- First Patient Dosed in Phase 1 AL102 Combination Trial with Novartis’ Anti-BCMA Agent for the Treatment of Multiple Myeloma -

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Ayala Pharmaceuticals Reports First Quarter 2021 Financial Results and Provides Business Update

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- Anticipate Emergency Use Submission for SARS-CoV-2Antibody Biosensor Test in the Second Half of 2021-

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GBS Inc. Reports First Quarter 2021 Financial Results and Recent Business Highlights

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Hamilton, Bermuda, May 14, 2021 – Auris Medical Holding Ltd. (NASDAQ: EARS), a clinical-stage company dedicated to developing therapeutics that address important unmet medical needs in neurotology, rhinology and allergy and CNS disorders, today announced that it has reached the midpoint for enrollment in Part B of its Phase 2 proof-of-concept trial of AM-125 (intranasal betahistine) in the treatment of acute peripheral vertigo.

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Auris Medical Reaches Midpoint for Enrollment in Part B of AM-125 Phase 2 TRAVERS Trial in Acute Peripheral Vertigo

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JERSEY CITY, N.J., May 14, 2021 (GLOBE NEWSWIRE) -- SCYNEXIS, Inc. (NASDAQ: SCYX), a biotechnology company pioneering innovative medicines to overcome and prevent difficult-to-treat and drug-resistant infections, today reported that it has secured a $60 million term loan facility with Hercules Capital, Inc. (NYSE: HTGC) and Silicon Valley Bank (SVB). The capital strengthens SCYNEXIS’ balance sheet ahead of the anticipated commercial launch of Brexafemme, the expected trade name for ibrexafungerp, an oral antifungal product candidate for the treatment of vaginal yeast infections, which is under regulatory review by the U.S. Food and Drug Administration (FDA) with a PDUFA target action date of June 1, 2021. This non-dilutive financing further extends SCYNEXIS’ projected cash runway into 2023, based on current operating plans.

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SCYNEXIS Secures Term Loan Facility for up to $60 Million with Hercules Capital and Silicon Valley Bank

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CAMBRIDGE, Mass., May 14, 2021 (GLOBE NEWSWIRE) -- Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for central nervous system (CNS) disorders characterized by neuronal imbalance, today announced that management will participate in the following upcoming virtual investor conferences:

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Praxis Precision Medicines to Present at Upcoming Investor Conferences

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Underwriters’ Full Exercise of Option Brings Gross Proceeds to $34.5 Million

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Recro Announces Closing of Public Offering of Common Stock and Full Exercise of Underwriters’ Option to Purchase Additional Shares

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CAMBRIDGE, Mass. and AVENTURA, Fla., May 14, 2021 (GLOBE NEWSWIRE) -- Cytovia Therapeutics, Inc., a biopharmaceutical company developing allogeneic “off-the-shelf” gene-edited Chimeric Antigen Receptor (CAR)-NK cells derived from induced pluripotent stem cells (iPSCs) and NK cell engager multifunctional antibodies, announced today that its CEO, Dr. Daniel Teper, will be presenting at the following industry conferences:

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Cytovia Therapeutics CEO Dr. Daniel Teper to Present at Two Upcoming Conferences

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Conference call scheduled for May 18, 2021 at 4:10 p.m. EDT.

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Qualigen Therapeutics, Inc. Reports First Quarter 2021 Financial Results and Provides Corporate Update

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VANCOUVER, British Columbia, May 14, 2021 (GLOBE NEWSWIRE) -- TOWER ONE WIRELESS CORP. (CSE: TO) (OTCQB: TOWTF) (Frankfurt: 1P3N) (“Tower One” or the “Company”) provides a construction update for the month of April 2021.

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Tower One Construction Update for the Month of April 2021

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TORONTO, May 14, 2021 (GLOBE NEWSWIRE) -- Aleafia Health Inc. (TSX: AH, OTCQX: ALEAF) (“Aleafia Health” or the “Company”) a global leader in cannabis wellness products and services, today announced that Benjamin Ferdinand, chief financial officer, is departing the Company on amicable terms to pursue a new opportunity in the technology sector. He will continue to serve as CFO during a transition period. The Company has initiated a search process for a new chief financial officer with the help of an executive search firm and will consider internal and external candidates.

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Aleafia Health Announces Changes to Executive Team

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SAN DIEGO, May 14, 2021 (GLOBE NEWSWIRE) -- Prometheus Biosciences, Inc. (Nasdaq: RXDX), a clinical-stage biotechnology company pioneering a precision medicine approach for the discovery, development, and commercialization of novel therapeutic and companion diagnostic products for the treatment of immune-mediated diseases, starting first with inflammatory bowel disease (IBD), today announced that Mark McKenna, President and CEO, will participate virtually in a fireside chat during the 2021 RBC Capital Markets Global Healthcare Conference on Wednesday, May 19, 2021 at 10:55 a.m. ET.

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Prometheus Biosciences to Present at 2021 RBC Capital Markets Global Healthcare Conference

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WORCESTER, Mass., May 14, 2021 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (“Mustang”) (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, today announced financial results and recent corporate highlights for the first quarter ended March 31, 2021.

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Mustang Bio Reports First Quarter 2021 Financial Results and Recent Corporate Highlights

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WALTHAM, Mass., May 14, 2021 (GLOBE NEWSWIRE) -- Apellis Pharmaceuticals, Inc. (Nasdaq: APLS), a global biopharmaceutical company and leader in targeted C3 therapies, today announced that the U.S. Food and Drug Administration (FDA) has approved EMPAVELI™ (pegcetacoplan), the first and only targeted C3 therapy for treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). EMPAVELI is approved for use in adults with PNH who are treatment naïve as well as patients switching from the C5 inhibitors Soliris® (eculizumab) and Ultomiris® (ravulizumab).

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Apellis Announces U.S. Food and Drug Administration (FDA) Approval of EMPAVELI™ (pegcetacoplan) for Adults with Paroxysmal Nocturnal Hemoglobinuria...

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PORTLAND, Ore., May 14, 2021 (GLOBE NEWSWIRE) -- Golden Leaf Holdings Ltd. (CSE:GLH) (OTCQB:GLDFF) (“Golden Leaf” or the “Company”), operating as Chalice Brands, a premier, consumer-driven cannabis company specializing in retail, production, processing, wholesale, and distribution, today announces it will report its first quarter 2021 results before market open on Tuesday, May 25th, 2021.

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Golden Leaf Announces Date for Release of First Quarter 2021 Financial Results and Provides Corporate Update

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Of late, there has been an increasing awareness regarding the therapeutic potential of stem cells for management of diseases which is boosting the growth of the stem cell therapy market. The development of advanced genome based cell analysis techniques, identification of new stem cell lines, increasing investments in research and development as well as infrastructure development for the processing and banking of stem cell are encouraging the growth of the global stem cell therapy market.

One of the key factors boosting the growth of this market is the limitations of traditional organ transplantation such as the risk of infection, rejection, and immunosuppression risk. Another drawback of conventional organ transplantation is that doctors have to depend on organ donors completely. All these issues can be eliminated, by the application of stem cell therapy. Another factor which is helping the growth in this market is the growing pipeline and development of drugs for emerging applications. Increased research studies aiming to widen the scope of stem cell will also fuel the growth of the market. Scientists are constantly engaged in trying to find out novel methods for creating human stem cells in response to the growing demand for stem cell production to be used for disease management.

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It is estimated that the dermatology application will contribute significantly the growth of the global stem cell therapy market. This is because stem cell therapy can help decrease the after effects of general treatments for burns such as infections, scars, and adhesion. The increasing number of patients suffering from diabetes and growing cases of trauma surgery will fuel the adoption of stem cell therapy in the dermatology segment.

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

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On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

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Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Report | Know the Cutting-Edge Innovations and Future Trends of Market - BioSpace

Cardiac Stem Cells Comments Off on Stem Cell Therapy Market Report | Know the Cutting-Edge Innovations and Future Trends of Market – BioSpace | May 15th, 2021

Researchers used a pig model of heart attacks, which more closely resembles the human heart in size and physiology, and thus has high clinical relevance to human disease.

Researchers used a pig model of heart attacks, which more closely resembles the human heart in size and physiology, and thus has high clinical relevance to human disease.In a large-animal study, researchers have shown that heart attack recovery is aided by injection of heart muscle cells derived from human induced pluripotent stem cell line, or hiPSCs, that overexpress cyclin D2. This research, published in the journal Circulation, used a pig model of heart attacks, which more closely resembles the human heart in size and physiology, and thus has higher clinical relevance to human disease, compared to studies in mice.

An enduring challenge for bioengineering researchers is the failure of the heart to regenerate muscle tissue after a heart attack has killed part of its muscle wall. That dead tissue can strain the surrounding muscle, leading to a lethal heart enlargement.

Heart experts thus have sought to create new tissue applying a patch of heart muscle cells or injecting heart cells to replace damaged muscle. Similarly, they have tried to stimulate division of existing heart muscle cells near the damaged area. This current study, led by researchers at the University of Alabama at Birmingham, shows progress in both goals.

After the experimental heart attack, heart tissue around the infarction site was injected with about 30 million bioengineered human cardiomyocytes that were differentiated from hiPSCs. These cells also overexpress cyclin D2, part of a family of proteins involved in cell division.

Compared to control human cardiomyocytes, the cyclin D2-cardiomyocytes showed enhanced potency to repair the heart. They proliferated after injection, and by four weeks, the hearts had less pathogenic enlargement, reduced size of dead muscle tissue and improved heart function.

Intriguingly, the cyclin D2-cardiomyocytes stimulated not only their own proliferation, but also proliferation of existing heart muscle cells around the infarction site of the pig heart, as well as showing angiogenesis, the development of new blood vessels.

These results suggest that the cyclin D2-cardiomyocyte transplantation may be a potential therapeutic strategy for the repair of infarcted hearts, said study leader Jianyi Jay Zhang, M.D., Ph.D., the chair of Biomedical Engineering, a joint department of the UAB School of Medicine and the UAB School of Engineering.

This ability of the graft cyclin D2-cardiomyocytes to stimulate the proliferation of nearby existing heart cells suggested paracrine signaling, a type of cellular communication where a cell produces a signal that induces changes in nearby cells.

Exosomes small blebs or tiny vesicles that are released by human or animal cells and contain proteins and RNA from the cells that release them are one common form of paracrine signaling.

Zhang and colleagues found that exosomes that they purified from the cyclin D2-cardiomyocyte growth media indeed promoted proliferation of cultured cardiomyocytes. In addition, the treated cardiomyocytes were more resistant to programmed cell death, called apoptosis, induced by low oxygen levels. The exosomes also induced proliferation of various other cell types, including human umbilical vein endothelial cells, human vascular smooth muscle cells and 7-day-old rat cardiomyocytes that have almost undetectable proliferation.

Part of the cargo that exosomes carry are microRNAs, or miRNAs. These short pieces of RNA have the ability to interact with messenger RNA in target cells, and they are robust players of gene regulation in cells. Humans have more than 2,000 miRNAs with different RNA sequences, and these are thought to regulate a third of the genes in the genome.

So, the researchers documented which microRNAs were present in exosomes from the cyclin D2-overexpressing cardiomyocytes and in exosomes from non-overexpressing cardiomyocytes. As expected, they found differences.

Jianyi Jay Zhang, M.D., Ph.D.Together, the exosomes from both types of cells contained 1,072 different miRNAs, and 651 were common to the two exosome groups. However, 332 miRNAs were found only in the cyclin D2-overexpressing cardiomyocytes, and 89 miRNAs were specific for the non-overexpressing cardiomyocytes. In preliminary work of characterizing the effects of specific miRNAs, one particular miRNA from the cyclin D2-overexpressing exosomes was shown to stimulate proliferation when delivered into rat cardiomyocytes.

Thus, as the therapeutic potential of exosomes for improving cardiac function becomes more evident, combining an exosome-mediated delivery of proliferative miRNAs with transplantation of cyclin D2-overexpressing cardiomyocytes, or cell products, could become a new promising strategy for upregulating proliferation of the recipient cardiomyocytes and reducing cardiac fibrosis, Zhang said. Altogether, our data suggest that cardiac cell therapy, involving cardiomyocytes with enhanced proliferation capacity, may become an efficacious future strategy for myocardial repair and prevention of congestive heart failure in patients with acute myocardial infarctions.

UAB Department of Biomedical Engineering co-authors with Zhang, in the study Cyclin D2 overexpression enhances the efficacy of human induced pluripotent stem cell-derived cardiomyocytes for myocardial repair in a swine model of myocardial infarction, are Meng Zhao, Yuji Nakada, Yuhua Wei, Weihua Bian, Anton V. Borovjagin, Yang Zhou and Gregory P. Walcott.

Additional co-authors are Yuxin Chu and Min Xie, Division of Cardiovascular Disease, UAB Department of Medicine; Wuqiang Zhu, Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Mayo Clinic Arizona, Scottsdale; Thanh Nguyen, UAB Informatics Institute; and Vahid Serpooshan, Emory University and Georgia Institute of Technology, Atlanta.

Support came from National Institutes of Health grants HL114120, HL131017, HL149137 and HL134764.

At UAB, Zhang holds the T. Michael and Gillian Goodrich Endowed Chair of Engineering Leadership.

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Heart attack recovery aided by injecting heart muscle cells that overexpress cyclin D2 - The Mix

Cardiac Stem Cells Comments Off on Heart attack recovery aided by injecting heart muscle cells that overexpress cyclin D2 – The Mix | May 15th, 2021

The report on the Rheumatoid Arthritis Stem Cell Therapy market provides a birds eye view of the current proceedings and the impact on the COVID-19 pandemic. Further, the report ponders over the various factors that are likely to impact the overall dynamics of the market once the COVID-19 pandemic subsides. The current trends, growth opportunities, restraining factors, and drivers are discussed in the report in detail.

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The growing prevalence and recurrence of rheumatoid arthritis is expected to be the major factor driving the growth of the rheumatoid arthritis stem cell therapy market over the forecast period. Although doctors do not know the exact cause of rheumatoid arthritis, but certain risk factors are observed to be associated with it.

These risk factors include age (most common between the age of 40 and 60), family history, gender, environment (a toxic chemical in the environment can up the odds), obesity and smoking. Changes in lifestyle and eating habits are contributing to the growing prevalence of rheumatoid arthritis.

Rheumatoid Arthritis Stem Cell Therapy Market: Segmentation

Tentatively, the global rheumatoid arthritis stem cell therapy market can be segmented on the basis of treatment type, application, end user and geography.

Based on treatment type, the global rheumatoid arthritis stem cell therapy market can be segmented into:

Based on application, the global rheumatoid arthritis stem cell therapy market can be segmented into:

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Based on distribution channel, the global rheumatoid arthritis stem cell therapy market can be segmented into:

Based on geography, the global rheumatoid arthritis stem cell therapy market can be segmented into:

Rheumatoid Arthritis Stem Cell Therapy Market: Regional Outlook

Geographically, the global rheumatoid arthritis stem cell therapy market can be segmented into viz. North America, Latin America, Europe, Asia-Pacific excluding Japan (APEJ), Japan and the Middle East and Africa (MEA). North America is expected to be the dominant region in the global rheumatoid arthritis stem cell therapy market, owing to the presence of various key players.

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The rheumatoid arthritis stem cell therapy market in Asia Pacific excluding Japan is expected to grow at a significant CAGR due to the expansion of product offerings by key players. Europe is expected to have the second large share in the global rheumatoid arthritis stem cell therapy market throughout the forecast period.

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Allogeneic Mesenchymal Stem Cell Segment Is Expected To Lead In the Global Rheumatoid Arthritis Stem Cell Therapy Market over the Forecast Period,...

Cardiac Stem Cells Comments Off on Allogeneic Mesenchymal Stem Cell Segment Is Expected To Lead In the Global Rheumatoid Arthritis Stem Cell Therapy Market over the Forecast Period,… | May 15th, 2021

Mice, rats and pigs all share a secret superpower: They can all use their intestines to breathe, and scientists discovered this by pumping oxygen up the animals' butts.

Why run such experiments, you ask? The research team wanted to find a potential alternative to mechanical ventilation, a medical treatment where a machine pushes air into a patient's lungs through the windpipe. Ventilators deliver oxygen to the lungs and help remove carbon dioxide from the blood, but the machines aren't always available.

Early in the COVID-19 pandemic, for example, hospitals faced a severe shortage of ventilators, The New York Times reported. Although doctors can also use a technique called extracorporeal membrane oxygenation (ECMO), where blood is pumped out of the body and reoxygenated with a machine, the procedure carries inherent risks, such as bleeding and blood clots; and it's often less readily available than ventilators, according to Mayo Clinic.

Related: The 10 weirdest medical cases in the animal kingdom

In search of another solution, the study authors drew inspiration from aquatic animals like sea cucumbers and freshwater fish called loaches (Misgumus anguillicandatus), which use their intestines for respiration. It was unclear whether humans and other mammals have similar capabilities, although some scientists attempted to answer that question in the 1950s and 1960s.

"We initially looked at a mouse model system to see if we could deliver oxygen gas intra-anusly," said senior author Dr. Takanori Takebe, a professor at the Tokyo Medical and Dental University and a director at the Center for Stem Cell and Organoid Research and Medicine at Cincinnati Children's Hospital Medical Center.

"Every time we performed experiments, we were quite surprised," Takebe told Live Science.

Without intestinal ventilation, mice placed in a low-oxygen environment survived for only about 11 minutes; with ventilation into their anuses, 75% survived for 50 minutes, thanks to an infusion of oxygen that reached their hearts. The team then tried using oxygenated liquid, rather than gas, in mice, rats and pigs, and they found similarly promising results. The team noted that more work still needs to be done to see if the approach is safe and effective in humans, according to a paper on their findings published May 14 in the journal Med.

"The pandemic has highlighted the need to expand options for ventilation and oxygenation in critical illness, and this niche will persist even as the pandemic subsides," as there will be times when mechanical ventilation is unavailable or inadequate on its own, Dr. Caleb Kelly, a clinical fellow and physician-scientist at Yale School of Medicine, wrote in a commentary of the study. If, after further evaluation, intestinal ventilation eventually becomes common practice in intensive care units, this new study "will be marked by historians as a key scientific contribution," he wrote.

Before starting their experiments in rodents, the team got very familiar with loach guts. The fish take in oxygen mostly through their gills, but occasionally, when exposed to low-oxygen conditions, loaches instead use a portion of their intestines for gas exchange, Takebe said. In fact, in response to the lack of oxygen, the structure of gut tissues near the anus changes such that the density of nearby blood vessels increases and secretion of fluids related to digestion decreases.

These subtle changes allow loaches to "suck up the oxygen more efficiently," Takebe said. In addition, the outermost lining of the loach gut the epithelium is very thin, meaning oxygen can easily permeate the tissue to reach the blood vessels beneath, he added. To simulate this structure in their mouse models, the team thinned out the gut epithelium of the rodents using chemicals and various mechanical procedures.

They then placed the mice under extremely low-oxygen conditions and used a tube to pump oxygen gas up the animals' bums and into their large intestines.

Related: 8 bizarre animal surprises from 'True or Poo' Can you tell fact from myth?

Compared with mice whose gut epithelium had not been thinned, the mice with thin epitheliums survived significantly longer in the experiment with most surviving 50 minutes as compared with about 18 minutes. Again, mice not given any oxygen only survived for about 11 minutes. In addition to surviving longer, the group with thinned-out gut linings showed signs that they were no longer starved for oxygen; they stopped gasping for air or showing signs of cardiac arrest, and the oxygen pressure in their major blood vessels improved.

Although this initial experiment suggested that oxygen could pass through the intestine and into circulation, thinning out the gut epithelium would likely not be feasible in human patients, Takebe said.

Particularly in critically ill patients, "I think additional damage to the gut would be really dangerous, for the treatment perspective," Takebe said. But "over the course of the experiments, we realized that even the intact gut has some, not really efficient, but some capacity to exchange the gas," he noted, meaning there may be a way to introduce oxygen through the gut without first thinning out the tissues.

So in another experiment, rather than using oxygen gas, the team tried perfluorodecalin (PFD), a liquid fluorocarbon that can be infused with a large amount of oxygen. The liquid is already used in people, such as for use in the lungs of infants with severe respiratory distress, the authors noted in their report.

The liquid also acts as a surfactant a substance that reduces surface tension; since a surfactant lines the air sacs of the lungs and helps boost gas exchange in the organ, PFD may fulfill a similar purpose in the intestines, Takebe said.

Much like in the oxygen-gas experiments, the oxygenated PFD rescued mice from the effects of being placed in a low-oxygen chamber, enabling the rodents to meander about their cage more than mice not given the treatment. After just one injection of 0.03 ounces (1 milliliter) of the liquid, the rodents' improvements persisted for about 60 minutes.

"We are not quite sure why this improvement is persisting much longer than the original expectations," Takebe noted, as the authors expected the effects to wear off in just a couple minutes. "But the observation is really reproducible and very robust."

Related: Gasp! 11 surprising facts about the respiratory system

The team then moved on to a pig model of respiratory failure, where they placed pigs on ventilators and only provided a low level of oxygen and then injected PDF into the pigs' posteriors with a long tube. Compared with pigs not given the PFD treatment, pigs given PFD improved in terms of the oxygen saturation of their blood, and the color and warmth returned to their skin. A 13.5 oz (400 ml) infusion sustained these improvements for about 18 to 19 minutes, and the team found that they could give additional doses to the pigs without noticeable side effects.

The team also tested the safety of repeat dosing in rats and found that, while their oxygen levels rose, the animals showed no notable side effects, markers of organ damage or stray PFD lingering in their cells.

Following this success in animal models, Takebe said that his team hopes to start a clinical trial of the treatment in humans sometime next year. They would likely start by testing the safety of the approach in healthy volunteers and beginning to work out what dose levels would be reasonable, he said. However, to make the jump from animals to human patients, the team will need to address a number of critical questions.

For instance, the treatment could potentially stimulate the vagus nerve a long nerve that connects the gut and brain so trial organizers should likely be on the lookout for side effects like falling blood pressure or fainting, Takebe noted. Also, the lower gut contains relatively little oxygen compared with other organs in the body, he added. The community of bacteria and viruses that live in the gut are adapted to these low-oxygen conditions, and a sudden infusion of oxygen might disrupt those microbes, he said.

"The consequence of reversing this so-called 'physiologic hypoxia' is unknown," Kelly noted in his commentary, echoing Takebe's sentiments. In humans, it will be important to determine how many doses of oxygenated liquid could be safely administered into the gut without causing unintended changes to the intestinal environment, he wrote.

In addition, the animal models in the study don't fully reflect what critically ill patients experience during respiratory failure, a condition that often coincides with infection, inflammation and low blood flow, Kelly noted. So there may be additional factors to consider in critically ill patients that weren't relevant in rodents and pigs. And depending on a given patient's condition, they may need a higher or lower dose of PFD all of these fine details will need to be carefully assessed in future trials, Takebe said.

Originally published on Live Science.

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Pigs can breathe through their butts. Can humans? - Livescience.com

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KENILWORTH, N.J.--(BUSINESS WIRE)--Merck & Co. (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive results from the pivotal neoadjuvant/adjuvant Phase 3 KEYNOTE-522 trial investigating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy as pre-operative (neoadjuvant) treatment and then continuing as a single agent (adjuvant) treatment after surgery. KEYNOTE-522 met its dual primary endpoint of event-free survival (EFS) for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC). Based on an interim analysis conducted by the independent Data Monitoring Committee (DMC), neoadjuvant KEYTRUDA plus chemotherapy followed by adjuvant KEYTRUDA as monotherapy showed a statistically significant and clinically meaningful improvement in EFS compared with neoadjuvant chemotherapy alone. As previously communicated, KEYNOTE-522 met its other dual primary endpoint of pathological complete response (pCR). The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies; no new safety signals were identified.

KEYTRUDA is the first immunotherapy to show positive results for event-free survival in patients with high-risk early-stage TNBC, a particularly aggressive form of breast cancer, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. The improvement in pathological complete response rates initially observed following pre-operative treatment was encouraging, and now that we are seeing the data mature after four years to include a statistically significant improvement in event-free survival, we look forward to working with the FDA and other global authorities to bring this new option to patients as quickly as possible. We are grateful to the study participants who are critical to our efforts to advance potential treatment options for patients with TNBC.

An analysis of pCR from KEYNOTE-522 was presented at the European Society for Medical Oncology (ESMO) 2019 Congress and published in the New England Journal of Medicine. Findings showed a statistically significant increase in pCR for KEYTRUDA plus chemotherapy versus chemotherapy alone as neoadjuvant therapy in patients with early-stage TNBC, regardless of PD-L1 status. As previously announced, the company received a Complete Response Letter (CRL) from the FDA in March 2021 regarding Mercks supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA for the treatment of patients with high-risk early-stage TNBC based on these pCR data and early interim EFS findings. The CRL followed the FDAs Oncologic Drugs Advisory Committee meeting that voted 10-0 that a regulatory decision should be deferred until further data were available from KEYNOTE-522.

The KEYTRUDA clinical development program for TNBC encompasses several internal studies and external collaborative trials, including the ongoing studies KEYNOTE-242 and KEYNOTE-355.

Merck has an expansive clinical development program investigating KEYTRUDA in earlier lines of therapy including in neoadjuvant, adjuvant and locally advanced settings, with approximately 20 registrational studies ongoing.

About KEYNOTE-522

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488), evaluating a regimen of neoadjuvant KEYTRUDA in combination with chemotherapy followed by adjuvant KEYTRUDA as monotherapy versus a regimen of neoadjuvant chemotherapy followed by adjuvant placebo. The dual primary endpoints are pCR and EFS. The secondary endpoints include pCR rate using alternative definitions (i.e., no invasive or noninvasive residual cancer in breast or nodes) at the time of definitive surgery, overall survival, EFS in patients whose tumors express PD-L1 (Combined Positive Score [CPS] 1), safety and patient-reported outcomes. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

About Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Approximately 15-20% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in women who are younger than 40 years of age, who are African American or who have a BRCA1 mutation.

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, and 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 two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal 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 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

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

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

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

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

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

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

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

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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

Increased Mortality in Patients With Multiple Myeloma

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

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%).

Excerpt from:
Merck Announces Phase 3 KEYNOTE-522 Trial Met Dual Primary Endpoint of Event-Free Survival (EFS) in Patients With High-Risk Early-Stage...

Cardiac Stem Cells Comments Off on Merck Announces Phase 3 KEYNOTE-522 Trial Met Dual Primary Endpoint of Event-Free Survival (EFS) in Patients With High-Risk Early-Stage… | May 15th, 2021

A groundbreaking new study led by the University of Minnesota, Twin Cities has shown for the first time that lab-created heart valves implanted in young lambs for a year were capable of growth within the recipient.

The valves also showed reduced calcification and improved blood flow function compared to animal-derived valves currently used when tested in the same growing lamb model.

Currently, researchers have not been able to develop a heart valve that can grow and maintain function for paediatric patients. The only accepted options for these children with heart defects are valves made from chemically treated animal tissues that often become dysfunctional due to calcification and require replacement because they dont grow with the child. These children will often need to endure up to five (or more) open heart surgeries until a mechanical valve is implanted in adulthood. This requires them to take blood thinners the rest of their lives.

Minnesota Professor Robert Tranquillo and his colleagues used a hybrid of tissue engineering and regenerative medicine to create the growing heart valves. Over an eight-week period, they used a specialised tissue engineering technique they previously developed to generate vessel-like tubes in the lab from a post-natal donors skin cells. To develop the tubes, the researchers combined the donor sheep skin cells in a gelatine-like material, called fibrin, in the form of a tube and then provided nutrients necessary for cell growth using a bioreactor.

The researchers then used special detergents to wash away all the sheep cells from the tissue-like tubes, leaving behind a cell-free collagenous matrix that does not cause immune reaction when implanted. This means the tubes can be stored and implanted without requiring customised growth using the recipients cells.

The next step was to precisely sew three of these tubes (about 16 mm in diameter) together into a closed ring. The researchers then trimmed them slightly to create leaflets to replicate a structure similar to a heart valve about 19 mm in diameter.

After these initial steps, it looked like a heart valve, but the question then became if it could work like a heart valve and if it could grow, Prof Tranquillo said. Our findings confirmed both.

This second generation of tri-tube valves was implanted into the pulmonary artery of three lambs. After 52 weeks, the valve regenerated as its matrix became populated by cells from the recipient lamb, and the diameter increased from 19 mm to a physiologically normal valve about 25 mm. The researchers also saw a 17 to 34% increase in the length of the valve leaflets as measured from ultrasound images. In addition, researchers showed that the tri-tube valves worked better than current animal-derived valves, with almost none of the calcification or blood clotting that the other valves showed after being implanted in lambs of the same age.

We knew from previous studies that the engineered tubes have the capacity to regenerate and grow in a growing lamb model, but the biggest challenge was how to maintain leaflet function in a growing valved conduit that goes through 40 million cycles in a year, said Zeeshan Syedain, a senior research associate in Prof Tranquillos lab. When we saw how well the valves functioned for an entire year from young lamb to adult sheep, it was very exciting.

This is a huge step forward in paediatric heart research, Tranquillo said. This is the first demonstration that a valve implanted into a large animal model, in our case a lamb, can grow with the animal into adulthood.

If confirmed in humans, the new heart valves could prevent the need for repeated valve replacement surgeries in thousands of children born each year with congenital heart defects. The valves can also be stored for at least six months, which means they could provide surgeons with an off the shelf option for treatment.

The study has now been published in the journal Science Translational Medicine, while the valve-making procedure has been patented and licensed to University of Minnesota start-up company Vascudyne. Prof Tranquillo said the next steps are to implant the tri-tube valve directly into the right ventricle of the heart to emulate the most common surgical repair and then start the process of requesting approval from the US Food and Drug Administration (FDA) for human clinical trials over the next few years.

If we can get these valves approved someday for children, it would have such a big impact on the children who suffer from heart defects and their families who have to deal with the immense stress of multiple surgeries, Prof Tranquillo said. We could potentially reduce the number of surgeries these children would have to endure from five to one. Thats the dream.

Image credit: Syedain, et al, Tranquillo Lab, University of Minnesota.

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Lab-created heart valves grow with the recipient - Lab + Life Scientist

Skin Stem Cells Comments Off on Lab-created heart valves grow with the recipient – Lab + Life Scientist | May 3rd, 2021