might also raise your risk.

Peyronies takes time to develop. You might notice these other symptoms first:

Solution: Talk to your doctor if you think you might have Peyronies disease. If they agree, theyll refer you to a urologist. Peyronies is treatable, but the type of treatment depends on the severity of your symptoms.

First things first: POIS is a *rare* and serious cause of penis soreness.

Researchers are still trying to figure out what causes POIS. Most agree that it has something to with an allergic reaction to your own semen or hormones.

If you have POIS, youre likely to feel pain and fatigue almost immediately after ejaculating. The reaction can last anywhere from a few minutes to several hours.

Other signs of POIS:

How serious is POIS?

POIS isnt life-threatening, but it could impact your quality of life. No one wants to feel crappy after what should be a fun and intimate experience.

Its important to get a diagnosis so that you can work with a specialist on pinpointing the best treatment for you.

Solution: If you notice any of the above symptoms right after sex, make an appointment with your doctor. Tell them youre concerned about POIS.

If you winced reading that, youre absolutely correct (our eyes are also watering a little). No, your boner doesnt actually contain bones. But a penile fracture can occur all the same.

An erection involves the penis engorging with blood. This blood rushes into a body called the tunica albuginea. Penile trauma (yikes) or a sudden bending of the penis can tear this lining. This is absolutely a medical emergency.

Symptoms include:

A severe penile fracture might also cause a tear in your urethra (aka your pee-hole).

Penile fracture? Yep, its an emergency

Seek immediate treatment at your nearest ER if you notice signs of a penile fracture.

Surgery is the only way to fix it.

Read more from the original source:
Sore Penis After Sex: Why It Happens and How to Treat It - Greatist

Until last year, Anna Robertson never had problems with her skin. But in October, with the strain of lockdown culminating in the end of her marriage, the mother-of-three from Wiltshire, 47, noticed patches of rough, scaly, itchy skin. They started on my nose and spread to my eyelids, she says. Managing the sale of our house, working and looking after the children, aged seven, 12 and 15, during the pandemic has been incredibly stressful. I saw a private dermatologist who diagnosed stress-related eczema.

In the year since the coronavirus pandemic began, experts have reported a huge rise in skin complaints, from sudden outbreaks of eczema to acne to increased signs of ageing none of which is being helped by the current cold weather.

Increased screen use, changes to our diet, increased alcohol intakeand masks are all thought to raise the risk of breakouts and skin problemsthough, in many cases, stress is thought to be the key driver as it was for Anna, who'd never had eczema before in her life.

Dr Alia Ahmed, consultant dermatologist at the Frimley Health Foundation Trust, says she has seen an uptick in patients presenting with stress-related skin problemssuch as eczema, psoriasis, acne, alopecia (hair loss) and urticaria (hives).

I have also had to increase the potency of treatment for some patients to control their skin condition, says Dr Ahmed, who also runs a private practice. My patients both men and women are experiencing high levels of stress. The pandemic adds to existing problems like financial worries, poor sleep and diet and lack of motivation to exercise.

Dr Mayoni Gooneratne, a former NHS surgeon and founder of The Clinic private health and skincare clinics in London, adds: I have seen more acute conditions like eczema and other types of dermatitis than before. Ageing has become accelerated too.

Dermatologist Dr Hiba Injibar, founder of the Dermasurge Clinic on Harley Street, says the number of people enquiring about adult acne at her practice has gone up by 30 per cent. She says that, despitecoming into contact with fewer pore-blocking pollutants because we're at home, more people have fallen victim to adult acne this year due to falling out of their skincare routines and because stress is a major cause of cystic acne. There is also the added issue of maskne [acne caused by mask-wearing] and acne on the brow caused by visors, she says.

Its well known that stress has a major effect on skin, with psychodermatology where psychological techniques are used to treat skin complaints increasingly popular.Studies have shown that emotional stress slows wound healing and can increase acne severity and some research suggests antidepressants have the side-effect of improved skin.

The brains stress response causes the release of various chemicals and hormones, including the stress hormonecortisol, that drive inflammation both in the body and the skin, Dr Ahmed explains.

Our skin becomes less able to defend itself, delaying the healing process and driving allergic responses.

Stress hormones can also alter the production and breakdown of collagen and elastin, causing premature ageing, lines, wrinkles, increased pigmentation and dull skin, and reduce production of hyaluronic acid which results in dehydrated skin.

The longer the pandemic lasts, the more likely that our skin will suffer, says Dr Ahmed. Long-term or chronic stress results in the body entering a permanent stress-response state, which can aggravate existing skin problems through a poor natural immune response, ongoing inflammation and loss of an effective skin barrier.

Stress can also encourage unhealthy lifestyle habits and poor sleep one in four of us are struggling to sleep well during the pandemic, according to researchers at Southampton University. Its a vicious circle: stress hormones correlate with lack of sleepand sleep deprivation activates their release. This is one of the reasons why poor sleep is associated with signs of premature aging, lack of hydration, larger pores, textural changes, and changes in blood flow to the skin. In addition, lack of sleep can disrupt the process of skin repair overnight, says Dr Ahmed.

For Nicola McCamley, 30, lockdown brought back the acne she thought she had beaten years ago. I stopped running and going to the gym, which was how I managed stress, and was glued to the news on TV. Everything felt so uncertain and frightening. I wasnt sure how the pandemic would affect my financial stability, and I was worried about my family.

Soon, she saw changes in her skin. It started with red and bumpy spots on the side of my face which then spread down my neck and even onto my chest. I was so upset.

She saw a dermatologist, at the Woodford Medical chain of cosmetic clinics, who ruled out allergies as she was not using any new productsand advised it was caused by stress.

How can you tell if your skin is stressed? In terms of acne, a telltale sign that emotions are the cause is when it shows up around the lower face and jaw, says Dr Gooneratne.

Dr Ahmed advises keeping a symptom diary to see if flare ups have correlated with a stressful time in your life.

Treatment requires a holistic approach, she adds. I treat the mind and skin together, as stress can trigger skin disorders which in turn cause stress, creating a vicious circle.

For eczema, Dr Ahmed recommends using gentle soap substitutes, emollients and treatment creams that may contain steroids.Acne treatment can include topical or oral antibiotics, topical retinoids, or oral isotretinoin and rosacea treatment that can include topical antibiotics, antiparasitic medications or azelaic acid, oral antibiotics or low dose oral isotretinoin.

These chronic conditions benefit from treatment that manages the signs and symptoms as well as addressing the psychological impact with interventions such as stress management techniques, relaxation therapies and mindfulness, she says.

For premature aging, useful skincare ingredients include retinoids, vitamin C and hydroxy acids, says Dr Mayoni. Plus, when clinics are open, an injectable skin hydrating and plumping cosmetic treatment will help to give your skin a real zing.

Dr Ahmed says simple lifestyle changes can help too, including drinking 2.5 litres of fluid a day to keep skin hydratedand reduce anxiety taking regular exercise, and getting plenty of sleep.

Try meditation or mindfulness to help combat stress, she adds. I often recommend the Headspace App to my patients.

Create positivity around you. Surround yourself with your favourite scents, music or colours at home to improve your mental health.

Find an achievable act that makes you happy, incorporate it into your morning routine, and another into the evening. This way you start off the day with mood enhancement and you have the same to look forward to in the evening.

Anna was prescribed a mild steroid cream, but says things really improved when she completed her house sale. I started doing yoga with an online teacher and used a meditation app which have both helped me feel less anxious. My skin is much better, she says.

Nicolas acne improved after treatment, too, but she also addressed her lifestyle. My skin problems made me realise I had to tackle my stress, so I started running again, I exercise at home and limit the amount of news I watch - and my skin looks great.

See the article here:
From eczema to spots to wrinkles, why the pandemic is wreaking havoc on our skin - Telegraph.co.uk

Avocado is a great place to start for healthy skin, but the other toppings you sprinkle on your toast can also add glow and luster.

Image Credit: 1989_s/iStock/GettyImages

If you want to start each day by adding healthy luster to your skin, there's one breakfast dermatologists recommend you eat: avocado toast topped with lime juice, berries and seeds.

You may associate this staple with trendy cafes, but it's easy to make at home. Simply mash avocado with lime juice, spread it on whole-wheat toast and top with sliced strawberries and chia seeds.

This breakfast will benefit your skin in a number of ways, and as a bonus, the foods that benefit your skin also tend to boost your overall health.

While research on foods for healthy skin is still limited, antioxidant-rich foods seem to protect your skin, per the Mayo Clinic. On the other hand, a diet high in refined sugars, carbs and unhealthy fats is associated with skin aging one good reason to swap sugary cereal and bacon for this breakfast.

Here's why avocado toast, in particular, will give your skin a healthy boost.

Why Avocado Toast With Berries and Seeds Is the Best Breakfast for Healthy Skin

1. It Gives Your Skin More Luster

Let's start with the star ingredient: delicious avocado. You may already use it topically as part of a DIY mask, but eating this stone fruit will also support your skin.

"Avocados are famous for being chock-full of healthy fats, namely monounsaturated fats," says Elizabeth Geddes-Bruce, MD, a board-certified dermatologist. "A high intake of monounsaturated fats is associated with a lower risk of severe photoaging [premature aging of the skin due to ultraviolet radiation exposure], which is good news for our skin."

Monounsaturated fat is found in plant foods like avocados, nuts and vegetable oils, and eating moderate amounts of it in place of saturated and trans fat can benefit your overall health, per the U.S. National Library of Medicine (NLM).

Researchers surveyed 1,264 women and 1,655 men ages 45 to 60 and estimated their dietary monounsaturated fatty acid intakes in a September 2012 study in PLOS One. A lower risk of severe photoaging was associated with a higher intake of monounsaturated fatty acids from olive oil, but not animal sources, in both men and women.

One avocado contains 19.7 grams of monounsaturated fats, per the USDA. In addition to benefiting your skin, monounsaturated fats can help lower your LDL (bad) cholesterol level and develop and maintain your cells, per the NLM.

That said, avocado isn't the only powerhouse ingredient in this breakfast that will make your skin look dewy and tout.

"Chia seeds are loaded with antioxidants and have omega-3 fatty acids that contribute to the skin's luster and elasticity," says Michelle Henry, MD, a board-certified dermatologist. "They also contain small amounts of our skin's favorite trace minerals selenium and zinc which may be important in maintaining our skin's elasticity."

2. It Supports Collagen Production

Lime juice is a secret ingredient in your avocado toast that will help maintain your body's collagen levels, a structural protein that gives skin elasticity.

"It's high in vitamin C, a great antioxidant our skin relies upon to fight free radicals that cause damage and aging," Dr. Geddes-Bruce says. "In addition to that, vitamin C is needed for wound healing and is necessary to maintain the structure of collagen."

As you age, the vitamin C content in your skin and your body's production of collagen naturally decrease, per the Oregon State University Linus Pauling Institute.

That decline in collagen is what contributes to wrinkles and crepey skin, and it can also cause other health issues like weakening muscles, joint pain, osteoarthritis or even gastrointestinal problems due to the thinning of your digestive tract lining, according to the Cleveland Clinic. Apart from aging, a poor diet is the most common cause of too little collagen in the body.

"To increase intake of vitamin C, I like to eat avocado toast in the morning with some lime juice sprinkled on the top," says Anna Chacon, MD, a board-certified dermatologist.

Vitamin C is tied to improving skin appearance, wrinkling, elasticity and roughness, per a March 2015 review in the journal Nutrition Research. That said, the authors note that more research is needed to pinpoint the exact effect of dietary intake on appearance.

The juice of one lime contains 15 percent of your daily value (DV) of vitamin C. Add a quarter cup of sliced strawberries to your breakfast, and you'll get 27 percent more of your DV of C.

"Strawberries also have [the polyphenol] ellagic acid, which prevents collagen destruction," Dr. Henry says.

3. It Could Help You Avoid Acne

Swap white bread for a whole-grain slice, and you might be able to avoid a few unwanted pimples.

"Whole-grain alternatives have lower glycemic indexes than their refined counterparts, which means they do not cause as great of a spike in the blood hormone insulin," Dr. Geddes-Bruce says. "Insulin and insulin-like growth factor (IGF-1) increase inflammation and may increase acne. Skipping those highly processed and refined carbohydrates might help you skip a pimple or two."

That also goes for sugary pastries you eye up for breakfast: If it spikes your blood sugar, it may just spike your acne. "Some studies have shown a correlation of the high glycemic index in Western diets with acne," Dr. Chacon says.

Eating high-glycemic foods often can raise hormones that elevate the activity of your skin's oil glands, ultimately causing acne, per UW Health.

4. It May Protect Your Skin From Damage

"In addition to vitamin C, berries like strawberries contain anthocyanins," Dr. Geddes-Bruce says. "Anthocyanins are what give strawberries their rich red pigment, and they also function as powerful antioxidants and have anti-inflammatory properties."

Research has shown that anthocyanins are linked to protecting the skin from UV radiation damage, photoaging and skin cancer and they possess anti-carcinogenic potential on different types of cancer cell lines, per a September 2020 study in the journal Biomedicines, however, more research needs to be done to confirm these findings.

Meanwhile, the omega-3 fatty acids in chia seeds may help create a strong barrier to your skin. "Omega-3 fats are photoprotective, and they strengthen the lipid barrier of the outermost layer of our skin, the epidermis," Dr. Geddes-Bruce says.

3 More Tips for a Healthy-Skin Breakfast

The rest is here:
Why Avocado Toast Is the Best Breakfast for Healthy Skin - LIVESTRONG.COM

Medical science has come a long way since the days of "bikini medicine," when the only time doctors managed a woman's health differently than a man's was when treating the parts of her body found under a bikini.

Over the past few decades, researchers have uncovered countless ways in which women's and men's bodies react differently to the same diseases. And just as it's now widely recognized women experience heart disease differently than men, scientists are beginning to understand why the sexes experience illness differently in another vital organ the brain.

It's not that male and female brains are built differently, said Lisa Mosconi, director of the Women's Brain Initiative at Weill Cornell Medicine in New York. It's that they age differently.

Women bear the brunt of Alzheimer's disease, the most common form of dementia, accounting for 2 of every 3 people diagnosed. Women are twice as likely as men to experience major depression. They are three times more likely to be diagnosed with autoimmune disorders that attack the brain, such as multiple sclerosis. They are four times more likely to have migraines and also are more likely to die from strokes.

What's driving these disparities? While multiple factors are at play, Mosconi said, it's hormones testosterone in men and estrogen in women that are the orchestral conductors of the brain. They are responsible for whether it performs well, or not.

"We are used to thinking of sex hormones as important for fertility and reproduction," Mosconi said. "But hormones also play crucial roles in brain health."

Estradiol, the type of estrogen produced by the ovaries during a woman's reproductive years, is the most important driver of brain health, said Dr. Kejal Kantarci, director of the Women's Health Research Center and a radiology professor at Mayo Clinic in Rochester, Minnesota. Her research suggests longer exposure to estradiol may offer some protection to the brain.

In a 2020 study published in Brain Communications, she showed women with longer reproductive periods measured from the time they start menstruation to the time they enter menopause were better protected against progressive forms of multiple sclerosis. The study also showed the more pregnancies a woman had, the less her disease progressed, suggesting that the flood of estrogen during pregnancy increased protection.

Losing estradiol, on the other hand, can harm the brain. The end of a woman's reproductive years and the accompanying drop in estradiol triggers numerous brain changes, some of which, researchers are learning, may not become evident until decades later.

For example, studies show Alzheimer's disease, typically diagnosed in a woman's 70s, likely begins to develop while she is still in her 50s. Mosconi's research found evidence that amyloid plaques, the proteins associated with the development of Alzheimer's disease, were already accumulating in the brains of women as they transitioned to menopause, though the women showed no evidence of cognitive decline at that age. She also found shrinkage in the memory centers of the women's brains.

"We never talk about Alzheimer's disease as something that happens in midlife," Mosconi said. "But for women, that's the timeline we need to think about."

There are other signs the brain is changing at midlife, when the loss of estradiol makes women more vulnerable to disease, Mosconi said. Studies have shown an increase in anxiety, depression, multiple sclerosis and other immune disorders during menopause. "For women with a predisposition to these conditions, this is when the condition seems to get activated."

Mosconi has used imaging to track brain energy levels, showing that, on average, it "declines by 20% or more during menopause." Men at the same age showed no changes, she said, which could be because they don't typically experience a hormone decline as rapidly or as early as women do.

But more estrogen isn't always better, Kantarci said. "You can't just say estrogens are good for you. It's not that simple."

A growing body of research suggests that it's not just about how much estrogen a woman's brain gets exposed to but when.

For example, a 2005 review published in The Lancet Neurology about clinical trials in postmenopausal women 65 or older showed women who received hormone therapy, including estrogen, had an increased risk for dementia and other types of cognitive decline. But a more recent study in 2019 in the journal Menopause found taking estrogen therapy earlier within the first five years of menopause might protect against cognitive decline. It also showed women exposed longer to natural estrogen because of more reproductive years had better cognitive function later in life.

Kantarci's work supports the idea that the transition to menopause offers a critical window for intervention. Her research found women given estradiol in a patch during their 50s showed less brain shrinkage in later years. "The front of the brain, which is used for decision-making and attention, was relatively preserved," she said. "It did not decline as much as it did in the placebo group."

In an ongoing study, she and her team will continue to explore whether hormone therapy given during the transition to menopause is associated with any long-term cognitive impacts.

But Kantarci cautioned against placing all the blame on hormones.

"Women are also the caregivers to dementia patients, and they are at higher risk for mental health issues that may also increase their risk of cognitive impairment," she said. "They live longer, and they are caregivers. And because they are caregivers, they are at higher risk. It's a circular problem."

View post:
Hormones are key in brain health differences between men and women - The Philadelphia Tribune

Finding good health care can be challenging, but for certain communities, including queer and trans people, it can be nearly impossible. Stigma, lack of training and insensitivity are rampant for these groups of people, and with something as important as health care, the effects can be mentally and physically devastating.

A new startup, Folx Health, is working to change all that through a personalized approach that matches trans and queer people seeking care with providers and services who understand their unique needs. Folx just raised $25 million in series A venture funding and is accepting patients now.

When a patient contacts Folx, they begin by filling out a complete online medical history. If their need requires a consultation with a health provider, theyll be matched with someone for a virtual appointment by phone or video. Medication, labs and supplies are delivered to the patients door, according to the Folx Health website. One of the companys foundational principles is care on our terms, which means no judgement, gatekeeping or having to explain yourself.

One 2015 study conducted with more than 27,000 transgender people found that 19% reported being refused medical care, 28% harassed by providers and 50% had to educate health care providers on transgender care. Twenty-eight percent of respondents also told researchers that they avoid going to the doctor altogether because of such treatment.

Folx founder and CEO A.G. Breitenstein told Fast Company that theyre on the verge of becoming a one-stop resource for members of the queer and trans community from information you might find in subreddit threads to clinical information from sources like the Mayo Clinic.

Were about to launch what we call The Library, which is a set of resources, Breitenstein said. Well have a balance between really well clinically vetted information, but presented in a way thats accessible and usable for folks.

Current topics in The Library include sexual health, hormone treatment and company news. There are tips like how to overcome needle fears for self-injection, and explainers on hormone lab results.

In the future Folx is also preparing to expand services to include treatments for sexually transmitted infections, erectile dysfunction and lab samples taken at home.

Right now, users must pay a $59 monthly fee for access to the service, in addition to any treatment costs. Breitenstein said that theyre working to integrate with insurance companies so patients can take advantage of their health care plans. Folx is also working on creating a grant program for people who cant afford the monthly subscription cost, according to Axios.

Folx service is currently available in 12 states, including New York, California and Florida. The company plans to expand nationwide by the end of 2021.

Excerpt from:
Folx Makes Health Care More Accessible for the Trans Community - The Mighty

Are there updated data for LIBTAYO in advanced CSCC? What do they show?

Longer-term data from EMPOWER-CSCC-1 were presented at the 2020 American Society of Clinical Oncology (ASCO) virtual meeting. These results showed an ORR of 46% (95% CI: 39%-53%) following treatment with LIBTAYO, with a median time to response of 2 months (interquartile range: 2-4 months) across the three treatment groups, which were metastatic CSCC and locally advanced CSCC dosed at 3mg/kg every 2 weeks and metastatic CSCC dosed at 350mg every 3 weeks. The median time to CR was 11 months (interquartile range: 7.4-14.8months) among those who achieved a CR in any group. The median DoR hadyet to be reached for any treatment group (range for groups combined: 1.9-34.3 months).4,10

Updated response rates arein the table below.4,10

Safety was generally consistent with previous data. The most common adverse reactions reported were fatigue (35%), diarrhea (28%) and nausea (24%). The most common Grade 3 or higher adverse reactions were pneumonitis (3%), autoimmune hepatitis (2%), anemia, colitis and diarrhea (each 1%).

Warnings and Precautions

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue at any time after starting treatment. While immune-mediated adverse reactions usually occur during treatment, they can also occur after discontinuation. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously. Early identification and management are essential to ensuring safe use of PD-1/PD-L1 blocking antibodies. The definition of immune-mediated adverse reactions included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. 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.

No dose reduction for LIBTAYO is recommended. In general, withhold LIBTAYO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue LIBTAYO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated adverse reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating steroids.

Withhold or permanently discontinue LIBTAYO depending on severity. In general, if LIBTAYO 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 immune-mediated adverse reactions are not controlled with corticosteroids.

Immune-mediated pneumonitis:LIBTAYO can cause immune-mediated pneumonitis. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (22/591) of patients receiving LIBTAYO, including fatal (0.3%), Grade 4 (0.3%), Grade 3 (1.0%), and Grade 2 (1.9%). Pneumonitis led to permanent discontinuation in 1.9% of patients and withholding of LIBTAYO in 1.9% of patients. Systemic corticosteroids were required in all patients with pneumonitis. Pneumonitis resolved in 59% of the 22 patients. Of the 11 patients in whom LIBTAYO was withheld, 7 reinitiated after symptom improvement; of these 1/7 (14%) had recurrence of pneumonitis. Withhold LIBTAYO for Grade 2, and permanently discontinue for Grade 3 or 4. Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg per day (or equivalent) within 12 weeks of initiating steroids.

Immune-mediated colitis: LIBTAYO can cause immune-mediated colitis. The primary component of immune-mediated colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1 blocking antibodies. In cases of corticosteroid-refractory immune-mediated colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.2% (7/591) of patients receiving LIBTAYO, including Grade 3 (0.3%) and Grade 2 (0.7%). Colitis led to permanent discontinuation in 0.2% of patients and withholding of LIBTAYO in 0.7% of patients. Systemic corticosteroids were required in all patients with colitis. Colitis resolved in 71% of the 7 patients. Of the 4 patients in whom LIBTAYO was withheld, none reinitiated LIBTAYO. Withhold LIBTAYO for Grade 2 or 3, and permanently discontinue for Grade 4. Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg per day (or equivalent) within 12 weeks of initiating steroids.

Immune-mediated hepatitis:LIBTAYO can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.9% (11/591) of patients receiving LIBTAYO, including fatal (0.2%), Grade 4 (0.2%), and Grade 3 (1.5%). Hepatitis led to permanent discontinuation of LIBTAYO in 0.8% of patients and withholding of LIBTAYO in 0.8% of patients. Systemic corticosteroids were required in all patients with hepatitis. Additional immunosuppression with mycophenolate was required in 9% (1/11) of these patients. Hepatitis resolved in 64% of the 11 patients. Of the 5 patients in whom LIBTAYO was withheld, none reinitiated LIBTAYO.

For hepatitis with no tumor involvement of the liver: Withhold LIBTAYO if AST or ALT increases to more than 3 and up to 8 times the upper limit of normal (ULN) or if total bilirubin increases to more than 1.5 and up to 3 times the ULN. Permanently discontinue LIBTAYO if AST or ALT increases to more than 8 times the ULN or total bilirubin increases to more than 3 times the ULN.

For hepatitis with tumor involvement of the liver: Withhold LIBTAYO if baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN. Also, withhold LIBTAYO if baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN. Permanently discontinue LIBTAYO if AST or ALT increases to more than 10 times ULN or if total bilirubin increases to more than 3 times ULN. If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue LIBTAYO based on recommendations for hepatitis with no liver involvement.

Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg per day (or equivalent) within 12 weeks of initiating steroids.

Immune-mediated endocrinopathies: For Grade 3 or 4 endocrinopathies, withhold until clinically stable or permanently discontinue depending on severity.

Immune-mediated nephritis with renal dysfunction: LIBTAYO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (3/591) of patients receiving LIBTAYO, including Grade 3 (0.3%) and Grade 2 (0.2%). Nephritis led to permanent discontinuation in 0.2% of patients and withholding of LIBTAYO in 0.3% of patients. Systemic corticosteroids were required in all patients with nephritis. Nephritis resolved in all 3 patients. Of the 2 patients in whom LIBTAYO was withheld, none reinitiated LIBTAYO. Withhold LIBTAYO for Grade 2 or 3 increased blood creatinine, and permanently discontinue for Grade 4 increased blood creatinine. Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg per day (or equivalent) within 12 weeks of initiating steroids.

Immune-mediated dermatologic adverse reactions: LIBTAYO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Immune-mediated dermatologic adverse reactions occurred in 2.0% (12/591) of patients receiving LIBTAYO, including Grade 3 (1.0%) and Grade 2 (0.8%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation in 0.3% of patients and withholding of LIBTAYO in 1.4% of patients. Systemic corticosteroids were required in all patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 42% of the 12 patients. Of the 8 patients in whom LIBTAYO was withheld for dermatologic adverse reaction, 5 reinitiated LIBTAYO after symptom improvement; of these 60% (3/5) had recurrence of the dermatologic adverse reaction. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold LIBTAYO for suspected SJS, TEN, or DRESS. Permanently discontinue LIBTAYO for confirmed SJS, TEN, or DRESS. Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg per day (or equivalent) within 12 weeks of initiating steroids.

Other immune-mediated adverse reactions: The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in 591 patients who received LIBTAYO or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Infusion-related reactions

Severe infusion-related reactions (Grade 3) occurred in 0.2% of patients receiving LIBTAYO. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or 2, and permanently discontinue for Grade 3 or 4.

Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-fetal toxicity

LIBTAYO can cause fetal harm when administered to a pregnant woman due to an increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose.

Adverse reactions

Use in specific populations

Please click here for full Prescribing Information.

INDICATIONAND USAGE

LIBTAYO is indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation.

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References:

1. LIBTAYO (cemiplimab-rwlc) injection full U.S. prescribing information. Regeneron Pharmaceuticals, Inc., and sanofi-aventis U.S. LLC. Available at: https://www.regeneron.com/sites/default/files/Libtayo_FPI.pdf

2. Mansouri B, Housewright C. The treatment of actinic keratosesthe rule rather than the exception. J Am Acad Dermatol 2017; 153(11):1200. doi:10.1001/jamadermatol.2017.3395.

3.Schmults CD, et al. High-Risk Cutaneous Squamous Cell Carcinoma A Practical Guide for Patient Management. Springer. ISBN 978-3-662-47081-7 (eBook).DOI 10.1007/978-3-662-47081-7.

4. Data on File. Regeneron Pharmaceuticals Inc. 2020.

5. Data on File. Regeneron Pharmaceuticals Inc. 2018.

6. Migden M, Rischin D, Schmults C, Guminski A, Hauschild A, Lewis K et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. New England Journal of Medicine. 2018;379(4):341-351.

7. NCCNClinical Practice Guidelines in Oncology (NCCN Guidelines) forSquamous Cell Skin Cancer V.2.2020. National Comprehensive CancerNetwork, Inc. 2020.

8. Califano JA, Lydiatt WM, Nehal KS, et al. Cutaneous squamous cell carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Springer; 2017:171-181.

9. Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol. 2010;3(4):39-48.

10. RischinD, Khushalani NI, Schmults CD, et al. Phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC): longer follow-up. Poster presented at: American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program; May 29-31, 2020.

LIB.20.04.0063 1/21

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Transforming Outcomes in Advanced CSCC with Immunotherapy - LWW Journals

The Youth Fountain, a health and wellness clinic in New Jersey, is offering holistic weight loss treatments for patients. The clinic is spearheaded by Dr. Rada and Dr. Emil Shakov.

According to the CDC, the prevalence of obesity was 42.4% in 2017-2018, up from 30% in 1999-2000. Obesity brings along with it health conditions that can lead to premature death. These health conditions are diabetes, heart disease, stroke, and some types of cancer. In the United States alone, obesity is a contributor to anywhere from 100,000 to 400,000 deaths every year. The medical cost for people with obesity was on an average $1429 higher than one without. Apart from dangers to physical health, the stigma and ridicule associated with obesity are also known to cause psychological distress leading to poor quality of life.

Though obesity has a negative impact on ones health it is also completely preventable through lifestyle changes that include changes in diet. The Youth Fountain believes in holistic treatment that looks at not just short term weight loss goals but prepares the patient for lifelong wellness as well. The doctors first take the time to understand a patients health goals. They then quiz them about their lifestyle, trying to arrive at a treatment that will suit them the best. This attention to detail is provided to every patient. Dr. Emil and Rada understand that every patient is unique and no size fits all. The doctors then craft a treatment regiment that incorporates all the tools at their disposal. The doctors can also set up follow up appointments to monitor a patients progress throughout the treatment.

When asked about the clinics philosophy, Dr. Emil says, When clients come to us, they are doing so because they are looking for a change in their lives. We do our best to live up to the trust that they put in us. We listen and understand the clients problems. We come up with solutions that best suit them on a case by case basis. The goal is to not just hit your target weight but to give you the tools to stay there for the rest of your life. Follow us on our Facebook page to stay up to date with our services.

The Youth Fountain offers skincare treatments such as tattoo removal, IPL, laser genesis, Picogenesis, chemical peel, Dermapen, vein treatments, hair removal, and SecretRF. The clinic also offers injectable treatments such as fillers, BOTOX, Dysport, PRP, and Jeuveau. The clinics wellness treatments include IV Infusions, weight loss, anti-aging, hormone replacement, and peptides. They provide hair restoration treatments such as medical treatment, laser cap, mesotherapy, PRP, and surgery. They also provide body sculpting treatments such as EmSculpt, Coolsculpting, truSculpt iD, mesotherapy, and Laser Liposculpting.

Dr. Emil Shakov is a board-certified surgeon at The Youth Fountain with extensive experience and training in advanced surgical techniques, advanced aesthetics, anti-aging, weight-loss, and hair transplantation. Fellowship trained in Advanced GI, Bariatrics, and Minimally Invasive Surgery (MIS), he continued to further his training and education at The American Academy of Procedural Medicine and The American Academy of Aesthetic Medicine where he mastered aesthetic procedures, anti-aging, and medical weight-loss. Dr. Shakov brings his unique skill set to The Youth Fountain to provide a pleasant experience with the confidence you can trust.

Dr. Rada Shakov is a board-certified gastroenterologist at The Youth Fountain who specializes in all aspects of aesthetic medicine. She has extensive training in a variety of procedures and is always continuing her education to stay on the cutting edge of the newest and best practices. In practice since 2010, Dr. Shakov believes in seeing the patient as more than just their problem areas; taking an emphatic and whole-body approach.

A review of the clinics service by Rachel K. says, Dr. Rada Shakov and Dr. Emil Shakov are the finest doctors around. They are not only knowledgeable in their field but are also incredibly kind, helpful, and care tremendously about their patients. So happy with my outcome and I would highly recommend them and their wonderful office staff to anyone. I'm so glad I found them! More reviews can be viewed on the clinics GMB listing.

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For more information about The Youth Fountain, contact the company here:

The Youth FountainDr. Shakov+1 732-333-5992info@theyouthfountain.com501 Iron Bridge Rd Suite 9, Freehold,NJ 07728, United States

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New Jersey Health And Wellness Clinic The Youth Fountain Is Offering Holistic Weight Loss Treatments - Press Release - Digital Journal

President Joe Biden is already proving to be a better friend to the LGBTQ community than his predecessor. During his first week in office, Biden issuedan executive orderextending federal LGBTQ protections, reversedTrumps trans military ban, and includedgender-neutral pronouns and honorificson the White Houses contact page.

With these victories came the inevitable backlash. Abigail Shrier, author of the controversial bookIrreversible Damage: The Transgender Craze Seducing Our Daughters,denounced Bidens executive order on Twitter, claiming that it unilaterally eviscerates womens sports. Other self-described gender critical (i.e., anti-trans) feminists agreed, creating the hashtag#BidenErasesWomento voice their opposition. Meanwhile, at least 14 states have introduced aslew ofanti-trans bills. Contrary to what lawmakers and gender critical feminists say, its not about protecting women and children. Its an organized effort to legislate trans bodies based on misinformation, ignorance, and bigotry.

Earlier this year, Montana lawmakers introducedHB 113, which wouldvebarred health care professionals from providing gender-affirming services to trans adolescents such as puberty blockers and hormones. The bill died on its third reading in anarrow 51-49 voteon January 26 after five Republicans who initially supported HB 113 changed theirminds. Similar bills inUtah,Alabama,Missouri,Texas,Mississippi,Indiana, andNew Hampshireare still on the table.

The argument supporting these bills is the same that Shrier makes in her book, which is that providing puberty blockers and hormones to minors can cause a lifetime of damage. The facts are more nuanced. According to the MayoClinic, puberty blockers dontchange an adolescents body permanently. Instead, theMayo Clinics websiteexplains, it pauses puberty, providing time to determine if a child's gender identity is long lasting. If a child decides not to continue medical transitioning, normal development will resume once the child stops taking puberty blockers.

Atalking point among anti-trans activists is that 70 to 80 percent of adolescents diagnosed with gender dysphoria eventually grow out of it, or desist. The exact numbers are hard to pin down. A2008 studyfound that 61 percent of children with gender dysphoria desisted by the age of 29, while a2019 studyfound that about 10percent desisted within 18months of seeking treatment. The 80 percent number comes from a2013 study whichinitially reported that out of 127 Dutch children who sought gender-affirming health care at a clinic, 47 of them still went to the clinic as adolescents, while 80 of them stopped. It was initially reported that the 80 desisted, but asJame M. CantorandJesse Singalrespectively point out, only 56 of the 80 said they desisted, while the rest didntrespond to the researchers questionnaires. The actual study says 54 percent desisted, not 80.

Cantor and Singalwhovebeenheavily criticizedfor theirviews on trans issuesconclude that most children who initially report having gender dysphoria eventually grow out of it. Even if this is true, making gender-affirmingcare for children illegal isntthe solution. A study published inPediatricslast year shows that having access to puberty blockers in adolescence reduces the risk of suicidal thoughts in transgender adults. Is it worth risking the lives of trans kids who legitimately need puberty blockers and hormones because a few might later change their minds?

While Montanas HB 113 has been defeated,HB112remains. Known as the Save Womens Sports Act, the bill seeks to ban young trans girls from competing in girls sports. This is the latest example of an ongoing debate; the main argument against including trans women in sports is that since trans women naturally produced testosterone for a significant period before undergoing hormone replacement therapy (HRT), they have an unfair physical advantage over cis women. Once again, the truth is more complex.

Medicalphysicist Joanna Harper, whosalso an athlete and a trans woman, publisheda study in 2015that looked at run times for eight trans distance runners over a seven-year period, and found littledifference from cis runners times. Likewise, a2017 literature reviewfound no direct or consistent research that proves trans women have an unfair physical advantage. However,a 2019 studyshows only modest changes in muscle mass in trans women after a year on estrogen, as did amore recent studythat looked at the athletic abilities of trans women serving in the Air Force.

It's still no excuse to outright ban trans women from sports because rules can be adjusted. Dr. Timothy Roberts, who led the most recent study, toldNBC Newshe suggests making it so trans women athletes have to be on HRT for at least two years instead of the International Olympic Committees current one-year rule.Even then, Robertspointedout that many cis female athletes have physical advantages over others. We have a lot of elite female athletes who tend to be tall and thin with slender hips, he said, and we're not outlawing them.

HB 112 and HB 113 are just the latest attempts to banish trans women from public life. Like bathroom bills, these new bills perpetuate the ideathat the trans rights movement seeks to harm women andchildren. No evidence supports this; trans people, for the most part, just want to live their lives in peace with full bodily autonomy like everyone else.

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Lost in Translation - Splice Today

National Review

President Joe Bidens recent executive order to expand food assistance to U.S. households, while well-intentioned, represents a substantial overreach of the executive branch and a blatant attempt to override the intent of Congress. If successful, this dangerous precedent would open the door to major expansions of the social safety net without congressional approval. Congress must resist the presidents attempts to subvert the intent of existing law. Less than one week into the Biden presidency, the new administration issued a series of executive orders focused on COVID-19 economic relief. One such order seeks to expand food assistance through the Supplemental Nutrition Assistance Program (SNAP), or food stamps. In it, President Biden instructed the Department of Agriculture (USDA) to take immediate steps to make it easier for the hardest-hit families to enroll and claim more generous benefits in the critical food and nutrition assistance area. In reality, the executive order asks a federal agency the USDA to intentionally misinterpret the Families First Act and subvert the constitutional authority of Congress over the legislative process. The Families First Act, which passed in March 2020, clearly outlined that states could request waivers from the Agriculture Department to provide emergency allotments to SNAP households not greater than the applicable maximum monthly allotment for the household size. In normal times, 60 percent of households enrolled in SNAP do not receive the maximum benefit because they have income from other sources such as earnings that they can use for purchasing food. The emergency allotments recognized that millions of people lost jobs or faced other employment disruptions when the pandemic hit, and that those enrolled in SNAP were at particular risk for job loss in the early aftermath of the pandemic. Rather than requiring SNAP households to report a job or income change to their state agency and wait for bureaucrats to recalculate their benefits, the emergency allotments gave every SNAP recipient the maximum allowed. This was, admittedly, not a very targeted effort. Some families received a boost in SNAP dollars without a change in household income or financial circumstances. But the immediacy of the economic shock brought on by the pandemic, and the employment instability that persists today, necessitated an equally expedient policy response. The Agriculture Department, under President Trump, had approved emergency allotment plans for all 50 states, the District of Columbia, Guam, and the U.S. Virgin Islands but only in accordance with the law. The department extended these emergency-allotment waivers numerous times, most recently extending them through January 2021. The USDA and Congress itself also offered states flexibility in the aftermath of the pandemic. According to federal government spending data, all of the efforts outlined above have caused SNAP benefits to rise more than 40 percent in the last fiscal year, with more than $31 billion in added spending compared to FY 2019. Class-action suits have been filed in Pennsylvania and California by people who disagree with the USDAs interpretation of the law: that regular SNAP plus emergency allotments cannot extend benefits beyond the maximum benefit level. Lawyers for the lawsuits argue that the law allows the USDA to approve emergency allotments in the amount of the maximum benefit, which if true, would mean that households could receive the maximum SNAP benefit plus the maximum emergency allotment essentially doubling benefit amounts. A federal judge in California agreed with the USDA, while the Pennsylvania case is ongoing. The Biden administrations executive order is encouraging its USDA to misinterpret the 2020 law in a similar way. The legislative text is not ambiguous. It is hard to imagine Congress being any clearer than, to address temporary food needs not greater than the applicable maximum monthly allotment for the household size. If Congress had wanted to give people more than the SNAP maximum, it would have done so. In fact, Congress eventually did just that expanding benefits by 15 percent in the COVID-19 relief package passed last month. If the Biden administration is successful in this attempt, it will open the door to a number of executive actions aimed at expanding the safety net without congressional action. If political appointees in the Biden administration feel unconstrained by the law, we will see larger benefits directed to an increasing number of people. Such action not only undermines the integrity of the social safety net by going around Congress, it disregards the separation of powers ensconced in the founding documents of our republic. The American public has been largely supportive of efforts by Congress to provide economic relief to struggling households. Lets keep that authority in its proper place.

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The GOP's future is in flux as the party divides over support for Representatives Marjorie Taylor Greene and Liz Cheney - Yahoo News

Introduction

The onset of lactation results in a sudden and considerable demand for calcium, imposing arduous physiologic challenges to calcium homeostasis in dairy cows.1 Cows that are unable to adapt to this change in calcium demand develop hypocalcemia. Cows with hypocalcemia (colloquially referred to as milk fever) present with weakness, depression, inappetence, and an inability to rise.1 Cows with clinical hypocalcemia are more likely to develop secondary mastitis, as well as muscle and nerve damage from prolonged periods of recumbency.2 As the condition name would suggest, subclinical hypocalcemia shows no overt clinical signs in affected animals, despite low blood calcium; however, there are other negative health consequences. Hypocalcemia reduces the ability of immune cells to respond to stimuli, thus contributing to infections, such as mastitis or metritis.3,4 Hypocalcemia also reduces smooth muscle contraction,5 which can result in reduced rumen and abomasal motility, leading to reduced feed intake and subsequent transition disorders (displaced abomasum, mastitis, metritis, retained fetal membranes, ketosis, etc).6 Subclinical hypocalcemia has also been shown to negatively affect early lactation milk production and reproduction.7 An increased culling rate was also observed for animals with subclinical hypocalcemia.8 Clinical hypocalcemia may occur in up to 510% of dairy cows, whereas its subclinical form is more prevalent, with estimates ranging up to 50% of mature fresh cows.9 Some authors have estimated the overall economic cost of subclinical hypocalcemia to be 4 times that of clinical cases, resulting in a substantial impact on the profitability of dairy operations.10

Several strategies have been studied to enhance the ability of periparturient dairy cows to maintain calcium homeostasis. These practices include limiting total calcium intake prepartum (which may be difficult to achieve), adding a calcium chelator to the prepartum transition ration, and modifying the dietary cation-anion difference (DCAD) by feeding anionic salts prepartum, which has become the mainstay in many herds. Oral supplementation of calcium at calving has proven effective in reducing clinical milk fever.11 Research has shown that, even in very well-managed herds with a low incidence of clinical hypocalcemia, oral calcium supplementation may have health, reproductive, and increased production benefitsmost notably in lame and high producing cows.1214

There are several commercial boluses with substantial differences in composition, primarily with calcium chloride, calcium sulfate, and calcium carbonate. The dissolution properties of the commercial boluses will affect the delivery of product to the animal. Moreover, not all calcium salts are absorbed by the animal in the same manner. Calcium chloride and calcium sulfate are absorbed through the rumen wall by passive transport, whereas calcium carbonate is absorbed in the small intestine by vitamin D-dependant active transport.15 In addition, the acidogenic properties of calcium chloride and calcium sulfate stimulate parathyroid hormone (PTH) function, thereby increasing calcium resorption from bone, kidney tubular reabsorption of calcium, as well as absorption of calcium in the intestine.16

In order to evaluate differences in bolus composition with respect to calcium delivery, this study measured the dissolution times of three different boluses in fistulated animals and the in vivo uptake of two calcium sources utilizing two administration protocols.

The dissolution rate was evaluated for three commercially available boluses, each with different calcium chloride and calcium carbonate compositions: Bolus 1 (high calcium chloride, no calcium carbonate bolus): 209-g Bolus supplying 43 g of calcium from 112 g of calcium chloride dihydrate and 53.6 g of calcium sulfate (Cal-Boost Bolus, Solvet Animal Health, Calgary, Alberta, Canada); Bolus 2 (intermediate calcium chloride, intermediate calcium carbonate bolus): 176-g Bolus supplying 39.0 g of calcium from 106.9 g of calcium chloride, 4.5 g of calcium propionate, and 22.3 g of calcium carbonate (Transition Bolus, Vetoquinol N.-A Inc, Lavaltrie, Quebec, Canada); and Bolus 3 (low calcium chloride, high calcium carbonate bolus): 206-g Bolus supplying 54 g of calcium from 92.2 g of calcium chloride and 72.8 g of calcium carbonate (RumiLife CAL24 Bolus, Genex Cooperative Inc, Shawano, Wisconsin, USA). Table 1 shows the composition of these boluses. The research facility provided two fistulated steers, approximately 28 months of age and weighing 450 kg, 1-year post-cannulation. The steers were housed in an open-air feedlot pen approximately 18 meters deep and 36 meters wide and fed a total mixed ration (TMR) including barley silage, minerals, and vitamins from a feed mixer truck once daily (late afternoon) in a cement feed bunk upon the completion of the bolus study each day. Well water was supplied ad libitum from an automatic cattle waterer. A bolus was placed in a pre-weighed coarse mesh net with a recovery cord. The net and bolus were then placed in the rumen through a fistula. A pretreatment pH was determined using pH strips (pH Test Strips, EMD Millipore) and a pH meter (LRCpH logger, DASCOR Inc., Oceanside, California, USA). After 30, 60, 90, 120, 180, and 240 minutes, the bolus was recovered, weighed, described, and photographed. The recovered bolus was then returned to the rumen. The rumen pH was determined at each sampling time using pH strips, in order to ensure that the boluses were not causing acidosis. If the entire bolus was dissolved at the time of sample collection, sampling was terminated. Each animal only received one bolus at a time, with a minimum of one full day between tests. Each bolus type was tested a total of three times, meaning that it was tested twice in one animal and once in the other; the decision of which animal received which bolus type twice was made at random.

Table 1 Composition of the Commercially Available Boluses Used in This Study

A 380-cow Holstein dairy herd in the province of Quebec, Canada was selected. The study was conducted from November 2019 to March 2020. Cattle were housed in two tie-stall barns for the duration of their lactation, with a third tie stall barn dedicated to the dry and transition cows. Dry cows were moved to this third barn and were fed a dry cow ration. One month prior to their expected calving date, cows were transitioned to a prepartum ration consisting of 20 kg of grass silage, 5 kg of dry hay, 0.85 kg of soybean meal 48% and a 200-g mineral pack. The mineral concentration of this total ration was as follows: calcium 0.52% dry mass (DM.), phosphorus 0.33% DM, magnesium 0.38% DM, and potassium 2.4% DM. In mid-December, the potassium in the close-up ration was lowered. The new ration consisted of 7.85 kg of grass silage, 8 kg of corn silage, 3 kg of dry hay, and 4 kg of a supplement created for this farm. The modified mineral concentrations were calcium 0.56% DM, phosphorus 0.31% DM, magnesium 0.50% DM, and potassium 1.41% DM. The pre-partum ration was not prepared as a Total Mixed Ration (TMR) and therefore implementing a Dietary Cation-Anion Difference (DCAD) strategy was not deemed a practical option. Each cow was transferred to one of the milking barns the morning following calving.

Only cows in their second and third lactations were enrolled in this study. Because of the high level of potassium in both rations, all older cows (>third lactation) received intravenous calcium at calving to prevent clinical milk fever, sometimes followed by oral calcium supplementation, and were therefore not included in this study. Twenty-seven healthy second- and third-lactation cows with body condition score (BCS) of 2.753.5 and an estimated average weight of 767 kg (second lactation) or 787 kg (third lactation) were randomly allocated to one of three oral calcium treatment protocols (9 cows per group irrespective of parity). Treatment 1 received two high calcium chloride boluses (Cal-Boost Bolus, Solvet Animal Health, Calgary Alberta, Canada) at time 0; Treatment 2 received one high calcium chloride Cal-Boost Bolus (Solvet Animal Health, Calgary Alberta, Canada) at time 0 with a second bolus 12 hours later; and Treatment 3 received two high calcium carbonate boluses (RumiLife CAL24 Bolus, Genex Cooperative Inc, Shawano, Wisconsin, USA) at time 0. Treatments were initiated within 12 hours following calving and this was considered Time 0 (t=0). The intermediate calcium chloride/calcium carbonate bolus was excluded from this study as we were most interested in the two extremes (high calcium chloride vs high calcium carbonate). Cows calving between 5:00 p.m. and 5:00 a.m. commenced the protocol at 5:00 am. Cows calving between 5:00 a.m. and 5:00 p.m. started their protocol at 5:00 p.m. Blood was taken in a 10-mL red-topped vacutainer vial from the coccygeal vein pretreatment at time 0, and at 1, 6, 12, 13, and 24 hours post-treatment. The blood was immediately centrifuged on the farm (3000 rpm, 10 minutes) and the serum was transferred into a 3-mL red-topped vacutainer tube for storage at 18C. Total calcium was analyzed by an in-clinic Idexx Catalyst One Chemistry Analyzer. One cow in the Treatment 2 group developed clinical milk fever within 12 hours after receiving the initial bolus and was removed from the study because it did not receive the second bolus. Another cow in Treatment 3 also developed clinical milk fever; however, this was the day after the 24-hour study period and she was therefore included in the trial.

Even though allocation to treatment groups was randomized, there was an age discrepancy between groups. There were more older cows in Treatment 1, which explains the lower Time 0 serum calcium levels (Table 2). Upon analyzing the raw data from the first 27 animals, cows with more severe hypocalcemia had a greater response to oral calcium supplementation than cows with moderate hypocalcemia. With this new information, it was decided to end the original trial and to evaluate serum response to calcium supplementation depending on whether the cow had moderate (1.8 mmol/L) or severe (<1.8 mmol/L) hypocalcemia. The new trial consisted of second and third lactation cows assigned to Treatment 1. The additional enrollment resulted in 11 animals in the moderate and 10 in the severe hypocalcemia groups as depicted in Table 3.

Table 2 Initial Serum Calcium Concentration by Treatment Group

Table 3 Initial Serum Calcium Concentration in Animals with Severe vs Moderate Hypocalcemia

Statistical significance was determined based on a mixed model with repeated measures. Multiple comparisons (treatment effects at each time point) were analyzed using Tukeys multiple comparisons test or Sidaks multiple comparisons test. Data were assessed for normality using a ShapiroWilk test. The cut-off for significance was P < 0.05. The experimental unit was defined as each individual animal. Statistical analyses were carried out in Prism v 8.4.3 (GraphPad Software, San Diego, California, USA).

The dissolution rate of Bolus 1 (high calcium chloride, no calcium carbonate bolus) was the most rapid of the three calcium boluses tested, with the entire bolus being dissolved before 90 minutes in all three trials (Figure 1 and Table 4). Bolus 2 (intermediate calcium chloride, intermediate calcium carbonate bolus) was slower to dissolve, with complete dissolution by 240 minutes in two trials and 180 minutes in the third (Figure 1 and Table 4). Bolus 3 (low calcium chloride, high calcium carbonate bolus) was very slow to dissolve where, after 240 minutes, 75% of the original bolus weight was still present (Figure 1 and Table 4). No major fluctuations in rumen pH were observed over the time course for any of the tested boluses (Table 4).

Table 4 Wet Weights and Rumen pH of Various Calcium Boluses After Incubation in the Rumen of Fistulated Cattle

Figure 1 Dissolution of various calcium boluses in the rumen of fistulated cattle. Representative images of each bolus type are shown for each time point. Note that Bolus 1 had to be photographed in the recovery net at 30, 60, and 90 minutes due to its compromised structural integrity.

Treatment 2 (the single-dose regimen of high calcium chloride) yielded significantly higher serum calcium levels than Treatment 3 (the double dose of calcium carbonate bolus) at 1 hour, with similar calcium levels over the remainder of the time course (Figure 2). Treatment 1 (the double dose of the High Calcium Chloride bolus) yielded significantly higher serum calcium levels at 1 and 6 hours relative to Treatment 3, with similar levels over the remainder of the time course. Importantly, Treatment 1 yielded significantly higher serum calcium levels over the first 13 hours than Treatment 2 (Figure 2), indicating that two calcium chloride boluses at time 0 lead to a greater increase in serum calcium than the traditional regimen of giving one bolus each at t=0 and t=12 hours.

Figure 2 Changes in serum calcium upon treatment with commercial boluses. Treatments were initiated within 12 hours following calving (not before) and this time is considered Time 0 (t=0). Treatment 1 = two high calcium chloride boluses at Time 0; Treatment 2 = one high calcium chloride bolus at t=0 and another at t=12 hours; Treatment 3 = two high calcium carbonate boluses at t=0. Data represent the mean SEM (standard error of the mean) for 9 independent animals per treatment group. *P<0.05; **P<0.01; ***P<0.001, ****P<0.0001. Blue, orange, and red asterisks denote statistically significant differences between Treatment 1 vs 3, 2 vs 3, and 1 vs 2, respectively.

The severe hypocalcemia cattle had a greater and more persistent response to calcium supplementation than cows suffering from moderate hypocalcemia, with statistically significantly higher serum calcium levels at 6, 12, and 13 hours (Figure 3). The moderately hypocalcemic cows receiving Treatment 1 returned to their baseline value after 24 hours, while severely hypocalcemic cows receiving treatment 1 remained well above their baseline value even after 24 hours (Figure 3). These data suggest that two high calcium chloride boluses administered rapidly after calving are more effective at raising serum calcium compared to the traditional treatment of one bolus followed by a second bolus twelve hours later.

Figure 3 Changes in serum calcium upon treatment with two high calcium chloride boluses (Treatment 1) in animals with moderate hypocalcemia (>1.8 mmol/L) versus severe hypocalcemia (<1.8 mmol/L). Treatments were initiated within 12 hours following calving (not before) and this time is considered Time 0 (t=0). Data represent the mean SEM for 10 (severe hypocalcemic cows, treated with 2 high calcium chloride at t=0) or 11 (moderate hypocalcemic cows, treated with 2 high calcium chloride at t=0) animals. *P<0.05.

The objectives of this study were to evaluate dissolution times of boluses containing different calcium salts, and their effect on serum calcium in postpartum dairy cows. Calcium chloride and calcium sulfate are absorbed passively through the rumen wall by a process called paracellular absorption. Resistance to movement across the tight junction between epithelial cells can be overcome if the concentration of a mineral, in a freely ionized state, on the luminal side of the tight junction greatly exceeds the ionized concentration of that mineral in the extracellular fluids within the interstitial space on the other side of the tight junction.17 When ionized calcium in the rumen is greater than 6 millimoles (a fivefold increase from the extracellular fluid concentration), the diffusional force created by this difference will be great enough to push the calcium through the tight junction into the interstitial space, and from there it passes through the openings in the capillary endothelium and into the blood.17 This process is very rapid and serum calcium will peak in about an hour. Calcium carbonate is absorbed in the duodenum through the cell wall by vitamin D-dependent active transport. Parathyroid hormone (PTH) stimulates the kidneys to produce vitamin D which, in turn, activates the calcium-binding protein and the ATPase pump to transfer calcium ions through the cell wall into the blood. This process has little effect on raising serum calcium levels for at least 6 hours15 and this was confirmed in our study. In addition, calcium chloride and calcium sulfate are acidifying agents that increase the sensitivity of receptor cells to PTH. The in vivo dissolution study demonstrates that calcium boluses that contain calcium carbonate dissolve at a slower rate in the rumen. When comparing Bolus 2 and Bolus 3, the concentration of calcium carbonate is a good indicator of the boluss dissolution rate. The calcium uptake study confirmed that the bolus containing a high concentration of calcium carbonate did not raise serum calcium levels before at least 6 hours, even though two boluses were administered at once. Although this high calcium carbonate bolus contains approximately 44% calcium chloride, this calcium does not appear to be available to the cow before 6 hours. This is an important observation as cows need a rapid supplementation of calcium in the early postpartum period.15 The traditional protocol of administering one high calcium chloride bolus shortly after calving followed by a second bolus 12 hours later resulted in a similar two peak graph as reported in a Sampson et al (2009) study.16 Notably, the present study compared the traditional protocol (suggested by all brands) of giving one bolus at t=0 and another bolus 12 hours later to the more convenient protocol of giving two boluses at t=0, as the latter approach would be very appealing to a producer. Although it was not surprising that blood calcium peaked at a higher level following an initial dose of two high calcium chloride boluses because of the greater rumen calcium osmolarity, the persistence of this increase was higher than expected. Serum calcium levels were significantly superior to the two-bolus at a 12-hour interval regimen over the first 13 hours and remained numerically higher after 24 hours. When the trial involving Treatment 1 was prolonged to compare the response of cows with severe subclinical hypocalcemia to cows with normal/moderate hypocalcemia, both the serum calcium peak and serum calcium persistence was greater in the severe group. Both calcium chloride and calcium sulfate dissolve rapidly in the rumen. Passive transport of calcium ions between rumen epithelial cells into the extracellular fluid is dependent on diffusion down a concentration gradient.15 It stands to reason that the greater the difference between rumen calcium concentration and blood calcium concentration, the more efficient this passive transport will be, thus positively affecting the increase in serum calcium.

Before the arrival on the market of the calcium bolus, cows were commonly drenched with calcium salts. In one trial, various amounts of calcium chloride were administered to hypocalcemic cows as an oral drench. Three different amounts of calcium, provided by calcium chloride, were evaluated. Cows were orally administered either 50, 75 or 100 grams of calcium chloride twice within 24 hours. As expected, blood calcium concentrations increased as the doses of calcium chloride increased. However, three hours after the second treatment of 100 grams of calcium, the cow presented signs of severe metabolic acidosis with heavy and deep breathing. A treatment protocol of 75 grams of calcium from calcium chloride twice over 24 hours had no ill effects.15 In this study, calcium was provided as a pure calcium chloride solution.

In a more recent trial, cows received 86 grams of calcium for the first 2 days post calving followed by 3 consecutive days of 43 grams. Calcium was provided by triglyceride-coated oral boluses containing a combination of calcium chloride and calcium sulfate.18 They determined that the Blood pH did not differ with administration of oral calcium and averaged 7.488, 7.483, and 7.483 0.012 for 0, 43, and 86 g of calcium, respectively. Therefore, any negative health effects were not due to metabolic acidosis.

The present study suggests that administering two high calcium chloride/calcium sulfate boluses shortly after calving will be more effective in preventing clinical milk fever than the traditional protocol of one bolus after calving followed by a second bolus twelve hours later. Convenience is a huge factor when it comes to making decisions on the dairy farm and the recommendation to give two boluses 12 hours apart is neither convenient nor management or cow friendly.

Dairy cows experience many metabolic challenges around the time of calving. Some of these cows will experience clinical milk fever (510%), while up to 50% of mature cows in some herds will show no symptoms but have subclinical hypocalcemia (SCH).9,19 Recent studies have shown that chronic SCH is more damaging to health than transitory SCH.19,20 Our study focused on the serum calcium effects of supplementing calcium. Research conducted in the last decade has shown that SCH is associated with metabolic diseases,6 an increased susceptibility to metritis in the early postpartum period,3,4,6 a compromised reproductive performance,7 and increased culling rates in the early lactation.8 The awareness of the effects of subclinical hypocalcemia in postpartum dairy cows on the farm level has increased thanks to communication efforts by veterinarians and publications. The case for calcium supplementation has been made but many questions are left to answer on timing, composition, benefits, and dosing regimen of these boluses. Oetzel and Miller (2012) found that cows with higher previous lactation mature-equivalent milk production at 105% of their herd mates, that were supplemented with oral calcium boluses, produced 2.9 kg more milk at first DHIA (Dairy Herd Information Association) test than similar high producing cows not administered postpartum calcium supplementation.13 They also found that lame cows benefited from calcium supplementation. Martinez et al (2016) provided calcium boluses on multiple days with more than one bolus given at a time.21 High producing cows supplemented with calcium produced 0.8 to 2.7 kg more milk per day than their high producing peers not supplemented with calcium. They also concluded that supplementing cows with oral calcium reduced the incidence and prevalence of SCH, but that oral calcium increased the incidence of metritis. This negative effect was primarily observed in primiparous cows considered to be at low risk of metritis. However, reproductive performance improved in multiparous cows with this same regimen. Martinez et al (2016) suggested that this multiple-dose treatment regimen for oral calcium should be avoided in primiparous cows and target only populations at high risk of developing hypocalcemia.21 Domino et al (2017) found that cows with a high relative herd milk rank, that received calcium either subcutaneously or as a bolus, were almost half as likely as non-supplemented cows to be diagnosed with mastitis in the first 60 Days in Milk (DIM).22 They did not report any other health or production benefits between the control group and the two supplemented groups. Leno et al (2018) researched the effects of a single dose of oral calcium on postpartum plasma calcium concentration in Holstein cows and found that a single dose of an oral calcium bolus did not increase the blood calcium concentration between 1 and 24 hours following administration.12 However, responses observed for health and performance outcomes suggest that, in primiparous cows with higher age at first calving or higher body condition score (BCS) at parturition, calcium supplementation positively affected health status and early lactation performance, respectively.12 In multiparous cows, supplementation of cows with higher parity, higher BCS, and lameness also resulted in improved health status. Leno suggested that supplementing Ca could alleviate some of the underlying causes of increased risk for metabolic disease in these animals by supporting gut motility, which can be compromised when blood Ca declines.12 Improved gut motility could support a more rapid increase in postpartum intake and lead to a reduction in the rate or severity of metabolic disease, and higher DMI would support greater milk yield in these cows.12 For multiparous cows, those with low plasma calcium responded with decreased health disorders but cows with higher plasma calcium had varied responses. The authors concluded that low blood calcium concentration was less reliable than other periparturient risk factors to identify cows with a potential to favorably respond to calcium supplementation.

Target group calcium supplementation strategies have been found to be cost-effective.23 A two-bolus regimen, one administered after calving and the second about 24 hours later, was applied to herds following four treatment strategies: lame cows only, high producers only, lame cows and high producers, and all multiparous cows. Although there was a minor herd net impact with the blanket multiparous cow treatment strategy, the greatest return on investment was with the lame cows.

The question remains to be asked whether two boluses at once would be able to amplify these positive responses and whether giving two boluses simultaneously would reduce the number of animals in a herd with a persistent or delayed subclinical hypocalcemia. Giving two boluses at once would negate the need for additional handling (and the accompanying risk of injury to the animal) and likely reduce the behavioral impact of giving boluses the traditional way 12 hours apart. Our study demonstrates that a treatment of two initial high calcium chloride boluses significantly increases blood calcium over the first 13 hours after administration compared to the traditional administration of two boluses at a 12-hour interval. Furthermore, the persistence of these calcium levels remains numerically greater over the 24-hour period. Therefore, the recommendation to provide two boluses at once after calving is practical, convenient, safe, and will more than likely improve the compliance rate of providing the suggested application of two boluses.

A limitation of this study is the lack of blinding of farm personnel to treatments for the first part of the on-farm trial (27 cows) involving two different calcium boluses. However, treatments were administered to cows according to a randomized list prepared before commencement of the study. Farm personnel abided strictly by this list as well as the pre-established blood collection protocol. For the second part of the on-farm trial, all second- and third-lactation cows were administered the same type of bolus (Bolus 1; high calcium chloride) according to the same treatment regimen (two boluses simultaneously, within 12 hours of calving).

The dissolution study and the serum calcium response study in Quebec clearly demonstrate the complexity of a proper calcium supplementation. Boluses containing calcium carbonate may cause a delayed delivery of calcium when it is needed most, and this may ultimately have an impact on the health and wellbeing of the animal. Further research on the impact of calcium carbonate as it relates to the ability and to the timing of a serum calcium increase seems warranted. There are many different calcium boluses on the Canadian market and the dairy producer would likely benefit from the involvement of the herd veterinarian to help design a calcium bolus strategy. This study demonstrated that the increase in total calcium concentrations lasted for 24 hours when two high calcium chloride boluses were administered shortly after calving. Based on our study findings and on a literature review, the recommendation to provide two boluses at once after calving is practical, convenient, safe, and will likely improve the compliance rate of providing the suggested application of two boluses.

BCS, body condition score; DCAD, dietary cation-anion difference; DHIA, dairy herd information association; PTH, parathyroid hormone; SCH, subclinical hypocalcemia; TMR, total mixed ration.

The present field-based study was conducted in compliance with the best practice of veterinary care in accordance with the research guidelines set forth by the Canadian Council on Animal Care and was approved by the Institutional Animal Care and Use Committee (Airdrie, Alberta, Canada) and the Lacombe Research and Development Centre Animal Care Committee.

The owners provided informed consent for their animals to be used in the present study.

The authors wish to acknowledge the producer and the farm staff responsible for treatment administration, blood sample collection, centrifugation, and storage, as well as the technicians, the researchers, and the dairy animals that contributed to this study.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

The funding of both studies was entirely provided by Solvet Animal Health.

Dr Walter Verhoef reports personal fees from Solvet Canada, during the conduct of the study; personal fees from Bureau Vtrinaire de Richmond and Solvet Canada, outside the submitted work; is a partner in Bureau Vtrinaire de Richmond, and was consulting for Solvet. Dr Brenda Ralston reports Dr Merle Olson was her Masters supervisor in 2001; they have published numerous other papers and have collaborated on various grants. Dr Joseph A Ross reports compensation paid to his employer (Chinook Contract Research) for time spent writing, preparing figures, and statistical analyses for Alberta Veterinary Laboratories, during the conduct of the study. Dr Merle Olson reports personal fees from Alberta Veterinary Laboratories, during the conduct of the study; receives salary from Solvet, and Sjoert Zuidhof is providing consulting services to Solvet, which markets the Cal-Boost bolus. The authors report no other potential conflicts of interest for this work.

1. The Merck Veterinary Manual. 8th ed. Harcourt Brace & Co.; 1998.

2. Curtis CR, Erb HN, Sniffen CJ, et al. Association of parturient hypocalcemia with eight periparturient disorders in Holstein cows. J Am Vet Med Assoc. 1983;183(5):559561.

3. Martinez N, Risco CA, Lima FS, et al. Evaluation of peripartal calcium status, energetic profile, and neutrophil function in dairy cows at low or high risk of developing uterine disease. J Dairy Sci. 2012;95(12):71587172. doi:10.3168/jds.2012-5812

4. Martinez N, Sinedino LD, Bisinotto RS, et al. Effect of induced subclinical hypocalcemia on physiological responses and neutrophil function in dairy cows. J Dairy Sci. 2014;97(2):874887. doi:10.3168/jds.2013-7408

5. Daniel RC. Motility of the rumen and abomasum during hypocalcaemia. Can J Comp Med. 1983;47(3):276280.

6. Rodrguez EM, Ars A, Bach A. Associations between subclinical hypocalcemia and postparturient diseases in dairy cows. J Dairy Sci. 2017;100(9):74277434. doi:10.3168/jds.2016-12210

7. Chapinal N, Carson M, Duffield TF, et al. The association of serum metabolites with clinical disease during the transition period. J Dairy Sci. 2011;94(10):48974903. doi:10.3168/jds.2010-4075

8. Roberts T, Chapinal N, Leblanc SJ, Kelton DF, Dubuc J, Duffield TF. Metabolic parameters in transition cows as indicators for early-lactation culling risk. J Dairy Sci. 2012;95(6):30573063. doi:10.3168/jds.2011-4937

9. Reinhardt TA, Lippolis JD, McCluskey BJ, Goff JP, Horst RL. Prevalence of subclinical hypocalcemia in dairy herds. Vet J. 2011;188(1):122124. doi:10.1016/j.tvjl.2010.03.025

10. Sasidharan V. Prevent milk fever and economic loss with oral calcium supplements. Prog Dairyman. 2014.

11. Goff JP. Macromineral physiology and application to the feeding of the dairy cow for prevention of milk fever and other periparturient mineral disorders. Animal Feed Sci Technol. 2006;126(34):237257. doi:10.1016/j.anifeedsci.2005.08.005

12. Leno BM, Neves RC, Louge IM, et al. Differential effects of a single dose of oral calcium based on postpartum plasma calcium concentration in Holstein cows. J Dairy Sci. 2018;101(4):32853302. doi:10.3168/jds.2017-13164

13. Oetzel GR, Miller BE. Effect of oral calcium bolus supplementation on early-lactation health and milk yield in commercial dairy herds. J Dairy Sci. 2012;95(12):70517065. doi:10.3168/jds.2012-5510

14. Neves RC, Leno BM, Stokol T, Overton TR, McArt JAA. Risk factors associated with postpartum subclinical hypocalcemia in dairy cows. J Dairy Sci. 2017;100(5):37963804. doi:10.3168/jds.2016-11970

15. Goff JP, Horst RL. Oral administration of calcium salts for treatment of hypocalcemia in cattle. J Dairy Sci. 1993;76(1):101108. doi:10.3168/jds.S0022-0302(93)77328-2

16. Sampson JD, Spain JN, Jones C, Carstensen L. Effects of calcium chloride and calcium sulfate in an oral bolus given as a supplement to postpartum dairy cows. Vet Ther Fall. 2009;10(3):131139.

17. Goff JP. Invited review: mineral absorption mechanisms, mineral interactions that affect acid-base and antioxidant status, and diet considerations to improve mineral status. J Dairy Sci. 2018;101(4):27632813. doi:10.3168/jds.2017-13112

18. Martinez N, Sinedino LDP, Bisinotto RS, et al. Effects of oral calcium supplementation on mineral and acid-base status, energy metabolites, and health of postpartum dairy cows. J Dairy Sci. 2016;99(10):83978416. doi:10.3168/jds.2015-10527

19. Caixeta LS, Ospina PA, Capel MB, Nydam DV. Association between subclinical hypocalcemia in the first 3 days of lactation and reproductive performance of dairy cows. Theriogenology. 2017;94:17. doi:10.1016/j.theriogenology.2017.01.039

20. McArt JAA, Neves RC. Association of transient, persistent, or delayed subclinical hypocalcemia with early lactation disease, removal, and milk yield in Holstein cows. J Dairy Sci. 2020;103(1):690701. doi:10.3168/jds.2019-17191

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22. Domino AR, Korzec HC, McArt JAA. Field trial of 2 calcium supplements on early lactation health and production in multiparous Holstein cows. J Dairy Sci. 2017;100(12):96819690. doi:10.3168/jds.2017-12885

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[Full text] Dissolution Rates of Calcium Boluses and Their Effects on Serum Calciu | VMRR - Dove Medical Press

Participants and study design

The BioCycle Study (20052007) was a prospective cohort study designed to evaluate the relationship between reproductive hormones and oxidative stress levels throughout the menstrual cycle [26, 27]. The participant cohort consisted of 259 regularly menstruating, healthy women between the ages of 1844years, recruited from western New York. Participants were recruited in a variety of ways, including: advertising in clinical practices and the University at Buffalo student health center, paid advertising in print media, radio and television interviews, notices sent via list serves, and flyers at the university and throughout the region. For those interested, an initial screening phone call was conducted, followed by a mailing and an in-person visit. Exclusion criteria included factors that may interfere with a normal menstrual cycle or vitamin levels, such as: use of oral contraceptives during the study period or in the previous three months; use of Depo provera, implant or IUD in previous twelve months; current use of vitamin, mineral, or herbal supplements; use of prescription medications; pregnancy or breast feeding in the previous six months; reported attempts to conceive in the previous six months; diagnosis of uterine abnormalities or chronic conditions, such as ovulatory disorders and premenstrual dysphoric disorder (PMDD); and a self-reported body mass index (BMI) of <18 or >35kg/m2 at screening [27]. Those eligible and interested after the screening visit were scheduled for a baseline enrollment visit 12weeks prior to the start of their next menses. Women were followed for one (n=9) or two (n=250) menstrual cycles (Additional file 1: Figure S1).

Women completed up to 8 clinic visits per cycle for up to 2 cycles. Study visits were scheduled using fertility monitors (Clearblue Easy Fertility Monitor; Inverness Medical, Waltham, Massachusetts) to coincide with critical phases of the menstrual cycle, including menstruation; mid- and late follicular phases; luteinizing hormone (LH) surge (predicted ovulation); and early, mid-, and late luteal phases [28]. At each of these visits, fasting blood samples were collected from participants from which the antioxidant vitamins and oxidative stress concentrations were measured. Participants were highly compliant with the study protocol; 94% of the women completed 7 or 8 clinic visits, and 100% completed at least 5 clinic visits per cycle.

The University at Buffalo Health Sciences Institutional Review Board (IRB) approved this study and served as the IRB designated by the National Institutes of Health under a reliance agreement. All participants provided written informed consent. Further details of the study design are described elsewhere [27].

Ascorbic acid (vitamin C), retinol (vitamin A), and - and - tocopherol (vitamin E) were measured in all blood samples taken from participants across a menstrual cycle and subsequently averaged to reflect the mean levels across a cycle. Total ascorbic acid was determined by the dinitrophenylhydrazine (DNPH) method. Samples for ascorbate analysis were stabilized immediately following phlebotomy and centrifugation by adding 0.5mL of heparin plasma to 2.0mL of 6% meta-phosphoric acid and centrifuging at 3000g for 10min. Clear supernatant was decanted and frozen at 80C for analysis. The absorbance of each DNPH derivatized sample was determined at 520nm on a Shimadzu 160U spectrophotometer (Shimadzu Scientific Instruments, Inc.). Across the study period, the coefficient of variation (CV) for this test reported by the laboratory was 10%.

Fat-soluble vitamins (including retinol, and vitamin E components: - and -tocopherol) were measured at the Kaleida Health Center (Buffalo, New York) simultaneously in serum using high performance liquid chromatography with photodiode array detection [29]. -tocopherol was also detected but was below the lower limit of quantification for our assay (0.28). The limits of detection were 0.0054 for retinol, 0.0768 for -tocopherol, and 0.1052 for -tocopherol. The CV for these tests across the study period were <6% for retinol and <2% for - and -tocopherol. Continuous monitoring of standard reference material 968c from the National Institute of Standards and Technology (NIST) and participation in the NIST Micronutrients Measurement Quality Assurance Program provided external checks on analytical accuracy.

Mean concentrations of antioxidants, including vitamin A, vitamin C, -tocopherol, and -tocopherol, were calculated per cycle and were used in all analyses. Overall median concentrations were also compared with levels reported previously by reproductive aged women (i.e., 2039years) in the 2012 National Health and Nutrition Examination Survey (NHANES) to assess the comparability of our results with those of a nationally representative population [30].

Plasma free F2-isoprostane, a breakdown product of ROS and a marker of oxidative stress, was measured with a gas chromatography-mass spectrometrybased method by the Molecular Epidemiology and Biomarker Research Laboratory (University of Minnesota, Minneapolis, Minnesota) (CV=9.4%).

Frequency and severity of 20 premenstrual symptoms was assessed through questionnaires completed at four time points of each menstrual cycle: menses, follicular phase, peri-ovulation, and luteal phase (Additional file 2: Figure S2). Participants recalled the occurrence and severity of symptoms in the prior week. The symptoms included in this assessment were: sadness, crying spells, anger, nervousness, insomnia, tension, abdominal bloating, cravings of chocolates, cravings of sweets, cravings of salty foods, cravings of other foods, breast tenderness, lower abdominal cramping, general aches, backache, headache, acne outbreaks, change in appetite, fatigue, and swelling of the hands/feet. The severity of each symptom was ranked by the participant on a scale of 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe). The symptoms included in this questionnaire were adapted from validated surveysincluding the Daily Record of Severity of Problems (DRSP) and the Premenstrual Symptoms Screening Tool (PSST)but slightly modified, given that DRSP and the PSST were designed to identify patients with PMDD specifically (a population excluded in our study) [31,32,33,34].

We categorized severity as none/mild (reference group) or moderate/severe to estimate odds of having a moderate or severe symptom during the premenstrual week. We then calculated severity scores for groups of related symptoms by summing the severity score of symptoms (as reported in the premenstrual week) within each grouping to generate an overall score. The groupings were established based on clinical expertise and included: depression (sadness, crying spells, anger) and anxiety (nervousness, insomnia, tension); hydration (abdominal bloating) and cravings (chocolate cravings, sweets cravings, salty food cravings, other food cravings); pain (breast tenderness, lower abdominal cramping, general aches, backache, headache); and other (acne outbreak, change in appetite, fatigue, swelling of hands or feet).

Overall PMS severity was evaluated using four different approaches, which utilize information on all symptoms from the luteal and follicular phase questionnaires from each cycle: (1) 5 or more moderate or severe symptoms during the luteal phase; (2) 8 or more moderate or severe symptoms during the luteal phase; (3) 3 or more moderate or severe symptoms where the luteal phase score was 30% greater than the follicular phase and at least one symptom was psychological (referred to as PMS-1 in the tables and results); and (4) 5 or more moderate or severe symptoms where the luteal phase score was 30% greater than the follicular phase and at least one symptom was psychological (referred to as PMS-2 in the tables and results) [8, 35, 36]. When summing the number of moderate or severe symptoms for each cycle, each of the individual cravings symptoms were combined into a single variable. These criteria were based upon various defintions of PMSincluding those of the National Institute of Mental Health, [37] the American College of Obstetrics and Gynecology, [38] the American Psychiatric Association, [39] and the International Society for Premenstrual disorders (ISPMD) [40]which were further expanded and implemented in studies such as Gollenberg et al. [35] and Borenstein et al. [8] Of note, these approaches attempt to establish the necessary temporality between pre- and post-menstrual symptoms in line with traditional PMS definitions and diagnoses that assume resolution of symptoms within 12days of the onset of menses.

At study enrollment, a trained research assistant measured height and weight for the calculation of BMI using standardized protocols. Demographics such as age, race, education, smoking habits, reproductive history, and physical activity were also collected at baseline through self-reported questionnaires. Physical activity was assessed at baseline using the International Physical Activity Questionnaire, and estimated for high, moderate, and low levels of activity based upon accepted cutoffs [41]. Dietary information was obtained using 24-h recalls (up to 4 times per cycle) and analyzed using the Nutrition Data System for Research software (version 2005) developed by the Nutrition Coordinating Center of the University of Minnesota (Minneapolis, Minnesota). Cycle-averaged measures of total energy (kcal/day) and fiber (g/day) were used in these analyses, as we previously found these intakes do not vary significantly across the cycle [42]. All covariates assessed had at least a 95% response rate.

Demographic characteristics were compared between those with <5 versus 5 moderate or severe symptoms during the luteal phase of either study menstrual cycle, and between those with <8 versus 8 moderate or severe luteal phase symptoms in either cycle. Repeated measures ANOVA and McNemars tests were used for comparisons.

We estimated associations between mean antioxidant concentrations and F2-isoprostane concentrations from each menstrual cycle and odds of reporting a moderate/severe symptom during the premenstrual week for each cycle using generalized linear models. Next, we evaluated associations between antioxidant concentrations, F2-isoprostane concentrations, and scores for symptom severity within groups during the premenstrual week (e.g., depression, cravings, pain) using linear mixed models. We used generalized linear models to assess the association between mean antioxidant concentrations, F2-isoprostane concentrations, and overall PMS severity in each cycle using the four different classifications of PMS severity (5 or more moderate or severe symptoms, 8 or more moderate or severe symptoms, PMS-1 criterion, PMS-2 criterion). All models were adjusted for age, race, BMI, physical activity, smoking status, alcohol use, pain reliever use, and average total energy intake per cycle and accounted for repeated measures (i.e., multiple cycles per woman). Results were adjusted for multiple comparisons using the false discovery rate (FDR). An alpha of 0.05 was considered statistically significant. As antioxidants and oxidative stress measures have been shown to vary somewhat over the menstrual cycle [26, 43], we also evaluated associations between time-varying measures of antioxidants and oxidative stress, with time-varying symptoms as a sensitivity analysis. Splines were used to evaluate the assumption of linearity. We did not find evidence to suggest that linear modeling was inappropriate (e.g., quadratic or restricted cubic spline modeling did not help explain the associations in our population). All statistical analyses were calculated using SAS 9.4 (SAS Institute, Cary, North Carolina).

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National Review

President Joe Bidens recent executive order to expand food assistance to U.S. households, while well-intentioned, represents a substantial overreach of the executive branch and a blatant attempt to override the intent of Congress. If successful, this dangerous precedent would open the door to major expansions of the social safety net without congressional approval. Congress must resist the presidents attempts to subvert the intent of existing law. Less than one week into the Biden presidency, the new administration issued a series of executive orders focused on COVID-19 economic relief. One such order seeks to expand food assistance through the Supplemental Nutrition Assistance Program (SNAP), or food stamps. In it, President Biden instructed the Department of Agriculture (USDA) to take immediate steps to make it easier for the hardest-hit families to enroll and claim more generous benefits in the critical food and nutrition assistance area. In reality, the executive order asks a federal agency the USDA to intentionally misinterpret the Families First Act and subvert the constitutional authority of Congress over the legislative process. The Families First Act, which passed in March 2020, clearly outlined that states could request waivers from the Agriculture Department to provide emergency allotments to SNAP households not greater than the applicable maximum monthly allotment for the household size. In normal times, 60 percent of households enrolled in SNAP do not receive the maximum benefit because they have income from other sources such as earnings that they can use for purchasing food. The emergency allotments recognized that millions of people lost jobs or faced other employment disruptions when the pandemic hit, and that those enrolled in SNAP were at particular risk for job loss in the early aftermath of the pandemic. Rather than requiring SNAP households to report a job or income change to their state agency and wait for bureaucrats to recalculate their benefits, the emergency allotments gave every SNAP recipient the maximum allowed. This was, admittedly, not a very targeted effort. Some families received a boost in SNAP dollars without a change in household income or financial circumstances. But the immediacy of the economic shock brought on by the pandemic, and the employment instability that persists today, necessitated an equally expedient policy response. The Agriculture Department, under President Trump, had approved emergency allotment plans for all 50 states, the District of Columbia, Guam, and the U.S. Virgin Islands but only in accordance with the law. The department extended these emergency-allotment waivers numerous times, most recently extending them through January 2021. The USDA and Congress itself also offered states flexibility in the aftermath of the pandemic. According to federal government spending data, all of the efforts outlined above have caused SNAP benefits to rise more than 40 percent in the last fiscal year, with more than $31 billion in added spending compared to FY 2019. Class-action suits have been filed in Pennsylvania and California by people who disagree with the USDAs interpretation of the law: that regular SNAP plus emergency allotments cannot extend benefits beyond the maximum benefit level. Lawyers for the lawsuits argue that the law allows the USDA to approve emergency allotments in the amount of the maximum benefit, which if true, would mean that households could receive the maximum SNAP benefit plus the maximum emergency allotment essentially doubling benefit amounts. A federal judge in California agreed with the USDA, while the Pennsylvania case is ongoing. The Biden administrations executive order is encouraging its USDA to misinterpret the 2020 law in a similar way. The legislative text is not ambiguous. It is hard to imagine Congress being any clearer than, to address temporary food needs not greater than the applicable maximum monthly allotment for the household size. If Congress had wanted to give people more than the SNAP maximum, it would have done so. In fact, Congress eventually did just that expanding benefits by 15 percent in the COVID-19 relief package passed last month. If the Biden administration is successful in this attempt, it will open the door to a number of executive actions aimed at expanding the safety net without congressional action. If political appointees in the Biden administration feel unconstrained by the law, we will see larger benefits directed to an increasing number of people. Such action not only undermines the integrity of the social safety net by going around Congress, it disregards the separation of powers ensconced in the founding documents of our republic. The American public has been largely supportive of efforts by Congress to provide economic relief to struggling households. Lets keep that authority in its proper place.

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