"Cancer is a disease of genetics, yet clinical practice has struggled to keep pace with rapid advancements in research, particularly with respect to the role of germline genetics. Testing guidelines and medical policy often codify barriers, further lengthening the path to adoption of widespread testing and in some cases restricting access to precision therapies and clinical treatment trials," said Ed Esplin, M.D., Ph.D., FACMG, FACP, clinical geneticist at Invitae. "Research presented at ASCO shows that cancer-linked genetic changes are common across cancer types and when patients do receive germline testing, over two thirds of those with positive results are eligible for changes to their treatment plans. It's clear that incorporating germline testing alongside tumor profiling can help oncologists better tailor treatment for each patient."

Data from 250 pancreatic cancer patients from the landmark INTERCEPT study conducted at the Mayo Clinic found that nearly one in six patients with pancreatic cancer (n=38) showed cancer-linked genetic changes and, importantly, receiving germline testing was associated with improved survival.

A separate study of prostate cancer patients confirmed similar findings in other cancer types that limiting testing deprives patients and clinicians of actionable information. In the first-ever presentation of the PROCLAIM study, which was conducted primarily in community urology clinics, of patients diagnosed with prostate cancer, a significant number of cancer-linked variants were missed if testing was done based on NCCN guidelines. Of the 532 patients with clinician-reported data, nearly half, 45% (n=239), did not meet NCCN criteria. Overall, 59 patients had a cancer-linked variant; one in 10 of them did not meet the criteria (9.6%, n=23), and 12.3% (n=36) of patients met the criteria. When a 12-gene panel was used, only 29 patients were found to have a cancer-linked variant and one third of these patients were missed by guidelines.

A third study showed simply changing medical policy is not enough to drive changes in clinician adoption. In a review of two independent datasets, including commercially insured and Medicare Advantage enrollees, only 3% (n=1,675) of the 55,595 colorectal cancer patients received germline genetic testing, despite medical policy recommending germline genetic testing for all colorectal cancer patients (consistent with the INTERCEPT colorectal cancer study). Of the patients who received testing, 18% (n=143) had a cancer-linked variant and two thirds, or 67% (n=96), of those patients were potentially eligible for precision therapy and/or clinical trials.

"The data have been available for years that show knowing what changes patients have in their genes is beneficial to treating their cancer. Yet the oncology community has been slower to adopt germline testing than tumor profiling, for reasons that are not entirely clear. These data presented at ASCO highlight the need for oncologists to embrace germline genetic testing as routine practice for all cancer patients," said Robert Nussbaum, M.D., chief medical officer at Invitae. "A positive germline genetic result may enable patients to enroll in clinical trials or gain access to new precision medicines. And equally important, the discovery of an inherited variant can alert relatives to seek out earlier cancer screening, helping avoid later-stage diagnoses and offering a treatment benefit if cancer develops."

Invitae aims to help overcome obstacles to the adoption of genetic testing by providing physicians with clinical consults to help interpret results and reducing cost as a barrier to genetic information. Invitae also provides patients direct access to genetic counselors, helping to integrate routine genetic testing into patient care with GIA, a HIPAA-compliant chatbot. Family members are also able to receive no-charge genetic testing if a positive result is found.

Details of the 2021 ASCO presentations:

Oral Abstract Session: Prevention, Risk Reduction, and Hereditary Cancer

Poster Discussion Session: Prevention, Risk Reduction, and Hereditary Cancer

Poster Session: Prevention, Risk Reduction, and Hereditary Cancer

Poster Session: Gastrointestinal Cancer--GastroesophageaI, Pancreatic, and Hepatobiliary

About InvitaeInvitae Corporation(NYSE: NVTA) is a leading medical genetics company whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the benefits of germline testing and genetic information; and that the data presented at ASCO highlight the need for increased germline testing in all cancer patients regardless of medical policy. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's history of losses; the company's ability to compete; the company's failure to manage growth effectively; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended March 31, 2021. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:Laura D'Angelo[emailprotected](628) 213-3283

SOURCE Invitae Corporation

http://www.invitae.com

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Germline genetic testing can benefit all cancer patients as a routine practice in cancer care - PRNewswire

Recommendation and review posted by Bethany Smith

ADELAIDE, Australia, May 25, 2021 /PRNewswire/ --IVF Life Group, a leading group of IVF clinics across Spain, UK, and Germany, will be among the first in Europe to use Artificial Intelligence (AI) to non-invasively assess embryos to determine their genetic integrity. The AI product Life Whisperer, developed by global healthcare company Presagen, uses images of embryos to assess their quality to assist with embryo selection, and ultimately improve IVF outcomes for patients.

Currently, PGT-A genetic testing is one of the most used techniques that requires careful removal of three to five cells from an embryo to analyse its genetic integrity. As the procedure is still not available in some countries, and is quite invasive, Life Whisperer and its AI technology can also assist with this assessment.

Life Whisperer Genetics, which this month received CE Mark in Europe, requires only standard camera images of embryos to assess their genetic integrity. In a US study simulating 91,500 individual patient embryo cohorts, Life Whisperer Genetics ranked the genetically normal (euploid) embryo top in 82% of the patient cohorts. Furthermore, in 96% of the cohorts Life Whisperer Genetics ranked the at least one genetically normal embryo in the top two embryos.

Presagen's first product Life Whisperer Viability assesses the same images of embryos to determine their likelihood of leading to a pregnancy, and is already in use in IVF clinics globally.

Founder & President of IVF Life Group, Dr. Jon Aizpurua said "For the next two months, IVF Life will offer all patients, at no additional cost, the use of both Life Whisperer Genetics and Life Whisperer Viability. Although patients may still elect to use PGT-A testing, Life Whisperer offers an important pre-screen to help us select the best embryos for further genetic testing, transfer, or freezing."

Presagen CEO, Dr Michelle Perugini said "We are excited to be working with IVF Life to enable patients across Europe to access the latest AI technology to help improve their chances of a healthy pregnancy, whilst reducing treatment costs."

Life Whisperer is already authorised for sale in the UK, Canada, Australia, Japan, India, Thailand, New Zealand, Hong Kong, Singapore and Malaysia.

SOURCE Presagen

https://www.presagen.com/

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IVF Life the first clinic group in Europe to use Artificial Intelligence to non-invasively assess the genetic integrity of embryos - PRNewswire

Recommendation and review posted by Bethany Smith

A brief analysis of the basic details of Prenatal and Newborn Genetic Testing Market valuation, industry expansion, and market growth opportunities affecting market growth. Likewise, this analysis provides a comprehensive view of technology spending over the forecast period and offers a unique perspective on the Prenatal and Newborn Genetic Testing market in each of the categories included in the survey. The Prenatal and Newborn Genetic Testing Industry Review helps customers assess the challenges and prospects for the company. The investigation includes analyzing the latest keyword business forecast for the relevant period. In addition, the annual industry study contains the latest information on technical developments and market development opportunities depending on the geographic climate. The Prenatal and Newborn Genetic Testing market also includes technology / innovation, a comprehensive outlook on future developments, research and development activities and new products.

Advanced methods are also used to plan the Prenatal and Newborn Genetic Testing industry analysis, as well as the sales and supplier overview of the Prenatal and Newborn Genetic Testing industry. A study of the Prenatal and Newborn Genetic Testing market offers a complete analysis of geographic dynamics, market developments and market shares at the country level of the Prenatal and Newborn Genetic Testing market. A number of key factors were considered during the study, including product definition, market size, product classification, and various ecosystem participants in the Prenatal and Newborn Genetic Testing market.

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The report covers the following key players in the Prenatal and Newborn Genetic Testing Market:

Abbott Laboratories Bio-Rad Laboratories Qiagen N.V. Natera Illuminaxx

Segmentation of Prenatal and Newborn Genetic Testing Market:

This section of the report provides important information on various types of products and service variants available in the Prenatal and Newborn Genetic Testing market, as well as the scope of their futuristic developments and the associated ability to generate revenue. This section of the report clearly focuses on the usefulness of various products and services available in the market and the diverse developments that meet user preferences.

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Prenatal and Newborn Genetic Testing Market Report Scope

Prenatal and Newborn Genetic Testing Geographic Market Analysis:

This research study draws on multiple layers of data including business analysis (industry trends), high-level market share analysis, supply chain analysis, and brief company profiles that together provide and analyze fundamental perspectives on the competitive landscape. High growth business growth trends and segments, high growth countries, market forces, controls, market drivers, market restrictions and drivers, and restraints. This is the most recent study that includes a strategic assessment as well as an in-depth review of the market plans, approaches, brands and manufacturing capabilities of the world's leading industry leaders.

North America (USA, Canada, Mexico) Europe (Great Britain, France, Germany, Spain, Italy, Central and Eastern Europe, CIS) Asia Pacific (China, Japan, South Korea, ASEAN, India, rest of Asia Pacific) Latin America (Brazil, rest of LA) Middle East and Africa (Turkey, CCG, rest of the Middle East)

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This in-depth study also includes a detailed description and interpretation of each chapter of the analysis. In order to give the users of this study a detailed insight into the Prenatal and Newborn Genetic Testing industry, we have provided a comprehensive competitive landscape as well as a product inventory of the most important suppliers in different regions. Each chapter of the review is also defined and interpreted in detail in this systematic report. In order to provide users of this factsheet and a detailed overview of the Prenatal and Newborn Genetic Testing industry, we have created a broad competitive landscape as well as a product summary of the major suppliers in various geographic economies.

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Prenatal and Newborn Genetic Testing Market Size And Forecast 2021-2028 | Top Key Players Abbott Laboratories, Bio-Rad Laboratories, Qiagen NV,...

Recommendation and review posted by Bethany Smith

DNA molecule

KTSDESIGN / SCIENCE PHOTO LIBRARY / Getty Images

The Human Genome project was a huge feat for the scientific community at the turn of the 21st century. Charting our entire human genetic code, giving us the opportunity to predict disease and go on to create personalised drug treatments.

The techniques for personal genetic analysis are now relatively cheap and accurate, which has lead to a host of consumer products. Marketed for our individual health risks, personality types, athletic ability and ancestral roots; some of the common health predictors include breast/bowel cancer, diabetes, cholesterol, Parkinson's and Alzheimer's dementia. They include many rare medical conditions, but can also give you information on your eye colour, susceptibility to caffeine/alcohol/obesity, and even forecast the smell of your urine after eating asparagus (this doesn't happen to everyone).

However, despite providing some interesting insights, this convenient 'crystal ball' into our future selves, could equally offer false reassurance, heightened anxiety and some confusion. For example, would you want to live your life in fear of developing Alzheimer's dementia or Parkinson's without any cure on the horizon?

A pre-requisite to most genetic testing in hospital, is a consultant geneticist or a genetic counsellor to help navigate the complex ethical terrain and often misguided interpretation.

The 'Direct to Consumer' genetic test kits, which can be purchased online, usually rely on a saliva sample sent to the lab. It takes a few weeks before the results are delivered online, with detailed analysis and intriguing information. For those of you interested in carrying this out, I would urge you to consider the pros and cons:

PROS:

CONS:

In summary, It may be more important to focus on leading a healthy lifestyle, regardless of the results. Clean diets, regular exercise, careful weight control and avoiding environmental triggers such as smoking/ UV exposure etc. One of the best ways to identify health needs is to understand your family's medical history of mental and physical conditions.

If you have a positive result and have no clear family history of that condition, it is unlikely that you will suffer from it. Inversely, if you have a negative result, but have a strong family history, you may need to ask your GP for further clinical genetic testing. It would be worth first seeking the advice of a genetic counsellor before embarking on any commercial test.

If you are curious about certain traits such as ability to taste bitterness, your ice cream preference, propensity to get dandruff or back hair, then it is informative and interesting, but for health predictability, the industry seems to be outpacing the science. In the future, with Artificial Intelligence and larger databanks, these test should become more reliable.

Dr Tim Lebens is a private GP in Central London, with a subspecialty in health optimisation and latest advances in medicine. Visit his website drlebens.com or follow him on Instagram @_modernmedicine.Although every effort has been made to ensure that all health advice is accurate and up to date, it is for information purposes only and should not replace a visit to your doctor or health care professional.

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One of London's top doctors weighs up the pros and cons of DIY genetic test kits - Tatler

Recommendation and review posted by Bethany Smith

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Direct-To-Consumer (DTC) Genetic Testing market (2021-2028) current situation and development research possibilities pinpoint to change sharp elements and a point of view on the future of variables ?? or limiting the development of the industry. The Direct-To-Consumer (DTC) Genetic Testing market offers an exhaustive analysis of the market size, participation, degree of development, and Outlook of the Direct-To-Consumer (DTC) Genetic Testing business. This report gives all the fundamental data needed to understand the vital advances in market-to-market spending and the development of Direct-To-Consumer (DTC) Genetic Testing standards for each fragment and locality. The implementation of the action research, the Direct-To-Consumer (DTC) Genetic Testing markets, both in terms of volume and income and this is a factor that is valuable and effective for your business.

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Competitive Landscape

The full profile of the companies is mentioned. And the Direct-To-Consumer (DTC) Genetic Testing Market size, production, price, revenue, cost, terrifying margin, gross, sales volume, sales revenue, consumption, buildup rate, Import, Export, Supply, well along strategies and the technological developments they are making are moreover included in the report. Historical data from 2014 to 2019 and predict data from 2021 to 2028.

Direct-To-Consumer (DTC) Genetic Testing Market Leading Key players:

Market segmentation of Direct-To-Consumer (DTC) Genetic Testing market:

Direct-To-Consumer (DTC) Genetic Testing market is divided by type and application. For the period 2021-2028, cross-segment growth provides accurate calculations and forecasts of sales by Type and Application in terms of volume and value. This analysis can help you grow your business by targeting qualified niche markets.

Direct-To-Consumer (DTC) Genetic Testing Market breakdown by type:

Direct-To-Consumer (DTC) Genetic Testing Market breakdown by application:

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Direct-To-Consumer (DTC) Genetic Testing Market Report Scope

Regional market analysis Direct-To-Consumer (DTC) Genetic Testing can be represented as follows:

For clarity, analysts also segmented the market based on geography. This type of segmentation allows readers to understand the volatile political scenario in different regions and their impact on the global digital Isolator market. The base of geography, the world market of Direct-To-Consumer (DTC) Genetic Testing has segmented as follows:

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The scope of the report consolidates an in-depth examination of the global market Reached 2021-2028 with the apprehension given to the company's progress in specific regions.

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Market Research Intellect provides syndicated and customized research reports to clients from various industries and organizations in addition to the objective of delivering customized and in-depth research studies.

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Direct-To-Consumer (DTC) Genetic Testing Market Outlook 2021, Analysis and Forecast to 2028 by Manufacturers| Ancestry, Mapmygenome, Color Genomics,...

Recommendation and review posted by Bethany Smith

Researchers atThe Ohio State University Wexner Medical Centerled an international group of experts that worked together to classify 19 genes associated with dilated cardiomyopathy (DCM) as having high impact on the heart muscle disease.

Researchers believe most of DCM has a genetic background, and at least 30 percent of people with DCM have a family member with the disease. First-degree family members (daughters, sons, brothers, sisters and parents) of a patient with DCM are encouraged to undergo genetic testing for the disease.

However, current genetic testing panels analyze dozens, sometimes hundreds of genes, and they often have limited scientific support, making genetic results clinically difficult to interpret.

When we get results back for a patient with dilated cardiomyopathy, we often see multiple variants in multiple genes. For many genes, we dont know how strongly theyre associated with the condition. By narrowing down the number of genes thought to be disease causing to 19, we can better use genetic information for a diagnosis and give the family a genetic marker to test family members not showing any signs of the disease. Ideally, we can then find who is at risk before they develop DCM, said Elizabeth Jordan, a genetic counselor in the Division of Human Genetics at the Ohio State Wexner Medical Center, and lead author on the study published in the American Heart AssociationsCirculation.

Dilated cardiomyopathy is a condition in which the heart muscle weakens and the left ventricle enlarges. Its the most common cause for patients needing a heart transplant and is responsible for about half of heart failure cases.

For the yearlong study, Stephanie Schulte, head of research and education services at the Health Sciences Library at The Ohio State University, helped develop an initial list of 267 genes after examining various databases. Jordan, along with co-author Laiken Peterson, a genetic counselor atThe Ohio State University College of Medicine, and senior author,Dr. Ray Hershberger, division director of human genetics at the Ohio State Wexner Medical Center and a researcher at theDorothy M.Davis Heart and LungResearch Institute, narrowed the list down to 51, which was evaluated by an international panel of genetic counselors, cardiologists and laboratory scientists.

They used a method developed by the National Institute of Healths Clinical Genome Resource (ClinGen) to determine which genes were most strongly associated with DCM. The research was funded by the NIHs National Human Genome Research Institute and the National Heart, Lung, and Blood Institute.

The researchers evaluated clinical data in humans as well as experimental data in animal models to determine the likelihood that a gene had a role in the disease, Jordan said. Because we often see uncertain genetic results with dilated cardiomyopathy, our hope is that our findings will aid in the interpretation of results of large genetic testing panels, which should help genetic information be more useful in clinical care.

The findings will be extended by research currently being done by the Dilated Cardiomyopathy Consortium, led by Hershberger. In 2015, the NIH awarded $12.4 million to the consortium to study the genetic basis of DCM and lay the foundation for precision medicine for patients.

This was a great example of collaboration with genetic experts across the world. This research, along with additional work being done at The Ohio State University Wexner Medical Center, will provide a better understanding of the role of genetics with DCM and how to treat and prevent it, Hershberger said.

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Ohio State researchers name 19 genes associated with heart muscle disease - The Highland County Press

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This article was originally published here

Gynecol Oncol. 2021 May 19:S0090-8258(21)00407-8. doi: 10.1016/j.ygyno.2021.05.011. Online ahead of print.

ABSTRACT

PURPOSE: Several professional organizations recommend universal genetic assessment for people with ovarian cancer as identifying pathogenic variants can affect treatment, prognosis, and all-cause mortality for patients and relatives. We sought to evaluate the literature on genetic assessment for women with ovarian cancer and determine if any interventions or patient characteristics drive utilization of services.

METHODS: We searched key electronic databases to identify trials that evaluated genetic assessment for people with ovarian cancer. Trials with the primary aim to evaluate utilization of genetic assessment with or without interventions were included. Eligible trials were subjected to meta-analysis and the moderating influence of health interventions on rates of genetic assessment were examined.

RESULTS: A total of 35 studies were included (19 report on utilization of genetic services without an intervention, 7 with an intervention, and 9 with both scenarios). Without an intervention, pooled estimates for referral to genetic counseling and completion of genetic testing were 39% [CI 27-53%] and 30% [CI 19-44%]. Clinician-facilitated interventions included: mainstreaming of genetic services (99% [CI 86-100%]), telemedicine (75% [CI 43-93%]), clinic-embedded genetic counselor (76% [CI 32-95%]), reflex tumor somatic genetic assessment (64% [CI 17-94%]), universal testing (57% [28-82%]), and referral forms (26% [CI 10-53%]). Random-effects pooled proportions demonstrated that Black vs. White race was associated with a lower rate of genetic testing (26%[CI 17-38%] vs. 40% [CI 25-57%]) as was being un-insured vs. insured (23% [CI 18-28%] vs. 38% [CI 26-53%]).

CONCLUSIONS: Reported rates of genetic testing for people with ovarian cancer remain well below the goal of universal testing. Interventions such as mainstreaming can improve testing uptake. Strategies aimed at improving utilization of genetic services should consider existing disparities in race and insurance status.

PMID:34023131 | DOI:10.1016/j.ygyno.2021.05.011

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Achieving universal genetic assessment for women with ovarian cancer: Are we there yet? A systematic review and meta-analysis - DocWire News

Recommendation and review posted by Bethany Smith

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Direct Access Genetic Testing market (2021-2028) current situation and development research possibilities pinpoint to change sharp elements and a point of view on the future of variables ?? or limiting the development of the industry. The Direct Access Genetic Testing market offers an exhaustive analysis of the market size, participation, degree of development, and Outlook of the Direct Access Genetic Testing business. This report gives all the fundamental data needed to understand the vital advances in market-to-market spending and the development of Direct Access Genetic Testing standards for each fragment and locality. The implementation of the action research, the Direct Access Genetic Testing markets, both in terms of volume and income and this is a factor that is valuable and effective for your business.

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Competitive Landscape

The full profile of the companies is mentioned. And the Direct Access Genetic Testing Market size, production, price, revenue, cost, terrifying margin, gross, sales volume, sales revenue, consumption, buildup rate, Import, Export, Supply, well along strategies and the technological developments they are making are moreover included in the report. Historical data from 2014 to 2019 and predict data from 2021 to 2028.

Direct Access Genetic Testing Market Leading Key players:

Market segmentation of Direct Access Genetic Testing market:

Direct Access Genetic Testing market is divided by type and application. For the period 2021-2028, cross-segment growth provides accurate calculations and forecasts of sales by Type and Application in terms of volume and value. This analysis can help you grow your business by targeting qualified niche markets.

Direct Access Genetic Testing Market breakdown by type:

Direct Access Genetic Testing Market breakdown by application:

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Direct Access Genetic Testing Market Report Scope

Regional market analysis Direct Access Genetic Testing can be represented as follows:

For clarity, analysts also segmented the market based on geography. This type of segmentation allows readers to understand the volatile political scenario in different regions and their impact on the global digital Isolator market. The base of geography, the world market of Direct Access Genetic Testing has segmented as follows:

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Verified Market Intelligence is our BI-enabled platform to tell the story of this market. VMI provides in-depth predictive trends and accurate insights into more than 20,000 emerging and niche markets to help you make key revenue impact decisions for a brilliant future.

VMI provides a comprehensive overview and global competitive landscape of regions, countries, and segments, as well as key players in your market. Showcase your market reports and findings with built-in presentation capabilities, providing more than 70% of time and resources for investors, sales and marketing, R & D, and product development. VMI supports data delivery in Excel and interactive PDF formats and provides more than 15 key market indicators for your market.

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Scope of the report:-

The scope of the report consolidates an in-depth examination of the global market Reached 2021-2028 with the apprehension given to the company's progress in specific regions.

The Best Organizations Hit Market report is intended to provide our buyers with an overview of the most compelling players in the business. In addition, data on the exposure of various organizations, benefits, net benefit, vital activity and more are introduced through different assets.

For More Information or Query or Customization Before Buying, Visit @https://www.marketresearchintellect.com/product/direct-access-genetic-testing-market-size-and-forecast//

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Market Research Intellect provides syndicated and customized research reports to clients from various industries and organizations in addition to the objective of delivering customized and in-depth research studies.

We speak to looking logical research solutions, custom consulting, and in-severity data analysis lid a range of industries including Energy, Technology, Manufacturing and Construction, Chemicals and Materials, Food and Beverages. Etc Our research studies assist our clients to make higher data-driven decisions, admit push forecasts, capitalize coarsely with opportunities and optimize efficiency by bustling as their belt in crime to adopt accurate and indispensable mention without compromise.

Having serviced on the pinnacle of 5000+ clients, we have provided expertly-behaved assert research facilities to more than 100 Global Fortune 500 companies such as Amazon, Dell, IBM, Shell, Exxon Mobil, General Electric, Siemens, Microsoft, Sony, and Hitachi.

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Direct Access Genetic Testing Market Outlook 2021, Analysis and Forecast to 2028 by Manufacturers| 23andme, Myheritage, Labcorp, Myriad Genetics,...

Recommendation and review posted by Bethany Smith

Introduction

Gitelman syndrome (GS) is an autosomal recessive inherited disease initially reported in 1996 and is a rare renal tubular disorder with a prevalence of 1:40,000.1,2 GS is closely associated with the mutations of SLC12A3 gene coding for the thiazide-sensitive sodium-chloride cotransporter (NCCT) of the distal convoluted tubule (DCT).3 To date, more than 400 mutations of SLC12A3 have been identified in GS.48 Most of the mutations are missense, splice-site, nonsense, frameshift, deletions, and insertion mutations.9

The main clinical manifestations of GS are hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria and renin-angiotensin-aldosterone system (RAAS) activation. Besides, patients with GS may present with spasticity, muscle weakness, paresthesia, numbness, polyuria, and palpitation.10 However, GS lacks specific clinical manifestations and is easily confused with other diseases such as Bartter syndrome, renal tubular acidosis, and primary aldosteronism.11,12 In addition to history taking and clinical work-up, genetic testing is an important and effective tool for diagnosing GS in clinical practice.13 Here, our present study aimed to analyze the clinical features and genetic characteristics of a Chinese female patient with GS.

A 60-year-old female patient was admitted to the Department of Endocrinology in Tongde Hospital of Shanxi province because of recurrent hypokalemia. She had no obvious clinical symptoms such as palpitations, shortness of breath, muscle weakness of the lower limbs, vomiting, nausea, anorexia, diarrhea, polyphagia and emaciation and denied a history of chronic kidney disease. She was treated with potassium citrate or potassium chloride, but she had no history of other drugs such as diuretics, proton pump inhibitors, and anti-tumor agents.

The patient underwent detailed systemic physical examinations. Fasting blood samples and urine samples were obtained. The electrolytes of the blood and urine, plasma angiotensin, plasma renin activity, and plasma aldosterone were analyzed at the central chemistry laboratory of Tongde Hospital of Shanxi province. Besides, ECG, chest X-ray, bone mineral density (BMD) examination and ultrasound examination were conducted.

The diagnosis of Gitelman syndrome was based on the clinical symptoms, biochemical measurements and analysis of genetic mutations of SLC12A3 gene. Genomic DNA was extracted from peripheral blood samples of the female patient using a nucleic acid extraction kit (NO. BST01051, BaiO Technology Co., Ltd, Shanghai, China) according to the manufacturers protocol. The SLC12A3 gene was screened for mutations using Sanger sequencing. The nucleotide sequences of the PCR products were aligned to the UCSC database using SnapGee software (v3.2.1)

Blood pressure, heart rate, and body mass index (BMI) of the patient were 128/70 mmHg, 76 beats per minute, and 26.7 kg/m2, respectively. Systemic physical examinations showed no abnormalities. The results of laboratory tests of the patient are listed in Table 1. Laboratory assays revealed hypokalemia, hypomagnesemia, hypercalcemia, and metabolic alkalosis. Furthermore, the patient had elevated parathyroid hormone (PTH) and plasma renin activity and angiotensin II. 24-h urine analysis showed that the levels of urinary potassium and urinary calcium were normal. ECG revealed normal sinus rhythm, ST segment and T-waves abnormality but had no prolongation of the QT interval. The BMD data showed there was a significant decrease at the left forearm. Chest X-ray and ultrasound (thyroid, carotid, heart, abdomen, and pelvic cavity) did not show any obvious abnormalities (data not shown).

Table 1 Laboratory Tests of the Subject

Sanger sequencing of SLC12A3 gene was performed in the subject. Genetic analysis showed 4 mutations in the exons of SLC12A3 gene: c.366A > G in exon 2, c.791C > G in exon 6, c.1027C > T in exon 8, and c1456G>A in exon 12 (Figure 1).

Figure 1 Genetic analysis of the SLC12A3 gene. (A) c.366A > G in Exon 2. (B) c.791C > G in Exon 6. (C) c.1027C > T in Exon 8 and (D) c.1456 G > A in Exon 12. The mutant nucleotides are marked in the red frames.

After the diagnosis, spironolactone and potassium citrate were used to treat hypokalemia and potassium magnesium aspartate was used to treat hypomagnesaemia. The patient was discharged with normokalemia and no other discomfort following one week of treatment.

In the present study, we reported the case of a 60-year-old Chinese female patient with GS. The biochemical examination showed hypokalemia, metabolic alkalosis, hypomagnesemia, hypercalcemia, hyperreninemia, elevated angiotensin II, and PTH levels. ECG showed normal sinus rhythm, ST segment and T-waves abnormality but had no prolongation of the QT interval. Besides, BMD was decreased in the left forearm. Genetic analysis identified four mutations of SLC12A3 gene, c.366A > G in exon 2, c.791C > G in exon 6, c.1027C > T in exon 7, and c1456G>A in exon 12. The treatment with supplements of potassium and magnesium improved hypokalemia and hypomagnesemia.

GS is a rare inherited salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia, hypocalciuria and RAAS activation. GS is caused by mutations in SLC12A3 gene coding for the thiazide-sensitive NCCT of the DCT, which leads to a decrease in sodium reabsorption, increases potassium and hydrogen excretion and therefore develop hypokalemic metabolic alkalosis.14 The enhanced passive Ca2+ transport in the proximal tubule leads to hypocalciuria15 and the downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6) is a possible mechanism involved in hypomagnesemia.16 The mechanism of hypocalciuria is uncertain, but some studies have found that one reason for it may be hypovolemia. Meanwhile, hypovolemia activates RAAS.17,18 The patient had hypokalemia, metabolic alkalosis, hypomagnesemia, hyperreninemia, and elevated angiotensin II level, which was consistent with the clinical manifestations of GS. In the study, the elderly female had decreased BMD. Postmenopausal women are prone to develop hypocalcemia and postmenopausal osteoporosis, which is caused by estrogen deficiency after menopause. Long-term hypocalcemia may overstimulate the parathyroid gland and lead to secondary hyperparathyroidism.

Genetic identification is the golden standard for the diagnosis of GS. We identified compound mutations of SLC12A3, c.366A > G in exon 2, c.791C > G in exon 6, c.1027C > T in exon 7, and c1456G>A in exon 12. The c1456G>A in exon 12 is reported as a hotspot mutation of SLC12A3. A heterozygous mutation, c.366A > G in the gene has been reported. But c.366A > G in exon 2 was a homozygous mutation in this study. Moreover, c.791C > G and c.1027C > T are two novel mutations. Hence, we performed a complementary study on the mutations of SLC12A3.

GS and Bartter syndrome (BS) show extremely similar clinical and laboratory manifestations including hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. But BS presents with an early age of onset and exhibits apparent clinical symptoms.12 Simultaneously, BS is closely related to the mutations of CLCNKB gene. They can be differentiated by clinical manifestation and genetic tests.19,20

Our present study has several limitations. First, the mutation was detected in only one patient but not in pedigree. Further research should be performed in the pedigree. Second, a further exploration is needed to find the correlation between genotype and phenotype and then provide better understanding of GS. Moreover, more experiments are needed to reveal the underlying molecular mechanism of GS.

Overall, our study identified four mutations of SLC12A3 gene in a Chinese female patient and three of the mutations were novel. These findings might be useful for better understanding the function of this gene and aid with diagnosis and treatment decisions.

The study was conducted in compliance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Tongde Hospital of Shanxi province. The patient provided informed consent for the case details to be published.

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

This work was supported by grants from the Chinese National Natural Science Foundation [No. 81560044, No. 30860113], the Appropriate Technology for Medical Health Research and Development Projects of Guangxi [S201422-01] and Health Research Project of Shanxi [2019165].

The authors declare that they have no competing interests.

1. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys. 1966;79:221235.

2. Knoers NV, Levtchenko EN. Gitelman Syndrome. Orphanet J Rare Dis. 2008;3:22. doi:10.1186/1750-1172-3-22

3. Mastroianni N, Bettinelli A, Bianchetti M, et al. Novel molecular variants of the Na-cl cotransporter gene are responsible for Gitelman syndrome. Am J Hum Genet. 1996;59(5):10191026.

4. Glaudemans B, Yntema HG, San-Cristobal P, et al. Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome. Eur J Hum Genet. 2012;20:263270. doi:10.1038/ejhg.2011.189

5. Ma J, Ren H, Lin L, et al. Genetic features of Chinese patients with Gitelman syndrome: sixteen novel SLC12A3 mutations identified in a new cohort. Am J Nephrol. 2016;44:113121. doi:10.1159/000447366

6. Gug C, Mihaescu A, Mozos I. Two mutations in the thiazide sensitive NaCl co-transporter gene in a Romanian Gitelman syndrome patient: case report. Ther Clin Risk Manag. 2018;14:149155. doi:10.2147/TCRM.S150483

7. Vargas-Poussou R, Dahan K, Kahila D, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol. 2011;22:693703. doi:10.1681/ASN.2010090907

8. Reissinger A, Ludwig M, Utsch B, et al. Novel NCCT gene mutations as a cause of Gitelmans syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res. 2002;25(6):354362. doi:10.1159/000068695

9. Lu Q, Zhang Y, Song C, et al. A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review. J Endocrinol Investig. 2016;39(3):333340. doi:10.1007/s40618-015-0371-y

10. Munoz EV, Chang Q, Bindels RJ, et al. Gitelman syndrome: towards genotypephenotype correlations. Pediatr Nephrol. 2007;22(3):326332. doi:10.1007/s00467-006-0321-1

11. Fedeli GGC, Cosmai ML, Badalamenti S, et al. Gitelman syndrome: pathophysiological and clinical aspects. Q J Med. 2010;103(10):741748. doi:10.1093/qjmed/hcq123

12. Matsunoshita N, Nozu K, Shono A, et al. Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics. Genet Med. 2016;18(2):180188. doi:10.1038/gim.2015.56

13. Blanchard A, Bockenhauer D, Bolignano D, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO)controversies conference. Kidney Int. 2017;91:2433. doi:10.1016/j.kint.2016.09.046

14. Gvercin B, Kaynar K, Gler , et al. In the presence of hypokalemia and hypomagnesemia; remember Gitelman syndrome. Hippokratia. 2019;23.

15. Reilly RF, Huang CL. The mechanism of hypocalciuria with NaCl cotransporter inhibition. Nat Rev Nephrol. 2011;7:669674. doi:10.1038/nrneph.2011.138

16. Shahzad MA, Mukhtar M, Ahmed A, et al. Gitelman Syndrome: a rare cause of seizure disorder and a systematic review. Case Rep Med. 2019;2019:4204907. doi:10.1155/2019/4204907

17. Tseng MH, Yang SS, Hsu YJ, et al. Genotype, phenotype, and follow-up in Taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. J Clin Endocrinol Metab. 2012;97(8):E14781482. doi:10.1210/jc.2012-1707

18. Hsu YJ, Yang SS, Cheng CJ, et al. Thiazide-sensitive Na+cl Cotransporter (NCC) gene inactivation results in increased duodenal Ca2+ absorption,enhanced osteoblast differentiation and elevated bone mineral density. J Bone Miner Res. 2015;30(1):116127. doi:10.1002/jbmr.2306

19. Simon DB, Karet FE, Hamdan JM, et al. Bartters syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996;13(2):183188. doi:10.1038/ng0696-183

20. Shaer AJ. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci. 2001;322(6):316332. doi:10.1097/00000441-200112000-00004

See original here:
Homozygous Mutations of SLC12A3 gene in Gitelman Syndrome | IJGM - Dove Medical Press

Recommendation and review posted by Bethany Smith

Diet advice changes with the decades. I remember eating cheeseless pizzas during the "fat-free" fad (thanks, Dad). And I'll never forget my high school cross country team's T-shirts saying "Eat Pasta, Run Fasta."

If we've learned anything from these fads, it isn't how to eat better. It is that there is no one-size-fits-all diet.

Now, a growing field called "nutrigenomics" aims to provide people with personalized lifestyle guidance, based on their DNA. But is this a breakthrough for nutrition science, or just another fad?

Melina Jampolis is a board-certified physician and nutrition specialist. She helps people reach their goals for fitness and body composition by giving tailor-made diet recommendations.

"Nutrition is all about context. We don't eat nutrients, we eat foods."

A few years ago, a 32-year-old vegetarian man came to her seeking advice on how to build muscle and burn fat.

After four months without progress, Jampolis suggested a Nutrigenomix test. Nutrigenomix is one of several dozen companies that offer genetic tests that purport to give insight into personalized, gene-based nutrition.

Much like 23andMe or Ancestry.com, by sending salvia to a lab, people can learn more about their genetic makeup. Some of the gene-based nutrition companies accomplish this by interpreting genetic data downloaded from 23andMe or Ancestry.

The analysis a subject receives is intended to help them learn which foods to eat to switch on or off specific genes. It can help them understand what foods might affect weight loss, immune functions, or their predispositions to disease.

Jampolis says the test results "confirmed her clinical intuition." Even though a plant-based diet is a healthy option, vegetarianism wasn't quite right for this man.

According to the test results, her client had a variation in his genetic sequence making it more challenging to build muscle. At the same time, his metabolic panel indicated that he should have fewer carbohydrates. With that combined information, Jampolis recommended that he eat less protein from beans and more animal protein.

For Jampolis, despite some of the companies' claims, the genetic test isn't a magic "how to eat" formula. She says there are many ways to interpret the results, so it is best used with a healthcare professional's guidance.

"As a practitioner, you're taking (a genetic test) in the context of a patient and bringing in multiple variables," she says.

Nutrigenomix is one of the few nutrigenomics tests that must be administered by a medical professional. The founder, Ahmed El-Sohemy, specifically designed it that way to "restore credibility to the field."

El-Sohemy, also the nutrigenomics chair of the University of Toronto, says nutrition can be "vulnerable to snake oil science," and consumers should be cautious about genetic testing.

"It was a bit of a wild west. There were some shady operators (...) linking their tests to ridiculously overpriced supplements that were not justified. It was really tainting the whole field. So, we established a test based on the robust science and decided to make it available only through healthcare professionals so that they can answer questions and concerns that people have around genetic testing."

In 2008, El-Sohemy discovered that some people's genetics could be causing them to eat more sugar regularly than others. He pinpointed the sugar habit to a variation in the GLUT2 gene which became known as the "sweet tooth gene."

But El-Sohemy saw nutrigenomics companies extrapolate new meanings from his work claiming their test for the sweet tooth gene would reveal how a body processes sugar and the optimal sugar intake level.

"That's nonsense. That's not what the study showed," he says, adding other examples of wild claims like genetic tests "for" an anti-inflammatory diet, or low-carb versus low-fat, where "the science just isn't there yet."

Nonetheless, he does believe the field is making progress. When he first launched the Nutrigenomix in 2012, their test only looked at seven genes. By 2018, they were investigating 72.

In the past decade, more rigorous scientific research has been published with discoveries related to nutrigenomics. If "the science isn't there yet," when it comes to crafting personal diets from data, it is on its way.

David Mutch leads a nutrigenomics research program at the University of Guelph, studying diet-gene interactions, especially omega-3 dietary fats. He doesn't work with El-Sohemy but cites his 2006 study on coffee and heart attack risk as a prime example of robust nutrition science.

The study looked at a variant of the gene CYP182, which is associated with how well the body metabolizes caffeine. They found that having a particular version of the gene means that the body metabolizes caffeine slowly, and for this group, excessive coffee consumption may increase their risk of heart attacks.

Studies like this, Mutch says, are building a solid foundation for consumer nutrigenomics tests. If a person tests positive for that gene variant, then the recommendation would be to consume no more than two cups of coffee per day instead of the standard advice of a four-cup limit.

Mutch says that precision nutrition is about much more than DNA. It also takes into account gut bacteria (known as the microbiome), proteins, metabolites, etc. That is why he also supports nutrigenomics tests that are interpreted by a healthcare professional.

"Working with dieticians or healthcare practitioners is actually going to be the most efficient way to take that information you're getting and translate it into an actionable dietary plan. That's the challenge with nutrition. Nutrition is all about context. We don't eat nutrients, we eat foods."

The majority of chronic illnesses in the United States, such as hypertension, high cholesterol, obesity, and diabetes, are treated first with diet and exercise. However, research shows that patients are more likely to adhere to care plans tailored to their genetics instead of general dietary advice.

"This is a piece of the puzzle to better understand ourselves, to better understand what we may or may not want to think about when we're making choices about the foods we're eating or the lifestyle choices we're making," Mutch says.

Maybe someday, to reduce the risk of heart disease, Alzheimer's, or hypertension, doctors will prescribe food as medicine and know their prescription will stand the tests of time and science.

We'd love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at [emailprotected]

More here:
Nutrigenomics Could Be the Future of Eating - Freethink

Recommendation and review posted by Bethany Smith

A clerical error meant that a female polar bear, Tonja, born at Moscow Zoo, was listed as the daughter of the wrong parents, a spokeswoman for Tierpark Berlin told CNN on Wednesday.

Tonja was assigned documents meant for another female polar bear born at Moscow Zoo two days later, but in fact she was the offspring of the same parents as Wolodja, a male polar bear with whom she later mated in Berlin. The pair produced baby Hertha, who was born in December 2018.

Suspicions were raised when documents were found at Moscow Zoo that listed a different birth date for Tonja, and genetic testing has since confirmed she and Wolodja are siblings.

"That was a big shock for us," the spokeswoman said, adding that Moscow Zoo had been very transparent and informed its counterparts in Berlin when the documents were found.

"There was one unfortunate mistake," she said.

The bears are part of the European Endangered Species Programmes (EEP) breeding program for polar bears, which works to maintain the genetic diversity of polar bears in captivity.

Inbreeding reduces genetic diversity, which is "a crucial factor in the long-term survival of species," according to the European Association of Zoos and Aquaria (EAZA).

"This serious mistake is a very regrettable setback for the responsible work of the European Conservation Breeding Programme," Berlin Zoo's director, Andreas Knieriem, said in a statement.

"It must now be a matter of learning from such mistakes and putting our work in all areas even more on a scientific basis."

This kind of mix-up is not likely to happen again, as it is unlikely there will be two breeding pairs at the same zoo, the spokeswoman said. In addition, every animal born at Berlin Zoo is given a microchip containing identifying information, including who its parents are.

In the light of the discovery, neither Tonja nor Hertha will have any offspring for the foreseeable future because their family lineage is better represented in the captive polar bear population than previously thought, the spokeswoman said.

However, there is a chance that both bears will be bred in the future, she added.

"Our mission is to keep the genetic diversity as big as possible," said the spokeswoman.

Hertha is a "happy and healthy bear" who will remain at the zoo along with her mother, she added. Wolodja has already moved to a different zoo in the Netherlands.

Polar bears are listed as vulnerable by the International Union for Conservation of Nature (IUCN), which estimates that there are 22,000-31,000 left in the wild.

UK campaign organization Bear Conservation estimates that there are more than 300 polar bears in captivity around the world.

Read more from the original source:
Berlin zoo says its polar bear cub's parents were brother and sister - CNN

Recommendation and review posted by Bethany Smith

Potentially clinically actionable genomic alterations were identified in a majority of patients with advanced cancers with next-generation sequencing (NGS), a subcohort of whom showed clinical benefits with targeted treatment directed by the NGS. The results of the prospective study were published in JAMA Oncology.1

In their assessment of the Michigan Oncology Sequencing Program (Mi-ONCOSEQ) cohort study, investigators looked at the use of NGS in 1138 patients with advanced solid tumors, which was successful in 89.2% (n=1015). Of the NGS-successful patients, 817 (80.5%) were discovered to have actionable genomic alterations for treatment, with 132 (16.2%) receiving targeted therapy based on these results. Forty-nine patients had a clinical benefit from the targeted treatment, and responses lasted 12 months or longer in 19.7% of the treated population. These results support the use of directed germline testing in all patients with advanced cancer.

One goal for Mi-ONCOSEQ is to inform standards of practice as clinical sequencing increasingly becomes adopted as a routine standard of care, said Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and senior author of the study, in an article in the Michigan Health Lab report.2 This study helps demonstrate that the promise of individualized, precision medicine and precision oncology is becoming a reality for patients.

Observed molecular alterations were classified into 3 tiers, depending on the potential for treatment or potential treatment resistance based on the alteration. Tier 1 alterations included those with known clinical utility, germline variants that lead to increased cancer risk, and alterations that mark more or less benefit from an FDA-approved treatment. Tier 2 alterations included alterations that would suggest benefit from investigational or off-label targeted therapy or that would suggest resistance to an FDA-approved therapy. Tier 3 alterations were those without current therapeutic implications.

According to the investigators, 817 patients (80.5%) harbored a potentially actionable tier 1 or 2 alteration, 288 patients had tier 1 alterations, and 744 had tier 2 alterations. Among these alterations, 962 (94.8%) were identified by DNA sequencing and 645 (63.5%) by RNA sequencing. In 579 cases (57.0%), all 3 modes of integrated sequencing and analysis found informative alterations for potential treatment.

Sequencing-directed therapy (SDT) was started in 132 of the 817 patients (16.2%) with potentially clinically actionable alterations, with the median time to enrollment in the treatment being 3.8 months (range, 0.2-44.0). Seventy-four patients were enrolled and treated in a clinical trial, 43 were treated with off-label therapy, and 15 were treated with on-label therapy. Forty-nine patients (37.1%) experienced clinical benefit after being matched with treatment, with the most common cancers treated being sarcoma (12 of 138 [8.7%]) and prostate adenocarcinoma (10 of 154 [6.5%]).

Treatments for patients receiving SDT included targeted CDK4/6 inhibitors (n=21), PARP inhibitors (n =16), and FGFR inhibitors (n =11). The most common treatment received was immune checkpoint inhibitors, in 29 patients. The 26 patients who were deemed to have an exceptional response to SDT had a response duration ranging from 12.1 to 39.5 months. Ten of the patients had DNA repair defects, 5 of whom had double-strand DNA repair defects, including BRCA1, BRCA2, ATM, PALB2, and BRIP1.

Any family members who have also inherited those same mutations may be at increased risk for cancer, added Erin F. Cobain, MD, a coauthor in the study and a clinical lecturer and oncologist at Michigan Medicine, in a statement.2 So a lot of this testing prompted downstream genetic testing and counseling across families. Thats how sequencing can have even more far-reaching impact than just looking for therapies to directly help a current patient.

Several factors accounted for NGS testing not being successful in some patients, including the inability to safely test, patients withdrawal due to entering hospice, and inadequate tumor content from the biopsy. The average age of patients who enrolled was 57 years; 53% were men. Prior to enrollment, 855 patients had received systemic therapy and an average of 47 months had elapsed between the time of the patients diagnosis and their enrollment in the study.

Based on the data presented by Cobain and others, it is evident that such precision medicine strategies are especially fruitful in cancer types without clear standard-of-care options, such as carcinoma of unknown primary and other rare tumors, investigators wrote in an editorial accompanying the study, discussing the benefits of NGS for patients with rare cancers.3

NGS remains a challenge for oncologists for several reasons, among them that the definition of clinically actionable alterations changes as new therapies emerge and that a patients tumors can harbor multiple mutations. According to the investigators, more novel clinical trials need to be explored to expand treatment. However, systems also must develop large-scale precision oncology studies to continue to find ways to match patients with targeted treatments.

Our data support a recommendation for germline testing of DNA repair genes as standard practice in patients with metastatic solid tumors and comprehensive NGS profiling at diagnosis for patients with [cancer of unknown primary], the study authors concluded.1 With continued discovery of genomic biomarkers predictive of clinical benefit from anticancer therapies, we anticipate even broader clinical applicability of this technology.

References:

1. Cobain EF, Wu YM, Vats P, et al. Assessment of clinical benefit of integrative genomic profiling in advanced solid tumors. JAMA Oncol. 2021;7(4):525-533. doi:10.1001/jamaoncol.2020.7987

2. Demsky I. How useful is next-generation sequencing for patients with advanced cancer? Michigan Health Lab. March 11, 2021. Accessed March 23, 2021. https://bit.ly/3cjajLT

3. Yap TA, Johnson A, Meric-Bernstam F. Precision medicine in oncologytoward the integrated targeting of somatic and germline genomic aberrations. JAMA Oncol. 2021;7(4):507-509. doi:10.1001/jamaoncol.2020.7988

See the article here:
Large NGS Trial Identifies Actionable Alterations in Most Patients With Advanced Cancers - Targeted Oncology

Recommendation and review posted by Bethany Smith

This has brought along several changes in This report also covers the impact of COVID-19 on the global market.

The Breast Cancer Predictive Genetic Testing Market analysis summary by Reports Insights is a thorough study of the current trends leading to this vertical trend in various regions. In addition, this study emphasizes thorough competition analysis on market prospects, especially growth strategies that market experts claim.

Breast Cancer Predictive Genetic Testing Market competition by top manufacturers as follow: OncoCyte Corporation, Cancer Genetics, Myriad Genetics, Iverson Genetics, NeoGenomics, Roche, Quest Diagnostics, PerkinElmer, Invitae, Thermo Fisher Scientific

Get a Sample PDF copy of the report @ https://www.reportsinsights.com/sample/415404

The global Breast Cancer Predictive Genetic Testing market has been segmented on the basis of technology, product type, application, distribution channel, end-user, and industry vertical, along with the geography, delivering valuable insights.

The Type Coverage in the Market are: High Penetrant GenesIntermediate Penetrant GenesLow Penetrant Genes

Market Segment by Applications, covers:

HospitalsClinicsOther

Market Segment as follows:By RegionAsia-Pacific[China, Southeast Asia, India, Japan, Korea, Western Asia]Europe[Germany, UK, France, Italy, Russia, Spain, Netherlands, Turkey, Switzerland]North America[United States, Canada, Mexico]Middle East & Africa[GCC, North Africa, South Africa]South America[Brazil, Argentina, Columbia, Chile, Peru]

The research provides answers to the following key questions: What is the estimated growth rate and market share and size of the Breast Cancer Predictive Genetic Testing market for the forecast period 2021 2028? What are the driving forces in the Breast Cancer Predictive Genetic Testing market for the forecast period 2021 2028? Who are the prominent market players and how have they gained a competitive edge over other competitors? What are the market trends influencing the progress of the Breast Cancer Predictive Genetic Testing industry worldwide? What are the major challenges and threats restricting the progress of the industry? What opportunities does the market hold for the prominent market players?

For any other requirements, please feel free to contact us and we will provide you customized report.

Market segment by Regions/Countries, this report coversNorth AmericaEuropeChinaRest of Asia PacificCentral & South AmericaMiddle East & Africa

Major factors covered in the report:

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Our report offers:

Market share assessments for the regional and country level segments. Market share analysis of the top industry players. Strategic recommendations for the new entrants. Market forecasts for a minimum of 9 years of all the mentioned segments, sub segments and the regional markets. Market Trends (Drivers, Constraints, Opportunities, Threats, Challenges, Investment Opportunities, and recommendations). Strategic recommendations in key business segments based on the market estimations. Competitive landscaping mapping the key common trends. Company profiling with detailed strategies, financials, and recent developments. Supply chain trends mapping the latest technological advancements.

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Breast Cancer Predictive Genetic Testing Market 2021 In-Depth Insights and Business Scenario, Analysis by 2028 Brockville Observer - Brockville...

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Orphan: First Kill star Julia Stiles has teased another big twist in the upcoming horror prequel, one which may even rival the first movie's shocking finale. Many had wondered how, what with Orphan: First Kill taking place before the first movie and after audiences have been made aware of Esther's surprising identity, the prequel would bring the shocks and scares, but according to Stiles they have found a way.

Released in 2009, the first Orphan centers on a couple who, after the death of their unborn child, adopt a mysterious nine-year-old girl, Esther. As she demonstrates increasingly bizarre behaviour, it is revealed during the movie's climax that Esther is in fact an adult woman with hypopituitarism, a rare hormonal disorder that stunted her physical growth and caused proportional dwarfism.

While it remains unknown how exactly Orphan: First Kill will pull out a twist to rival the first movie, Stiles goes on to assure fans that the prequel will continue to opt for psychological scares rather than blood and gore.

Orphan: First Kill will once again follow Isabelle Fuhrman as Esther, who is now living under the name Leena Klammer. The horror begins when she orchestrates a brilliant escape from an Estonian psychiatric facility and travels to America by impersonating the missing daughter of a wealthy family. But Leena's new life as 'Esther' comes with an unexpected wrinkle and pits her against a mother who will protect her family at any cost.

Fuhrman, who is now 24 years old, will once again play the role of the adult killer who disguises herself as a child, with director William Brent Bell recently providing some insight into how the movie plans to resurrect Esther all these years later. "For me it's like, we know the secret of the first film, so the fun of bringing Isabelle Fuhrman back into the role - which was a whole process to get approved - that is a challenge in and of itself," the filmmaker said. "And likewise, not doing modern CGI... I mean, we use digital, we use CGI to help us... but not to create her at all. It's all old school techniques: forced perspective, camera angles, where we put the light."

Orphan: First Kill does not yet have a release date. This comes to us from Collider.

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Orphan: First Kill Has a Surprise Twist That Could Rival the Original's Shocking Ending - MovieWeb

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Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

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Data evaluating Opdivo plus Yervoy represent the longest reported median overall survival from a Phase 3 advanced melanoma trial

49% of patients treated with Opdivo plus Yervoy were alive at 6.5 years and 77% of these patients remained treatment-free

Data to be featured in an oral presentation during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) today announced new six-and-a-half-year data from CheckMate -067, a randomized, double-blind, Phase 3 clinical trial, demonstrating durable improvement in survival with first-line Opdivo (nivolumab) plus Yervoy (ipilimumab) therapy and Opdivo monotherapy, versus Yervoy alone, in patients with advanced melanoma. With a minimum follow-up of 6.5 years, median overall survival (OS) was 72.1 months with Opdivo plus Yervoy (95% CI: 38.2-NR), the longest reported median OS in a Phase 3 advanced melanoma trial, 36.9 months with Opdivo (95% CI: 28.2-58.7) and 19.9 months with the Yervoy group (95% CI: 16.8-24.6). In addition, the Opdivo plus Yervoy combination demonstrated a 6.5-year progression-free survival (PFS) rate of 34% (median of 11.5 months) while PFS rates were 29% (median of 6.9 months) and 7% (median of 2.9 months) for Opdivo alone and Yervoy alone, respectively. Of the 49% of patients alive and in follow-up, 77% of patients who received the combination (112/145), 69% of Opdivo-treated patients (84/122) and 43% (27/63) of Yervoy-treated patients have been off treatment and never received subsequent systemic therapy.

Durable, sustained clinical benefit was also observed with Opdivo plus Yervoy or Opdivo alone across relevant subgroups, including in patients with BRAF mutation, wild-type tumors, and baseline liver metastases. Among patients with BRAF-mutant tumors, the rate of OS at 6.5 years was 57% in patients who received Opdivo plus Yervoy, 43% for Opdivo alone, and 25% for Yervoy alone. In patients with BRAF wild-type tumors, the rate of OS was 46% in patients who received Opdivo plus Yervoy, 42% for Opdivo alone and 22% for Yervoy alone. The rate of OS among patients with liver metastases was 38% for those who received Opdivo plus Yervoy, 31% for Opdivo alone, and 22% for Yervoy alone. Median duration of response (DoR) was not reached for those who received Opdivo plus Yervoy nor Opdivo, while the DoR for Yervoy-treated patients was 19.2 months.

The sustained overall survival and progression-free survival benefit shown with nivolumab-based treatment, particularly the nivolumab plus ipilimumab combination, has changed the way we look at long-term efficacy outcomes for patients with advanced melanoma, said Jedd D. Wolchok, M.D., Ph.D., FASCO, Chief, Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center. These new results from the CheckMate -067 trial, with nearly half of patients treated with the nivolumab and ipilimumab combination surviving to six-and-a-half years, confirm the durable, sustained benefit of the combination in patients with advanced melanoma.

The safety profile for Opdivo plus Yervoy was consistent with prior findings, with no new safety signals observed and no additional treatment-related deaths occurring since the five-year analysis. Grade 3/4 treatment-related adverse events were reported in 59% of patients in the combination group, 24% of patients in the Opdivo group, and 28% of patients in the Yervoy group.

These results build upon our decade-long legacy in treating melanoma, which began when the average life expectancy following a diagnosis of metastatic melanoma was roughly six months and less than 10% of patients survived beyond five years, said Gina Fusaro, development lead, melanoma, Bristol Myers Squibb. With some of the longest follow-up with immunotherapies to date, Opdivo and Yervoy have consistently demonstrated durable, long-term survival benefits for patients diagnosed with advanced melanoma.

Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -067 clinical trial. The 6.5-year CheckMate -067 data (Abstract #9506) will be presented in an oral abstract session on Sunday, June 6, 2021 from 8:00 a.m. to 11:00 a.m. EDT at the American Society of Clinical Oncology (ASCO) Annual Meeting 2021 from June 4-8.

Dr. Wolchok has provided consulting services to Bristol Myers Squibb.

About CheckMate -067

CheckMate -067 is a Phase 3, double-blind, randomized trial that evaluated the combination of Opdivo plus Yervoy or Opdivo monotherapy versus Yervoy monotherapy in 945 patients with previously untreated advanced melanoma. Patients in the combination group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg every three weeks (Q3W) for four doses followed by Opdivo 3 mg/kg every two weeks (Q2W). Patients in the Opdivo monotherapy group (n=316) received Opdivo 3 mg/kg Q2W plus placebo. Patients in the Yervoy monotherapy group (n=315) received Yervoy 3 mg/kg Q3W for four doses plus placebo. Patients were treated until progression or unacceptable toxic effects. Overall survival (OS) and progression-free survival (PFS) were dual endpoints of the trial. Secondary endpoints included objective response rates (ORR), descriptive efficacy assessments and safety.

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 106,110 new diagnoses of melanoma and about 7,180 related deaths are estimated for 2021. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths. Melanoma is mostly curable when treated in its very early stages; however, survival rates decrease if regional lymph nodes are involved.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible 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. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, 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 corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO 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. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. 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 OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to 2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in 2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent (n=74), the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 649, the most common adverse reactions (20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma; Checkmate 649previously untreated advanced or metastatic gastric or gastroesophageal junction or esophageal adenocarcinoma.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies as single agents and combination regimens for patients with cancer in Japan, South Korea and Taiwan.

About Bristol Myers Squibb

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Six-and-a-Half-Year Outcomes for Opdivo (nivolumab) in Combination with Yervoy (ipilimumab) Continue to Demonstrate Durable Long-Term Survival...

Recommendation and review posted by Bethany Smith

Opinion Supports Use of KEYTRUDA in Combination With Platinum- and Fluoropyrimidine-Based Chemotherapy in Patients Whose Tumors Express PD-L1 (CPS 10)

Recommendation Based on Significant Survival Benefit Demonstrated With KEYTRUDA Plus Chemotherapy Versus Chemotherapy in Phase 3 KEYNOTE-590 Trial

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

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Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal...

Recommendation and review posted by Bethany Smith

By Sofia MoutinhoMay. 20, 2021 , 11:05 AM

They are no bigger than sesame seeds, and they pulse with a hypnotic rhythm. These are human minihearts, the first to be created in the lab with clearly beating chambers. The miniature organs, or organoids, mimic the working heart of a 25-day-old human embryo and could help unravel many mysteriesincluding why babies hearts dont scar after they experience a heart attack.

This is a great study, says Zhen Ma, a bioengineer who develops heart organoids at Syracuse University and was not part of the new research. The experiment is very important for understanding congenital heart defects and human heart formationwork that has so far relied on animal models, he says.

Although miniorgans like brains, guts, and livers have been grown in dishes for more than 10 years, heart organoids have been more challenging. The first ones, comprised of mouse cardiac cells, could contract rhythmically in a dish, but they looked more like a lump of cardiac cells than a proper heart, says Aitor Aguirre, a stem cell biologist at Michigan State University who has created his own beating human heart organoid, described in a preprint posted to Research Square. An organoid should recapitulate the function of the organ, he says. With a heart, You would expect chambers and pumping, because this is what the heart does.

To create heart organoids whose cells self-organize like those in an embryo, the authors of the new study programmed human pluripotent stem cells, which have the ability to differentiate into any kind of tissue, into various types of cardiac cells. They aimed to create the three tissue layers present in the walls of a heart chamber, one of the first parts of the heart to develop. Next, the researchers immersed the stem cells in different concentrations of growth-promoting nutrients until they found a recipe that coaxed the cells to form tissues in the same order and shape seen in embryos.

After 1 week of development, the organoids are structurally equivalent to the heart of a 25-day-old embryo. At this stage, the heart has only one chamber, which will become the left ventricle of the mature heart. The organoids are about 2 millimeters in diameter and include the main types of cells typically present in this stage of development: cardiomyocytes, epithelial cells, fibroblasts, and epicardium. They also have a clearly defined chamber that beats at 60 to 100 times per minute, the same rate of an embryos heart around the same age, the team reports today in Cell.

When I saw it the first time, I was amazed that these chambers could form on their own, says lead author Sasha Mendjan, a stem cell biologist at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences. The amazing thing is that you see immediately whether the experiment worked and the organoid is functional, since it beatsunlike other organs.

The minihearts, which have so far survived for more than 3 months in the lab, will help scientists see heart development in unprecedented detail. They might also reveal the origins of cardiac problems like congenital heart defects in babies and cardiac cell death after heart attacks, Mendjan says. You cannot fully understand something until you can re-create it, he says, loosely quoting the Nobel physicist Richard Feynman.

Mendjan and his colleagues also froze pieces of the organoids to test their response to injury. They saw that cardiac fibroblasts, a type of cell responsible for maintaining tissue structure, migrated to the damaged areas to repair the dead cells, just as in babies that experience heart attacks. It has long been a mystery why babies hearts can regenerate after such injury without scarring, unlike those of adults. Now, we have a controlled and clean system outside of the human body to easily study this process, Mendjan says.

Aguirre says the next logical step is to connect beating heart organoids to vascular networks and test their ability to pump blood. Mendjans team plans to try to adjust the nutrient broth to produce organoids with all four chambers. With such advanced heart organoids, researchers could explore the many developmental heart problems that arise when these additional cavities start to form.

For Ma, growing a more adultlike heart organoid, with all its chambers and structures, is the future of the field. But he doesnt think this will happen in the next decade. For a complete heartlike organoid, he says, there is still a long way to go.

Continued here:
Lab-grown minihearts beat like the real thing - Science Magazine

Recommendation and review posted by Bethany Smith

DUBLIN, May 21, 2021 /PRNewswire/ -- The "Cell Therapy - Technologies, Markets and Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. The role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

The cell-based markets was analyzed for 2020, and projected to 2030. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair, as well as diabetes mellitus, will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 316 of these are profiled in part II of the report along with tabulation of 306 alliances. Of these companies, 171 are involved in stem cells.

Profiles of 73 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 67 Tables and 26 Figures. The bibliography contains 1,200 selected references, which are cited in the text.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering, and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation, and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. The current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

Key Topics Covered:

Part One: Technologies, Ethics & Regulations

Executive Summary

1. Introduction to Cell Therapy

2. Cell Therapy Technologies

3. Stem Cells

4. Clinical Applications of Cell Therapy

5. Cell Therapy for Cardiovascular Disorders

6. Cell Therapy for Cancer

7. Cell Therapy for Neurological Disorders

8. Ethical, Legal and Political Aspects of Cell therapy

9. Safety and Regulatory Aspects of Cell Therapy

Part II: Markets, Companies & Academic Institutions

10. Markets and Future Prospects for Cell Therapy

11. Companies Involved in Cell Therapy

12. Academic Institutions

13. References

For more information about this report visit https://www.researchandmarkets.com/r/oletip

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716

SOURCE Research and Markets

http://www.researchandmarkets.com

Originally posted here:
Global Cell Therapy Markets, Technologies, and Competitive Landscape Report 2020-2030: Applications, Cardiovascular Disorders, Cancer, Neurological...

Recommendation and review posted by Bethany Smith

DUBLIN, May 21, 2021 /PRNewswire/ -- The "Cardiovascular Drug Delivery - Technologies, Markets & Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

The cardiovascular drug delivery markets are estimated for the years 2018 to 2028 on the basis of epidemiology and total markets for cardiovascular therapeutics.

The estimates take into consideration the anticipated advances and availability of various technologies, particularly drug delivery devices in the future. Markets for drug-eluting stents are calculated separately. The role of drug delivery in developing cardiovascular markets is defined and unmet needs in cardiovascular drug delivery technologies are identified.

Drug delivery to the cardiovascular system is approached at three levels: (1) routes of drug delivery; (2) formulations; and finally (3) applications to various diseases.

Formulations for drug delivery to the cardiovascular system range from controlled release preparations to delivery of proteins and peptides. Cell and gene therapies, including antisense and RNA interference, are described in full chapters as they are the most innovative methods of delivery of therapeutics. Various methods of improving the systemic administration of drugs for cardiovascular disorders are described including the use of nanotechnology.

Cell-selective targeted drug delivery has emerged as one of the most significant areas of biomedical engineering research, to optimize the therapeutic efficacy of a drug by strictly localizing its pharmacological activity to a pathophysiologically relevant tissue system. These concepts have been applied to targeted drug delivery to the cardiovascular system. Devices for drug delivery to the cardiovascular system are also described.

The role of drug delivery in various cardiovascular disorders such as myocardial ischemia, hypertension, and hypercholesterolemia is discussed. Cardioprotection is also discussed. Some of the preparations and technologies are also applicable to peripheral arterial diseases. Controlled release systems are based on chronopharmacology, which deals with the effects of circadian biological rhythms on drug actions. A full chapter is devoted to drug-eluting stents as treatment for restenosis following stenting of coronary arteries.Fifteen companies are involved in drug-eluting stents.

New cell-based therapeutic strategies are being developed in response to the shortcomings of available treatments for heart disease. Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure.

Cell therapy approaches include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes, conversion of bone marrow stem cells into cardiomyocytes, and transplantation of myocytes or other cells into injured myocardium.

Advances in the molecular pathophysiology of cardiovascular diseases have brought gene therapy within the realm of possibility as a novel approach to the treatment of these diseases. It is hoped that gene therapy will be less expensive and affordable because the techniques involved are simpler than those involved in cardiac bypass surgery, heart transplantation and stent implantation.

Gene therapy would be a more physiologic approach to deliver vasoprotective molecules to the site of vascular lesions. Gene therapy is not only a sophisticated method of drug delivery; it may at times need drug delivery devices such as catheters for transfer of genes to various parts of the cardiovascular system.

Selected 83 companies that either develop technologies for drug delivery to the cardiovascular system or products using these technologies are profiled and 80 collaborations between companies are tabulated. The bibliography includes 200 selected references from recent literature on this topic.

Key Markets

Key Topics Covered:

Executive Summary

1. Cardiovascular Diseases

2. Methods for Drug Delivery to the Cardiovascular System

3. Cell Therapy for Cardiovascular Disorders

4. Gene Therapy for Cardiovascular Disorders

5. Drug-Eluting Stents

6. Markets for Cardiovascular Drug Delivery

7. Companies involved in Cardiovascular Drug Delivery

8. References

For more information about this report visit https://www.researchandmarkets.com/r/qqxmpd

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716

SOURCE Research and Markets

http://www.researchandmarkets.com

Originally posted here:
Global Cardiovascular Drug Delivery Markets Report 2021: Cell and Gene Therapies, Including Antisense and RNA Interference are Described in Detail -...

Recommendation and review posted by Bethany Smith

DUBLIN--(BUSINESS WIRE)--The "Cardiovascular Drug Delivery - Technologies, Markets & Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

The cardiovascular drug delivery markets are estimated for the years 2018 to 2028 on the basis of epidemiology and total markets for cardiovascular therapeutics.

The estimates take into consideration the anticipated advances and availability of various technologies, particularly drug delivery devices in the future. Markets for drug-eluting stents are calculated separately. The role of drug delivery in developing cardiovascular markets is defined and unmet needs in cardiovascular drug delivery technologies are identified.

Drug delivery to the cardiovascular system is approached at three levels: (1) routes of drug delivery; (2) formulations; and finally (3) applications to various diseases.

Formulations for drug delivery to the cardiovascular system range from controlled release preparations to delivery of proteins and peptides. Cell and gene therapies, including antisense and RNA interference, are described in full chapters as they are the most innovative methods of delivery of therapeutics. Various methods of improving the systemic administration of drugs for cardiovascular disorders are described including the use of nanotechnology.

Cell-selective targeted drug delivery has emerged as one of the most significant areas of biomedical engineering research, to optimize the therapeutic efficacy of a drug by strictly localizing its pharmacological activity to a pathophysiologically relevant tissue system. These concepts have been applied to targeted drug delivery to the cardiovascular system. Devices for drug delivery to the cardiovascular system are also described.

The role of drug delivery in various cardiovascular disorders such as myocardial ischemia, hypertension, and hypercholesterolemia is discussed. Cardioprotection is also discussed. Some of the preparations and technologies are also applicable to peripheral arterial diseases. Controlled release systems are based on chronopharmacology, which deals with the effects of circadian biological rhythms on drug actions. A full chapter is devoted to drug-eluting stents as treatment for restenosis following stenting of coronary arteries.Fifteen companies are involved in drug-eluting stents.

New cell-based therapeutic strategies are being developed in response to the shortcomings of available treatments for heart disease. Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure.

Cell therapy approaches include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes, conversion of bone marrow stem cells into cardiomyocytes, and transplantation of myocytes or other cells into injured myocardium.

Advances in the molecular pathophysiology of cardiovascular diseases have brought gene therapy within the realm of possibility as a novel approach to the treatment of these diseases. It is hoped that gene therapy will be less expensive and affordable because the techniques involved are simpler than those involved in cardiac bypass surgery, heart transplantation and stent implantation.

Gene therapy would be a more physiologic approach to deliver vasoprotective molecules to the site of vascular lesions. Gene therapy is not only a sophisticated method of drug delivery; it may at times need drug delivery devices such as catheters for transfer of genes to various parts of the cardiovascular system.

Selected 83 companies that either develop technologies for drug delivery to the cardiovascular system or products using these technologies are profiled and 80 collaborations between companies are tabulated. The bibliography includes 200 selected references from recent literature on this topic.

Key Markets

Key Topics Covered:

Executive Summary

1. Cardiovascular Diseases

2. Methods for Drug Delivery to the Cardiovascular System

3. Cell Therapy for Cardiovascular Disorders

4. Gene Therapy for Cardiovascular Disorders

5. Drug-Eluting Stents

6. Markets for Cardiovascular Drug Delivery

7. Companies involved in Cardiovascular Drug Delivery

8. References

For more information about this report visit https://www.researchandmarkets.com/r/p5l8t6

Follow this link:
Global Cardiovascular Drug Delivery Markets Report 2021: Diseases, Methods, Cell Therapy, Gene Therapy, Drug-eluting Stents, Key Markets -...

Recommendation and review posted by Bethany Smith

Myocardial revascularization is an alternate procedure for patients suffering from ischemic heart disease and who cannot undergo interventions like heart bypass surgery due to widespread coronary artery disease, procedure failure, small coronary arteries, or cardiac stenosis. Further, reparative stem cells can restore the function of damaged tissue by renewing cell growth in cardiac cells destroyed by heart disease.

(**Note: The sample of this report is updated with COVID-19 impact analysis**)

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Report Introduction, Overview, and In-depth industry analysis

NOTE: Our analysts monitoring the situation across the globe explains that the market will generate remunerative prospects for producers post the COVID-19 crisis. The report aims to provide an additional illustration of the latest scenario, economic slowdown, and COVID-19 impact on the overall industry.

The report is a combination of qualitative and quantitative analysis of the Myocardial Revascularization, Repair, And Regeneration Products And Therapies Market industry. The global market majorly considers five major regions, namely, North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America (SACM). The report also focuses on the exhaustive PEST analysis and extensive market dynamics during the forecast period.

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Myocardial Revascularization, Repair, And Regeneration Products And Therapies Market Business Strategy and Forecast to 2028 Top Companies Abbott...

Recommendation and review posted by Bethany Smith

Introduction

Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1).

Figure 1 The possible role of epitherapy in the current framework of HFrEF and HFpEF management. The unstable transition state from the ACC/AHA Stage A/B to Stage C/D-Acute/Hospitalized HF is the key point in the treatment of HFrEF and HFpEF. The epitherapy, mainly apabetalone, statins, metformin, SGLT2i, and PUFAs in addition to the standard of the care may improve personalized therapy of affected patients.

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium glucose co-transporter 2 inhibitors; PUFAs, polyunsaturated fatty acids.

The bromodomain and extra terminal domain (BET) proteins, including the ubiquitous BRD2, BRD3, BRD4, and the testis-restricted BRDT, are epigenetic readers (via bromodomains) existing in the form of nuclear multidomain docking platforms which control the cell-specific activation of gene expression profiles.23 Experimental data demonstrated that BETs regulate vascular cells, cardiac myocytes, and inflammatory cells,24 and their activity may be extended to the regulation of calcification, thrombosis, as well as lipid and lipoprotein metabolism, all of which participate in atherogenesis.2527 In particular, BRD4 facilitated the expression of multiple proinflammatory and proatherosclerotic targets involved in thrombosis, leukocyte adhesion, and endothelial barrier function, thus identifying BRD4 as a possible therapeutic target in CVD setting.24 The quinazolone (RVX-208), known as apabetalone, is a derivative of the plant polyphenol resveratrol. Apabetalone acts as a direct epidrug by selectively targeting the BET family member BRD4 to block its interaction with acetylated lysines located in histones.28 Apabetalone-BRD4 binding can impact cholesterol levels and inflammation; in fact, apabetalone stimulates ApoA-I gene expression and increases high-density lipoprotein (HDL).29,30 Besides, apabetalone may attenuate the development of cardiac hypertrophy31 and cardiac fibrosis,32 suggesting novel options for the management of HF.

Resverlogix developed apabetalone (RVX-208), a first-in-class, orally available, small molecule for the treatment of atherosclerosis and associated CVDs.20 BETonMACE (NCT02586155) is the first Phase 3 clinical trial evaluating the cardiovascular efficacy and safety of apabetalone.22 Recent results from the BETonMACE study have demonstrated that apabetalone is associated with a reduction in first HF hospitalization and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome as compared to controls (placebo-treated patients).22 Additionally, a significant increase in HDL and a decrease in alkaline phosphatase levels have been observed following 24 weeks of apabetalone treatment as compared to the placebo group.22 However, investigators were unable to make a distinction between HF in the setting of preserved or reduced ejection fraction. Thus, further clinical trials should be designed to evaluate the putative beneficial effects of apabetalone in HFrEF and HFpEF, separately.

Preclinical studies demonstrated that pharmacological HDACi,3336 BET inhibitors,31,37 and DNA methylation inhibitors38 can attenuate cardiac remodeling (cardiomyocyte hypertrophy and fibrosis). Although not originally developed as epidrugs, hydralazine (anti-hypertensive drug), metformin, and SGLT2i (anti-diabetic drugs), statins (anti-dyslipidemic drugs), and PUFAs (nutraceuticals) might have downstream epigenetic-oriented effects in cardiac cells. Hydralazine, for example, lowers blood pressure by a direct relaxation of vascular smooth muscle; additionally, it may reduce DNA methylation and improve cardiac function through increasing sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and modulating calcium homeostasis in cardiomyocytes.39 Statins are used as a first-line treatment to decrease serum cholesterol levels in dyslipidemic patients and as primary and secondary prophylaxis against atherosclerosis and associated CVDs.6 Many of their non-classical pleiotropic properties relevant for endothelial health are mediated by epigenetic mechanisms which improve blood flow, decrease LDL oxidation, enhance atherosclerotic plaque stability and decrease proliferation of vascular smooth muscle cells and platelet aggregation.6 Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients.10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs).40 Both metformin41,42 and statins43,44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.45 Animal models have demonstrated that empagliflozin46,47 and dapagliflozin48 may improve hemodynamics in HF by increasing renal protection and cardiac fibrosis. Interestingly, inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by empagliflozin;49 this observation has provided insights about mechanisms by which SGLT2i can reduce cardiovascular mortality in man (EMPA-REG trial).50

An effective therapy for HFpEF has yet to be established. Hydralazine is frequently used in HFrEF, and represents a potential DNA methylation inhibitor.39 DNA methylation is the most studied direct epigenetic change with potential clinical implications in major CVDs and the development of HF.7,14 This epigenetic signature mainly involves methylation of CpG islands in the gene promoters leading to a specific long-term silencing of gene expression.7,14 A completed Phase 2 clinical trial (NCT01516346) evaluated the effect of prolonged therapy (24 weeks) with isosorbide dinitrate (ISDN) hydralazine on arterial wave reflections (primary endpoint) as well as left ventricular (LV) mass, fibrosis and diastolic function, and exercise capacity (6-minute walk test) in patients with HFpEF, New York Heart Association (NYHA) Class IIIV symptoms, and standard therapy as defined by ACEi, ARB, beta-blockers, or calcium channel blockers (CCBs).51 Results from this trial reported that ISDN, with or without hydralazine, had deleterious effects on reflection magnitude, LV remodeling, or submaximal exercise thus not supporting their routine use in patients with HFpEF.51

Metformin has been associated with a reduced mortality in patients with HFpEF, even if female gender was associated with worse outcomes.52 Recently, it has been observed that a long-term treatment with metformin can improve LV diastolic function and hypertrophy, decrease the incidence of new-onset HFpEF, and delay disease progression in patients with type 2 diabetes and hypertension.53 Besides, a prospective phase 2 clinical trial (NCT03629340) is testing the therapeutic efficacy of metformin in patients with pulmonary hypertension and HFpEF by evaluating exercise hemodynamics, functional capacity, skeletal muscle signaling, and insulin sensitivity. However, results have not been published. A recent study based on the JASPER registry, a multicenter, observational, prospective cohort of Japanese patients aged 20 years requiring hospitalization for acute HFpEF has reported that the use of statins could reduce mortality in affected patients without coronary heart disease.54 Furthermore, the use of statins was associated with improved clinical outcomes in patients with HFpEF but not in patients with HFrEF (or mid-range ejection fraction).55 A reduced rate of major adverse cardiac events, cardiovascular death and all-cause mortality was associated with SGLT2i treatment in both HFpEF and HFrEF patients as compared to placebo.56,57 However, the observed cardiovascular and renal benefits cannot be fully explained by improvement in risk factors (such as glycemia, blood pressure or dyslipidemias) suggesting that other molecular mechanisms may explain the cardiovascular benefits.56 Interestingly, the SGLT2i-related epigenetic interference may arise from their ability to increase the circulating and tissue levels of -hydroxybutyrate, a specific molecule able to generate a pattern of histone modifications (known as -hydroxybutyrylation) which are associated with the beneficial effects of fasting.58 Besides, the DELIVER (NCT03619213) multicenter, randomized, double-blind, placebo-controlled study of 6263 HFpEF patients will evaluate the effect of dapagliflozin 10 mg (1 per day) as compared to placebo in addition to the standard of care in order to reduce the composite of cardiovascular death or HF events. However, results have not yet been published.

The use of metformin has been generally considered a contraindication in HFrEF patients owing the potential risk of lactic acidosis; however, recent evidence has reported that metformin can provide beneficial effects in reducing the risk of incident HF and mortality in diabetic patients.5961 A completed, observational clinical trial (NCT03546062) has recently performed the evaluation of seriated cardiac biopsies from healthy implanted hearts in type 2 diabetes recipients during 12-month follow-up upon heart transplantation.21 Even if the intra-cardiomyocyte lipid accumulation in type 2 diabetes recipients may start in the early stages after heart transplantation, metformin therapy could reduce lipid accumulation independently of immunosuppressive therapy.21 The DANHEART trial (NCT03514108), a multicenter, randomized, double-blind, placebo-controlled study in 1500 patients with HFrEF will evaluate: 1) whether hydralazine-isosorbide dinitrate as compared to placebo may reduce the incidence of death and HF hospitalization, and 2) if metformin as compared to placebo may reduce the incidence of death, worsening of HF, acute myocardial infarction, and stroke in patients with diabetes or prediabetes. Two large randomized trials demonstrated that statins did not have beneficial effects in management of patients with HFrEF.62,63 Specifically, the CORONA phase 3 trial randomized more than 5000 patients with ischemic HFrEF to rosuvastatin as compared to placebo resulting in no benefits on the primary endpoints, as death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.62 According to CORONA trial, the GISSI-HF study randomized almost 5000 patients with clinically apparent HF of any cause to rosuvastatin as compared to placebo and observed no benefits on the primary endpoints, as all-cause death or cardiovascular hospitalization.63 However, it is needed to highlight that both trials demonstrated that statins are safe in HF patients. In contrast with the previous evidence, the trial based on the Swedish Heart Failure Registry (21,864 patients with HFrEF, of whom 10,345 were treated with statins) reported an association between the use of statins and improved outcomes, as all-cause mortality, cardiovascular mortality, HF hospitalization, and combined all-cause mortality or cardiovascular hospitalization, especially in patients with ischemic HF.64 Thus, further randomized controlled trials focused on ischemic HF may be warranted. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are key players in modulating inflammatory process by limiting leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelium interaction as well as T cell reactivity.65 EPA and DHA are mainly gained from marine food consumption and large population-based studies have shown that Mediterranean diet with PUFA supplementation may aid to prevent CVDs owing to their ability in promoting the release of nitric oxide from endothelial cells and decreasing serum levels of triglycerides.66 Recent evidence has indicated that PUFAs can significantly affect the cellular epigenome mainly thought DNA methylation-sensitive mechanisms.67,68 The GISSI multicenter, double-blind trial enrolled 6975 HF patients (New York Heart Association class IIIV, irrespective of cause and LV ejection fraction) and randomized them to low dose (0.84 g per day) of PUFAs as compared to placebo. PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy.19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function.69 Taken together, these results suggest that PUFAs may aid to prevent HFrEF. More recently, the MESA longitudinal trial including 6562 participants 45 to 84 years has demonstrated that higher plasma levels of EPA were significantly associated with reduced risk both in HFpEF and HFrEF.70

Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs4148 can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine39 and empagliflozin (Figure 2).49 Of note, metformin and SGLT2i can impact on the epigenetic memory phenomenon. This latter suggests that an early glycemia normalization can arrest hyperglycemia-induced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids.71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF;19,6264,69,7375 however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF. Thus, further randomized trials are needed to clarify whether apabetalone, as well as non-canonical repurposed epidrugs, will really be able to save failing hearts in different HF clinical phenotypes or prevent irreversible damages in high-risk patients. In this context, Network Medicine approaches may help to evaluate a possible repurposing of epidrugs in patients with major CVDs.15,76,77

Figure 2 Direct and indirect epigenetic drugs in preclinical models of HF. Cardiac remodeling includes different pathological phenotypes and each type of drug can selectively improve inflammation, cardiac fibrosis and hypertrophy, calcium homeostasis, and lipid metabolism.

Abbreviations: HF, heart failure; SGLT2i, sodium glucose co-transporter 2 inhibitors.

This work was supported by PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli).

The authors report no conflicts of interest in this work.

1. Gronda E, Sacchi S, Benincasa G, et al. Unresolved issues in left ventricular postischemic remodeling and progression to heart failure. J Cardiovasc Med (Hagerstown). 2019;20:640649. doi:10.2459/JCM.0000000000000834.

2. Gronda E, Vanoli E, Sacchi S, et al. Risk of heart failure progression in patients with reduced ejection fraction: mechanisms and therapeutic options. Heart Fail Rev. 2020;25(2):295303. doi:10.1007/s10741-019-09823-z

3. Sokos GG, Raina A. Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan. Vasc Health Risk Manag. 2020;16:4151. doi:10.2147/VHRM.S197291

4. Cacciatore F, Amarelli C, Maiello C, et al. Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty. ESC Heart Fail. 2020;7:757762. doi:10.1002/ehf2.12610.

5. Clark KAA, Velazquez EJ. Heart failure with preserved ejection fraction: time for a reset. JAMA. 2020;324:15061508. doi:10.1001/jama.2020.15566.

6. Schiano C, Benincasa G, Franzese M, et al. Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases. Pharmacol Ther. 2020;210:107514. doi:10.1016/j.pharmthera.2020.107514.

7. Schiano C, Benincasa G, Infante T, et al. Integrated analysis of DNA methylation profile of HLA-G gene and imaging in coronary heart disease: pilot study. PLoS One. 2020;15:e0236951. doi:10.1371/journal.pone.0236951.

8. Benincasa G, Cuomo O, Vasco M, et al. Epigenetic-sensitive challenges of cardiohepatic interactions: clinical and therapeutic implications in heart failure patients. Eur J Gastroenterol Hepatol. 2020. doi:10.1097/MEG.0000000000001867.

9. Benincasa G, Franzese M, Schiano C, et al. DNA methylation profiling of CD04+/CD08+ T cells reveals pathogenic mechanisms in increasing hyperglycemia: PIRAMIDE pilot study. Ann Med Surg (Lond). 2020;60:218226. doi:10.1016/j.amsu.2020.10.016.

10. Napoli C, Benincasa G, Schiano C, et al. Differential epigenetic factors in the prediction of cardiovascular risk in diabetic patients. Eur Heart J Cardiovasc Pharmacother. 2020;6:239247. doi:10.1093/ehjcvp/pvz062.

11. Napoli C, Coscioni E, de Nigris F, et al. Emergent expansion of clinical epigenetics in patients with cardiovascular diseases. Curr Opin Cardiol. 2021;36(3):295300. doi:10.1097/HCO.0000000000000843.

12. Infante T, Forte E, Schiano C, et al. Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography. PLoS One. 2019;14:e0210909. doi:10.1371/journal.pone.0210909.

13. de Nigris F, Cacciatore F, Mancini FP, et al. Epigenetic hallmarks of fetal early atherosclerotic lesions in humans. JAMA Cardiol. 2018;3:11841191. doi:10.1001/jamacardio.2018.3546.

14. Napoli C, Benincasa G, Donatelli F, et al. Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics. Am Heart J. 2020;224:113128. doi:10.1016/j.ahj.2020.03.007.

15. Sarno F, Benincasa G, List M, et al. Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside. Clin Epigenetics. 2021;13:66. doi:10.1186/s13148-021-01047-z.

16. Grimaldi V, Vietri MT, Schiano C, et al. Epigenetic reprogramming in atherosclerosis. Curr Atheroscler Rep. 2014;17:476. doi:10.1007/s11883-014-0476-3.

17. Sabia C, Picascia A, Grimaldi V, et al. The epigenetic promise to improve prognosis of heart failure and heart transplantation. Transplant Rev (Orlando). 2017;31:249256. doi:10.1016/j.trre.2017.08.004.

18. Vasco M, Benincasa G, Fiorito C, et al. Clinical epigenetics and acute/chronic rejection in solid organ transplantation: an update. Transplant Rev (Orlando). 2021;35:100609. doi:10.1016/j.trre.2021.100609.

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30. Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55:25802589. doi:10.1016/j.jacc.2010.02.035.

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34. Ferguson BS, McKinsey TA. Non-sirtuin histone deacetylases in the control of cardiac aging. J Mol Cell Cardiol. 2015;83:1420. doi:10.1016/j.yjmcc.2015.03.010.

35. Chen Y, Du J, Zhao YT, et al. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol. 2015;14:99. doi:10.1186/s12933-015-0262-8.

36. Zhang CL, McKinsey TA, Chang S, et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110(4):479488. doi:10.1016/s0092-8674(02)00861-9

37. Spiltoir JI, Stratton MS, Cavasin MA, et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J Mol Cell Cardiol. 2013;63:175179. doi:10.1016/j.yjmcc.2013.07.017.

38. Russell-Hallinan A, Neary R, Watson CJ, et al. Repurposing from oncology to cardiology: low-dose 5-azacytidine attenuates pathological cardiac remodeling in response to pressure overload injury. J Cardiovasc Pharmacol Ther. 2020:107424842097923. doi:10.1177/1074248420979235

39. Kao YH, Cheng CC, Chen YC, et al. Hydralazine-induced promoter demethylation enhances sarcoplasmic reticulum Ca2+ -ATPase and calcium homeostasis in cardiac myocytes. Lab Invest. 2011;91:12911297. doi:10.1038/labinvest.2011.92.

40. Bridgeman SC, Ellison GC, Melton PE, et al. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab. 2018;20(7):15531562. doi:10.1111/dom.13262.

41. Xiao H, Ma X, Feng W, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res. 2010;87:504513. doi:10.1093/cvr/cvq066.

42. Zhao Q, Song W, Huang J, et al. Metformin decreased myocardial fibrosis and apoptosis in hyperhomocysteinemia -induced cardiac hypertrophy. Curr Res Transl Med. 2021;69:103270. doi:10.1016/j.retram.2020.103270.

43. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120:229243. doi:10.1161/CIRCRESAHA.116.308537.

44. Sun F, Duan W, Zhang Y, et al. Simvastatin alleviates cardiac fibrosis induced by infarction via up-regulation of TGF- receptor III expression. Br J Pharmacol. 2015;172:37793792. doi:10.1111/bph.13166.

45. Gronda E, Jessup M, Iacoviello M, et al. Glucose metabolism in the kidney: neurohormonal activation and heart failure development. J Am Heart Assoc. 2020;9(23):e018889. doi:10.1161/JAHA.120.018889.

46. Lee HC, Shiou YL, Jhuo SJ, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45. doi:10.1186/s12933-019-0849-6.

47. Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18:15. doi:10.1186/s12933-019-0816-2.

48. Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19:7. doi:10.1186/s12933-019-0980-4.

49. Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017;13:370385. doi:10.1016/j.redox.2017.06.009.

50. Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 Diabetes. N Engl J Med. 2016;374:1094. doi:10.1056/NEJMc1600827

51. Zamani P, Akers S, Soto-Calderon H, et al. Isosorbide Dinitrate, with or without hydralazine, does not reduce wave reflections, left ventricular hypertrophy, or myocardial fibrosis in patients with heart failure with preserved ejection fraction. J Am Heart Assoc. 2017;6:e004262. doi:10.1161/JAHA.116.004262.

52. Halabi A, Sen J, Huynh Q, et al. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020;19(1):124. doi:10.1186/s12933-020-01100-w.

53. Gu J, Yin ZF, Zhang JF, et al. Association between long-term prescription of metformin and the progression of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and hypertension. Int J Cardiol. 2020;306:140145. doi:10.1016/j.ijcard.2019.11.087.

54. Marume K, Takashio S, Nagai T, et al. Effect of statins on mortality in heart failure with preserved ejection fraction without coronary artery disease. Report from the JASPER Study. Circ J. 2019;83:357367. doi:10.1253/circj.CJ-18-0639.

55. Lee MS, Duan L, Clare R, et al. Comparison of effects of statin use on mortality in patients with heart failure and preserved versus reduced left ventricular ejection fraction. Am J Cardiol. 2018;122:405412. doi:10.1016/j.amjcard.2018.04.027.

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Epigenetic therapies for heart failure | VHRM - Dove Medical Press

Recommendation and review posted by Bethany Smith

A passion for the natural world drives many of our adventures. And when were not actually outside, we love delving into the discoveries about the places where we live and travel. Here are some of the best natural history links weve found this week.

Elephants are dying in droves in Botswana: Between January and March 2021, 39 Africa elephants turned up dead in Botswana. All deaths occurred in the Moremi Game Reserve, the same region where 350 elephants died in mid-2020. Preliminary results indicate that cyanobacteria toxins are to blame. Water sources in the area are becoming warmer, creating an environment in which the toxic cyanobacteria thrive.

Scientists have grown a mini beating heart: Researchers in Vienna have grown tiny 3D heart-like organs in the lab. Made from human stem cells, the organoids, as theyre called, are the size of a sesame seed and beat the same way our hearts do. Unlike previous efforts that required artificial scaffolding, these cells organized themselves to grow a hollow chamber. Scientists hope that the mini-hearts will provide a better understanding of how the cardiac system responds to disease.

The largest iceberg in the world. Photo: ESA/Earth Observation

Worlds largest iceberg breaks away from Antarctic ice shelf: An iceberg bigger than Majorca has broken away from the Ronne Ice Shelf into the Weddell Sea. Unimaginatively named A-76, the iceberg is 4,320 square kilometres in area and is currently the largest iceberg in the world. Of course, it is bigger than Rhode Island, the standard comparison for such giant objects. The Antarctic region from which it comes is generally unaffected by climate change. [The break-off] is part of a natural cycle, says Alex Brisbourne, a glaciologist at the British Antarctic Survey.

Scientists dig deepest ocean hole in history: Researchers off the coast of Japan have drilled the deepest ocean hole in the history in the Pacific Ocean. The hole reaches nine kilometres below the surface of the ocean. It took just two hours and 40 minutes for the giant piston corer to reach the bottom of the Japan Trench. The team extracted a 37m-long sediment core from the bottom of the sea. The site is very close to the epicentre of the 2011 Tohoku-oki earthquake, the largest ever to strike Japan. Scientists hope that the sediments will help them understand the regions earthquake history.

Researcher want to find out if tardigrades could survive in space. Photo: Forbes.com

Tardigrades shot from gun to see if they can survive space travel: Tardigrades, also known as water bears and moss piglets, are microscopic invertebrates that are found almost everywhere water exists. If required (by drought, for example), they are able to drain their cells of liquid and enter suspended animation. In this state, they can survive everything from subzero temperatures to radiation. Researchers have put the Tardigrades into nylon bullets and fired them at sand targets in a vacuum chamber at speeds of up to 1,000 metres per second to see if they could withstand being shot onto other planets.

Death Valley is no longer the hottest place on Earth: Death Valley has held the record for the worlds hottest air temperature since 1913 when Furnace Creek reached 56.7C. Recently, two locations have surpassed Death Valley at its hottest. Satellite data reveal that the Lut Desert in Iran and the Sonoran Desert along the Mexican-U.S. border have reached a sizzling 80.8C.

Rebecca is a freelance writer and science teacher based in the UK.

She is a keen traveler and has been lucky enough to backpack her way around Africa, South America, and Asia. With a background in marine biology, she is interested in everything to do with the oceans and aims to dive and open-water swim in as many seas as possible.

Her areas of expertise include open water sports, marine wildlife and adventure travel.

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Science Links of the Week Explorersweb - ExplorersWeb

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Exosome therapeutic marketis expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

International Exosome Therapeutic market report offers the best market and business solutions to pharmaceutical industry in this rapidly revolutionizing market place to thrive in the market. Market definition of the document gives the scope of particular product with respect to the driving factors and restraints in the market. Competitor strategies such as new product launches, expansions, agreements, joint ventures, partnerships, and acquisitions can be utilized well by the pharmaceutical industry to take better steps for selling goods and services. Exosome Therapeutic market analysis report is a careful investigation of current scenario of the market and future estimations which spans several market dynamics.

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The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Key questions answered in Exosome Therapeutic Report:

Scope of the Exosome Therapeutic Market

The global exosome therapeutic market is segmented on the basis of countries into U.S., Mexico, Turkey, Hong Kong, Australia, South Korea, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua and Uruguay.

All country based analysis of the exosome therapeutic market is further analyzed based on maximum granularity into further segmentation. On the basis of type, the market is segmented into natural exosomes and hybrid exosomes. Based on source, the market is segmented into dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, urine and others. On the basis of therapy, the market is segmented into immunotherapy, gene therapy and chemotherapy. On the basis of transporting capacity, the market is segmented into bio macromolecules and small molecules. On the basis of application, the market is segmented into oncology, neurology, metabolic disorders, cardiac disorders, blood disorders, inflammatory disorders, gynecology disorders, organ transplantation and others. On the basis of route of administration, the market is segmented into pa oral and parenteral. On the basis of end user, the market is segmented into hospitals, diagnostic centers and research & academic institutes and others.

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Exosome Therapeutic Market Drivers:

Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

Exosome Therapeutic Market Restraints:

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market.

TOC of Exosome Therapeutic Market Report Contains:

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Customization Available:Global Exosome Therapeutic Market

Data Bridge Market Researchis a leader in advanced formative research. We take pride in servicing our existing and new customers with data and analysis that match and suits their goal. The report can be customised to include price trend analysis of target brands understanding the market for additional countries (ask for the list of countries), clinical trial results data, literature review, refurbished market and product base analysis. Market analysis of target competitors can be analysed from technology-based analysis to market portfolio strategies. We can add as many competitors that you require data about in the format and data style you are looking for. Our team of analysts can also provide you data in crude raw excel files pivot tables (Factbook) or can assist you in creating presentations from the data sets available in the report.

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Data Bridge adepts in creating satisfied clients who reckon upon our services and rely on our hard work with certitude. GetCustomizationandDiscounton Report by emailingsopan.gedam@databridgemarketresearch.com. We are content with our glorious 99.9 % client satisfying rate.

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Global Exosome Therapeutic Market Updates, Future Growth, Industry Analysis and Comprehensive Study on Key Players-ReNeuron Group plc, Capricor...

Recommendation and review posted by Bethany Smith