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Archive for the ‘Clinical & Translational’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Babies born at or before 25 weeks have quite low survival outcomes, and in the US it is the leading cause of infant mortality and morbidity. Just a few weeks of extra ‘growing time’ can be the difference between severe health problems and a relatively healthy baby.

 

Researchers from The Children’s Hospital of Philadelphia (USA) Research Institute have shown it’s possible to nurture and protect a mammal in late stages of gestation inside an artificial womb; technology which could become a lifesaver for many premature human babies in just a few years.

 

The researchers took eight lambs between 105 to 120 days gestation (the physiological equivalent of 23 to 24 weeks in humans) and placed them inside the artificial womb. The artificial womb is a sealed and sterile bag filled with an electrolyte solution which acts like amniotic fluid in the uterus. The lamb’s own heart pumps the blood through the umbilical cord into a gas exchange machine outside the bag.

 

The artificial womb worked in this study and after just four weeks the lambs’ brains and lungs had matured like normal. They had also grown wool and could wiggle, open their eyes, and swallow. Although this study is looking incredibly promising but getting the research up to scratch for human babies still requires a big leap.

 

Nevertheless, if all goes well, the researchers hope to test the device on premature humans within three to five years. Potential therapeutic applications of this invention may include treatment of fetal growth retardation related to placental insufficiency or the salvage of preterm infants threatening to deliver after fetal intervention or fetal surgery.

 

The technology may also provide the opportunity to deliver infants affected by congenital malformations of the heart, lung and diaphragm for early correction or therapy before the institution of gas ventilation. Numerous applications related to fetal pharmacologic, stem cell or gene therapy could be facilitated by removing the possibility for maternal exposure and enabling direct delivery of therapeutic agents to the isolated fetus.

 

References:

 

https://www.nature.com/articles/ncomms15112

 

 

https://www.sciencealert.com/researchers-have-successfully-grown-premature-lambs-in-an-artificial-womb

 

http://www.npr.org/sections/health-shots/2017/04/25/525044286/scientists-create-artificial-womb-that-could-help-prematurely-born-babies

 

http://www.telegraph.co.uk/science/2017/04/25/artificial-womb-promises-boost-survival-premature-babies/

 

https://www.theguardian.com/science/2017/apr/25/artificial-womb-for-premature-babies-successful-in-animal-trials-biobag

 

http://www.theblaze.com/news/2017/04/25/new-artificial-womb-technology-could-keep-babies-born-prematurely-alive-and-healthy/

 

http://www.theverge.com/2017/4/25/15421734/artificial-womb-fetus-biobag-uterus-lamb-sheep-birth-premie-preterm-infant

 

http://www.abc.net.au/news/2017-04-26/artificial-womb-could-one-day-keep-premature-babies-alive/8472960

 

https://www.theatlantic.com/health/archive/2017/04/preemies-floating-in-fluid-filled-bags/524181/

 

http://www.independent.co.uk/news/health/artificial-womb-save-premature-babies-lives-scientists-create-childrens-hospital-philadelphia-nature-a7701546.html

 

https://www.cnet.com/news/artificial-womb-births-premature-lambs-human-infants/

 

https://science.slashdot.org/story/17/04/25/2035243/an-artificial-womb-successfully-grew-baby-sheep—-and-humans-could-be-next

 

http://newatlas.com/artificial-womb-premature-babies/49207/

 

https://www.geneticliteracyproject.org/2015/06/12/artificial-wombs-the-coming-era-of-motherless-births/

 

http://news.nationalgeographic.com/2017/04/artificial-womb-lambs-premature-babies-health-science/

 

https://motherboard.vice.com/en_us/article/artificial-womb-free-births-just-got-a-lot-more-real-cambridge-embryo-reproduction

 

http://www.disclose.tv/news/The_Artificial_Womb_Is_Born_Welcome_To_The_WORLD_Of_The_MATRIX/114199

 

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Scientists think excessive population growth is a cause of scarcity and environmental degradation. A male pill could reduce the number of unintended pregnancies, which accounts for 40 percent of all pregnancies worldwide.

 

But, big drug companies long ago dropped out of the search for a male contraceptive pill which is able to chemically intercept millions of sperm before they reach a woman’s egg. Right now the chemical burden for contraception relies solely on the female. There’s not much activity in the male contraception field because an effective solution is available on the female side.

 

Presently, male contraception means a condom or a vasectomy. But researchers from Center for Drug Discovery at Baylor College of Medicine, USA are renewing the search for a better option—an easy-to-take pill that’s safe, fast-acting, and reversible.

 

The scientists began with lists of genes active in the testes for sperm production and motility and then created knockout mice that lack those genes. Using the gene-editing technology called CRISPR, in collaboration with Japanese scientists, they have so far made more than 75 of these “knockout” mice.

 

They allowed these mice to mate with normal (wild type) female mice, and if their female partners don’t get pregnant after three to six months, it means the gene might be a target for a contraceptive. Out of 2300 genes that are particularly active in the testes of mice, the researchers have identified 30 genes whose deletion makes the male infertile. Next the scientists are planning a novel screening approach to test whether any of about two billion chemicals can disable these genes in a test tube. Promising chemicals could then be fed to male mice to see if they cause infertility.

 

Female birth control pills use hormones to inhibit a woman’s ovaries from releasing eggs. But hormones have side effects like weight gain, mood changes, and headaches. A trial of one male contraceptive hormone was stopped early in 2011 after one participant committed suicide and others reported depression. Moreover, some drug candidates have made animals permanently sterile which is not the goal of the research. The challenge is to prevent sperm being made without permanently sterilizing the individual.

 

As a better way to test drugs, Scientists at University of Georgia, USA are investigating yet another high-tech approach. They are turning human skin cells into stem cells that look and act like the spermatogonial cells in the testes. Testing drugs on such cells might provide more accurate leads than tests on mice.

 

The male pill would also have to start working quickly, a lot sooner than the female pill, which takes about a week to function. Scientists from University of Dundee, U.K. admitted that there are lots of challenges. Because, a women’s ovary usually release one mature egg each month, while a man makes millions of sperm every day. So, the male pill has to be made 100 percent effective and act instantaneously.

 

References:

 

https://www.technologyreview.com/s/603676/the-search-for-a-perfect-male-birth-control-pill/

 

https://futurism.com/videos/the-perfect-male-birth-control-pill-is-coming-soon/?utm_source=Digest&utm_campaign=c42fc7b9b6-EMAIL_CAMPAIGN_2017_03_20&utm_medium=email&utm_term=0_03cd0a26cd-c42fc7b9b6-246845533

 

http://www.telegraph.co.uk/women/sex/the-male-pill-is-coming—and-its-going-to-change-everything/

 

http://www.mensfitness.com/women/sex-tips/male-birth-control-pill-making

 

http://health.howstuffworks.com/sexual-health/contraception/male-bc-pill.htm

 

http://europe.newsweek.com/male-contraception-side-effects-study-pill-injection-518237?rm=eu

 

http://edition.cnn.com/2016/01/07/health/male-birth-control-pill/index.html

 

http://www.nhs.uk/Conditions/contraception-guide/Pages/male-pill.aspx

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3D Liver Model in a Droplet

Curator: Marzan Khan, BSc

Recently, a Harvard University Professor of Physics and Applied Physics, David Weitz and his team of researchers have successfully generated 3D models of liver tissue composed of two different kinds of liver cells, precisely compartmentalized in a core-shell droplet, using the microfluidics approach(1). Compared to alternative in-vitro methods, this approach comes with more advantages – it is cost-effective, can be quickly assembled and produces millions of organ droplets in a second(1). It is the first “organ in a droplet” technology that enables two disparate liver cells to physically co-exist and exchange biochemical information, thus making it a good mimic of the organ in vivo(1).

Liver tissue models are used by researchers to investigate the effect of drugs and other chemical compounds, either alone or in combination on liver toxicity(2). The liver is the primary center of drug metabolism, detoxification and removal and all of these processes need to be carried out systematically in order to maintain a homeostatic environment within the body(2) Any deviation from the steady state will shift the dynamic equilibrium of metabolism, leading to production of reactive oxygen species (ROS)(2). These are harmful because they will exert oxidative stress on the liver, and ultimately cause the organ to malfunction. Drug-induced liver toxicity is a critical problem – 10% of all cases of acute hepatitis, 5% of all hospital admissions, and 50% of all acute liver failures are caused by it(2).

Before any novel drug is launched into the market, it is tested in-vitro, in animal models, and then progresses onto human clinical trials(1). Weitz’s system can produce up to one-thousand organ droplets per second, each of which can be used in an experiment to test for drug toxicity(1). Clarifying further, he asserts that “Each droplet is like a mini experiment. Normally, if we are running experiments, say in test tubes, we need a milliliter of fluid per test tube. If we were to do a million experiments, we would need a thousand liters of fluid. That’s the equivalent of a thousand milk jugs! Here, each droplet is only a nanoliter, so we can do the whole experiment with one milliliter of fluid, meaning we can do a million more experiments with the same amount of fluid.”

Testing hepatocytes alone on a petri dish is a poor indicator of liver-specific functions because the liver is made up of multiple cells systematically arranged on an extracellular matrix and functionally interdependent(3). The primary hepatocytes, hepatic stellate cells, Kupffer cells, endothelial cells and fibroblasts form the basic components of a functioning liver(3). Weitz’s upgraded system contains hepatocytes (that make up the majority of liver cells and carry out most of the important functions) supported by a network of fibroblasts(3). His microfluidic chip is comprised of a network of constricted, circular channels spanning the micrometer range, the inner phase of which contains hepatocytes mixed in a cell culture solution(3). The surrounding middle phase accommodates fibroblasts in an alginate solution and the two liquids remain separated due to differences in their chemical properties as well as the physics of fluids travelling in narrow channels. Addition of a fluorinated carbon oil interferes with the two aqueous layers, forcing them to become individual monodisperse droplets(3). The hydrogel shell is completed when a 0.15% solution of acetic acid facilitates the cross-linking of alginate to form a gelatinous shell, locking the fibroblasts in place(3). Thus, the aqueous core of hepatocytes are encapsulated by fibroblasts confined to a strong hydrogel network, creating a core-shell hydrogel scaffold of 3D liver micro-tissue in a droplet(3). Using empirical analysis, scientists have shown that albumin secretion and urea synthesis (two important markers of liver function) were significantly higher in a co-culture of hepatocytes and fibroblasts 3D core-shell spheroids compared to a monotypic cell-culture of hepatocyte-only spheroids(3). These results validate the theory that homotypic as well as heterotypic communication between cells are important to achieve optimal organ function in vitro(3).

This system of creating micro-tissues in a droplet with enhanced properties is a step-forward in biomedical science(3). It can be used in experiments to test for a myriad of drugs, chemicals and cosmetics on different human tissue samples, as well as to understand the biological connectivity of contrasting cells(3).

diagram

Image source: DOI: 10.1039/c6lc00231

A simple demonstration of the microfluidic chip that combines different solutions to create a core-shell droplet consisting of two different kinds of liver cells.

References:

  1. National Institute of Biomedical Imaging and Bioengineering. (2016, December 13). New device creates 3D livers in a droplet.ScienceDaily. Retrieved February 9, 2017 from https://www.sciencedaily.com/releases/2016/12/161213112337.htm
  2. Singh, D., Cho, W. C., & Upadhyay, G. (2015). Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants: An Overview.Frontiers in Physiology,6, 363. http://doi.org/10.3389/fphys.2015.00363
  3. Qiushui Chen, Stefanie Utech, Dong Chen, Radivoje Prodanovic, Jin-Ming Lin and David A. Weitz; Controlled assembly of heterotypic cells in a core– shell scaffold: organ in a droplet; Lab Chip, 2016, 16, 1346; DOI: 10.1039/c6lc00231

Other related articles on 3D on a Chip published in this Open Access Online Scientific Journal include the following:

 

What could replace animal testing – ‘Human-on-a-chip’ from Lawrence Livermore National Laboratory

Reporter: Aviva Lev-Ari, PhD, RN

AGENDA for Second Annual Organ-on-a-Chip World Congress & 3D-Culture Conference, July 7-8, 2016, Wyndham Boston Beacon Hill by SELECTBIO US

Reporter: Aviva Lev-Ari, PhD, RN

Medical MEMS, BioMEMS and Sensor Applications

Curator and Reporter: Aviva Lev-Ari, PhD, RN

Contribution to Inflammatory Bowel Disease (IBD) of bacterial overgrowth in gut on a chip

Larry H. Bernstein, MD, FCAP, Curator

Current Advances in Medical Technology

Larry H. Bernstein, MD, FCAP, Curator

 

Other related articles on Liver published in this Open Access Online Scientific Journal include the following:

 

Alnylam down as it halts development for RNAi liver disease candidate

by Stacy Lawrence

LIVE 9/21 8AM to 2:40PM Targeting Cardio-Metabolic Diseases: A focus on Liver Fibrosis and NASH Targets at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

Reporter: Aviva Lev-Ari, PhD, RN

2016 Nobel in Economics for Work on The Theory of Contracts to winners: Oliver Hart and Bengt Holmstrom

Reporter: Aviva Lev-Ari, PhD, RN

LIVE 9/20 2PM to 5:30PM New Viruses for Therapeutic Gene Delivery at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

Reporter: Aviva Lev-Ari, PhD, RN

Seven Cancers: oropharynx, larynx, oesophagus, liver, colon, rectum and breast are caused by Alcohol Consumption

Reporter: Aviva Lev-Ari, PhD, RN

 

Other related articles on 3D on a Chip published in this Open Access Online Scientific Journal include the following:

 

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute,  Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

Trovagene’s ctDNA Liquid Biopsy urine and blood tests to be used in Monitoring and Early Detection of Pancreatic Cancer

Reporters: David Orchard-Webb, PhD and Aviva Lev-Ari, PhD, RN

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

Real Time Coverage of the AGENDA for Powering Precision Health (PPH) with Science, 9/26/2016, Cambridge Marriott Hotel, Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

 

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Inotuzumab Ozogamicin: Success in relapsed/refractory Acute Lymphoblastic Leukemia (ALL)

Reporter: Aviva Lev-Ari, PhD, RN

 

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22,9 a cell surface antigen expressed on approximately 90 percent of B-cell malignancies,10 linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.11

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.

Acute lymphoblastic leukemia (ALL)

is an aggressive type of leukemia with high unmet need and a poor prognosis in adults.4The current standard treatment is intensive, long-term chemotherapy.5 In 2015, it is estimated that 6,250 cases of ALL will be diagnosed in the United States6, with about 1 in 3 cases in adults. Only approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.7 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.8

REFERENCES

1 Fielding A. et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2006; 944-950.

2 U.S. Food and Drug Administration Safety and Innovation Act. Available at: http://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf(link is external).Accessed July 11, 2015.

3 U.S. Food and Drug Administration Frequently Asked Questions: Breakthrough Therapies. Available at:http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm(link is external). Accessed July 11, 2015.

4 National Cancer Institute: Adult Acute Lymphoblastic Leukemia Treatment (PDQ®) – General Information About Adult Acute Lymphoblastic Leukemia (ALL). Available at:http://www.cancer.gov/cancertopics/pdq/treatment/adultALL/HealthProfessional/page1(link is external). Accessed July 11, 2015.

5 American Cancer Society: Typical treatment of acute lymphocytic leukemia. Available at:http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acute-lymphocytic-treating-typical-treatment(link is external). Accessed July 11, 2015.

6 American Cancer Society: What are the key statistics about acute lymphocytic leukemia? Available at:http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acute-lymphocytic-key-statistics(link is external). Accessed February 18, 2015.

7 Manal Basyouni A. et al. Prognostic significance of survivin and tumor necrosis factor-alpha in adult acute lymphoblastic leukemia. doi:10.1016/j.clinbiochem.2011.08.1147.

8 Fielding A. et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2006; 944-950.

9 Clinicaltrials.gov. A Study of Inotuzumab Ozogamicin versus Investigator’s Choice of Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01564784?term=inotuzumab&rank=7(link is external). Accessed July 11, 2015.

10 Leonard J et al. Epratuzumab, a Humanized Anti-CD22 Antibody, in Aggressive Non-Hodgkin’s Lymphoma: a Phase I/II Clinical Trial Results. Clinical Cancer Research. 2004; 10: 5327-5334.

11 DiJoseph JF. Antitumor Efficacy of a Combination of CMC-544 (Inotuzumab Ozogamicin), a CD22-Targeted Cytotoxic Immunoconjugate of Calicheamicin, and Rituximab against Non-Hodgkin’s B-Cell Lymphoma. Clin Cancer Res. 2006; 12: 242-250.

SOURCE

http://www.pfizer.com/news/press-release/press-release-detail/pfizer_s_inotuzumab_ozogamicin_receives_fda_breakthrough_therapy_designation_for_acute_lymphoblastic_leukemia_all

Other related article Published on this Open Access Online Scientific Journal include the following:

STORY OF A LEUKEMIA FIGHTER

Nicole L. Gularte, MBA

https://pharmaceuticalintelligence.com/2016/08/21/cancer-the-future-immunotherapy/

https://pharmaceuticalintelligence.com/?s=Acute+Lymphoblastic+Leukemia+%28ALL%29+

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Juno Therapeutics to Resume JCAR015 Phase II ROCKET Trial AND Acquires privately held Boston, MA-based RedoxTherapies

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 11/13/2017

Juno analysis of shuttered study offers clues for CAR-T

https://www.biopharmadive.com/news/juno-analysis-of-shuttered-study-offers-clues-for-car-t/510634/

 

UPDATED on 11/28/2016

Latest deaths in Juno trial underscore the need for greater transparency in clinical trials

 

quote

In recent years, numerous states have passed so-called “right-to-try” laws that encourage patients to seek access to experimental drugs outside of the clinical trial framework. In addition, libertarian activists and even some individuals associated with the incoming Trump administration continue to propose moving new medicines out into widespread use after only scant safety testing. That would increase the number of patients at risk for adverse outcomes, like the ones observed in the Juno trials, before we even know whether the drugs work.

READ MORE

Right-to-try laws could curtail the development of innovative new therapies

 

The best way to identify transformative new medicines, protect patients from unexpectedly dangerous drugs, and avoid wasting health care resources is by subjecting experimental products to well-designed clinical trials that enroll sufficient numbers of patients and test relevant clinical outcomes that can then be independently reviewed by the experts at the FDA. When severe, unanticipated problems arise, the FDA needs a transparent and systematic evaluation process that can provide public insight into what happened and why. That would contribute to the progress of science and the development of the next generation of safer, better therapies.

https://www.statnews.com/2016/11/24/deaths-juno-trial-transparency-fda/

 

 

Juno Therapeutics to Resume JCAR015 Phase II ROCKET Trial

SEATTLE–(BUSINESS WIRE)–Jul. 12, 2016– Juno Therapeutics, Inc. (Nasdaq: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, today announced that the U.S. Food and Drug Administration has removed the clinical hold on the Phase II clinical trial of JCAR015 (known as the “ROCKET” trial) in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL).

Under the revised protocol, the ROCKET trial will continue enrollment using JCAR015 with cyclophosphamide pre-conditioning only.

 

SOURCE

http://ir.junotherapeutics.com/phoenix.zhtml?c=253828&p=irol-newsArticle&ID=2184987

 

 

Juno buys early-stage biotech for access to immuno-oncology candidate

Jul 14 2016, 16:32 ET | About: Juno Therapeutics (JUNO) | By: Douglas W. House, SA News Editor

 

Juno Therapeutics (NASDAQ:JUNOacquires privately held Boston, MA-based RedoxTherapies. Juno’s primary aim of the deal was to secure an exclusive license to vipadenant, a small molecule adenosine A2a receptor antagonist that may disrupt key immunosuppressive pathways in the tumor microenvironment in certain cancers.

Redox licensed vipadenant from London-based Vernalis in October 2014. It was under development for the treatment of Parkinson’s disease by Biogen (NASDAQ:BIIB) but safety concerns scuppered the effort in 2010 despite encouraging efficacy in mid-stage studies. Biogen returned the rights to Vernalis in 2011.

Under the terms of the transaction, Juno will pay $10M in upfront cash plus undisclosed milestones.

SOURCE

http://seekingalpha.com/news/3193337-juno-buys-early-stage-biotech-access-immuno-oncology-candidate?source=email_rt_mc_readmore&app=1&uprof=46#email_link

 

Other related articles published in this open Access Online Scientific Journal include the following:

What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial

Reporters and Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/09/what-does-this-mean-for-immunotherapy-fda-put-a-temporary-hold-on-jcar015-three-death-of-celebral-edema-in-car-t-clinical-trial-and-kite-pharma-announced-phase-ii-portion-of-its-car-t-zuma-1-trial/

 

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Previously undiscerned value of hs-troponin

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

LPBI

 

Troponin Rise Predicts CHD, HF, Mortality in Healthy People: ARIC Analysis

Veronica Hackethal, MD

Increases in levels of cardiac troponin T by high-sensitivity assay (hs-cTnT) over time are associated with later risk of death, coronary heart disease (CHD), and especially heart failure in apparently healthy middle-aged people, according to a report published June 8, 2016 in JAMA Cardiology[1].

The novel findings, based on a cohort of >8000 participants from the Atherosclerosis Risk in Communities (ARIC) study followed up to 16 years, are the first to show “an association between temporal hs-cTnT change and incident CHD events” in asymptomatic middle-aged adults,” write the authors, led by Dr John W McEvoy (Johns Hopkins University School of Medicine, Baltimore, MD).

Individuals with the greatest troponin increases over time had the highest risk for poor cardiac outcomes. The strongest association was for risk of heart failure, which reached almost 800% for those with the sharpest hs-cTnT rises.

Intriguingly, those in whom troponin levels fell at least 50% had a reduced mortality risk and may have had a slightly decreased risk of later HF or CHD.

“Serial testing over time with high-sensitivity cardiac troponins provided additional prognostic information over and above the usual clinical risk factors, [natriuretic peptide] levels, and a single troponin measurement. Two measurements appear better than one when it comes to informing risk for future coronary heart disease, heart failure, and death,” McEvoy told heartwire from Medscape.

He cautioned, though, that the conclusion is based on observational data and would need to be confirmed in clinical trials. Moreover, high-sensitivity cardiac troponin assays are widely used in Europe but are not approved in the US.

An important next step after this study, according to an accompanying editorial from Dr James Januzzi (Massachusetts General Hospital, Boston, MA), would be to evaluate whether the combination of hs-troponin and natriuretic peptides improves predictive value in this population[2].

“To the extent prevention is ultimately the holy grail for defeating the global pandemic of CHD, stroke, and HF, the main reason to do a biomarker study such as this would be to set the stage for a biomarker-guided strategy to improve the medical care for those patients at highest risk, as has been recently done with [natriuretic peptides],” he wrote.

The ARIC prospective cohort study entered and followed 8838 participants (mean age 56, 59% female, 21.4% black) in North Carolina, Mississippi, Minneapolis, and Maryland from January 1990 to December 2011. At baseline, participants had no clinical signs of CHD or heart failure.

Levels of hs-cTnT, obtained 6 years apart, were categorized as undetectable (<0.005 ng/mL), detectable (≥0.005 ng/mL to <0.014 ng/mL), and elevated (>0.014 ng/mL).

Troponin increases from <0.005 ng/mL to 0.005 ng/mL or higher independently predicted development of CHD (HR 1.41; 95% CI 1.16–1.63), HF (HR 1.96; 95% CI 1.62–2.37), and death (HR 1.50; 95% CI 1.31–1.72), compared with undetectable levels at both measurements.

Hazard ratios were adjusted for age, sex, race, body-mass index, C-reactive protein, smoking status, alcohol-intake history, systolic blood pressure, current antihypertensive therapy, diabetes, serum lipid and cholesterol levels, lipid-modifying therapy, estimated glomerular filtration rate, and left ventricular hypertrophy.

Subjects with >50% increase in hs-cTnT had a significantly increased risk of CHD (HR 1.28; 95% CI 1.09–1.52), HF (HR 1.60; 95% CI 1.35–1.91), and death (HR 1.39; 95% CI 1.22–1.59).

Risks for those end points fell somewhat for those with a >50% decrease in hs-cTnT (CHD: HR 0.47; 95% CI 0.22–1.03; HF: HR 0.49 95% CI 0.23–1.01; death: HR 0.57 95% CI 0.33–0.99).

Among participants with an adjudicated HF hospitalization, the group writes, associations of hs-cTnT changes with outcomes were of similar magnitude for those with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).

Few biomarkers have been linked to increased risk for HFpEF, and few effective therapies exist for it. That may be due to problems identifying and enrolling patients with HFpEF in clinical trials, Dr McEvoy pointed out.

“We think the increased troponin over time reflects progressive myocardial injury or progressive myocardial damage,” Dr McEvoy said. “This is a window into future risk, particularly with respect to heart failure but other outcomes as well. It may suggest high-sensitivity troponins as a marker of myocardial health and help guide interventions targeting the myocardium.”

Moreover, he said, “We think that high-sensitivity troponin may also be a useful biomarker along with [natriuretic peptides] for emerging trials of HFpEF therapy.”

But whether hs-troponin has the potential for use as a screening tool is a question for future studies, according to McEvoy.

In his editorial, Januzzi pointed out several implications of the study, including the possibility for lowering cardiac risk in those with measurable hs-troponin, and that HF may be the most obvious outcome to target. Also, optimizing treatment and using cardioprotective therapies may reduce risk linked to increases in hs-troponin. Finally, long-term, large clinical trials on this issue will require a multidisciplinary team effort from various sectors.

“What is needed now are efforts toward developing strategies to upwardly bend the survival curves of those with a biomarker signature of risk, leveraging the knowledge gained from studies such as the report by McEvoy et al to improve public health,” he concluded.

 

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Toxicities Associated with Immuno-oncology Treatment

Larry H. Bernstein, MD, FCAP

Curator: LPBI

 

ICLIO: Be Aware of Novel Toxicities With New Ca Drugs  

Advent of new immunotherapies warrants education for non-oncologists

by Eric T. Rosenthal
Special Correspondent, MedPage Today
http://www.medpagetoday.com/HematologyOncology/Chemotherapy/58582

CHICAGO — A new class of cancer immunotherapies, led by pembrolizumab (Keytruda), has taken the oncology world by storm. But with this novel type of treatment comes a new challenge.

The Association of Community Cancer Centers (ACCC) wants to ensure that non-oncologist physicians know how to take care of their patients receiving these agents since doctors in other specialties may not be aware of the side effects related to the immunotherapies.

The initiative is one of the steps taken by the association’s Institute of Clinical Immuno-Oncology’s (ICLIO) in making immunotherapy available in the community.

ICLIO was launched 1 year ago to help prepare community cancer teams and centers to deal with the clinical, coverage, and reimbursement issues related to immunotherapy.

During the American Society of Clinical Oncology annual meeting here MedPage Todayspoke with ACCC President Jennie R. Crews, MD, and ICLIO Chair Lee S. Schwartzberg, MD, about the institute’s growth and future plans.

Schwartzberg, chief of the division of hematology and oncology at the University of Tennessee, as well as executive director of the West Cancer Center in Memphis, said that the field of immunotherapy “is moving so fast that we can’t have enough education.”

“Needs change over time and last year many cancer practices became familiar with immuno-oncology and now we have to go deeper and broader.”

The broadening, he explained, involves educating other medical subspecialists about immune-related toxicities from the new agents.

“The problem is that we see related toxicities that are not managed well, and we’re having trouble with this.”

He cited as two primary examples toxic side effects such as colitis and pneumonitis and the necessity of educating gastroenterologists and pulmonologists about their relationship to immunotherapy.

Many times these subspecialists, as well as dermatologists, endocrinologists, emergency physicians, and internists see autoimmune-related toxicities and first think they are from chemotherapy or infection, according to Schwartzberg.

“But they are going to be going down a very bad path with these patients if they think this way,” noting that a colleague from a leading cancer center had recently mentioned that the institution’s emergency room staff didn’t always understand about immunotherapy reactions.

He said that, although ICLIO does not have direct access to reaching many other subspecialists, it was beginning to develop educational materials that oncologists could share with other medical colleagues, as well as to work with some of the subspecialty societies.

“Education, however, has to be across the board, and has to include patients as well,” he said, adding that many cancer immunotherapy patients were being provided with cards that explained their immunotherapy and could be handed to nurses and physicians at the outset of their medical intervention, saving time and the risk of undergoing the wrong treatment.

In a separate interview, Crews, medical director for Cancer Services PeaceHealth at St. Joseph Medical Center in Bellingham, Wash., said that ACCC members include both academic centers and community practices including both hospital-based and private. (An ACCC public relations representative monitored the interview.)

“We are not focused on what the science is, but rather on how do we take this technology out to the community to bring cancer to where patients are,” she said, adding that she and others are very passionate in the belief that cancer care should be delivered wherever cancer patients live.

She said since ICLIO started in June 2015, much of its infrastructure and programs have been established, including a webinar series, eNewsletters, eLearning Modules, tumor subcommittee working groups, an on-site preceptorship program, an ICLIO stakeholder summit, and an upcoming second national conference this fall in Philadelphia.

That conference will be preceded by a stakeholder summit bringing together providers, patient advocates, payers, pharmaceutical producers, and others, which the ACCC hopes will produce a white paper.

The last year has seen the growth of the initiative’s Scholars Program to about 50 oncologists who have received training through ICLIO’s learning modules.

These scholars will in turn eventually be able to serve as mentors to the 2,000 cancer programs with some 20,000 individual members that make up ACCC’s membership.

Crews said that to date about 700 cancer programs involving some 1,900 individuals have participated in the webinars, and about 100 people attended ICLIO’s first annual conference last October.

She said that in addition to the charitable contribution initially made by Bristol-Myers Squibb last year to help launch ICLIO, Merck has also provided an educational grant, but she would not disclose the amount of the funding.

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