Category Archives: Transhuman News

The oncologist was blunt: Stefanie Johos colon cancer was raging out of control and there was nothing more she could do. Flanked by her parents and sister, the 23-year-old felt something wet on her shoulder. She looked up to see her father weeping.

I felt dead inside, utterly demoralized, ready to be done, Joho remembers.

But her younger sister couldnt accept that. When the family got back to Johos apartment in New Yorks Flatiron district, Jess opened her laptop and began searching frantically for clinical trials, using medical words shed heard but not fully understood. An hour later, she came into her sisters room and showed her what shed found. Im not letting you give up, she told Stefanie. This is not the end.

That search led to a contact at Johns Hopkins University, and a few days later, Joho got a call from a cancer geneticist co-leading a study there. Get down here as fast as you can! Luis Diaz said. We are having tremendous success with patients like you.

What followed is an illuminating tale of how one womans intersection with experimental research helped open a new frontier in cancer treatment with approval of a drug that, for the first time, capitalizes on a genetic feature in a tumor rather than on the diseases location in the body.

The breakthrough, made official last week by the Food and Drug Administration, immediately could benefit some patients with certain kinds of advanced cancer that arent responding to chemotherapy. Each should be tested for that genetic signature, scientists stress.

These are people facing death sentences, said Hopkins geneticist Bert Vogelstein. This treatment might keep some of them in remission for a long time.

In August 2014, Joho stumbled into Hopkins for her first infusion of the immunotherapy drug Keytruda. She was in agony from a malignant mass in her midsection, and even with the copious amounts of oxycodone she was swallowing, she needed a new fentanyl patch on her arm every 48 hours. Yet within just days, the excruciating back pain had eased. Then an unfamiliar sensation hunger returned. She burst into tears when she realized what it was.

As months went by, her tumor shrank and ultimately disappeared. She stopped treatment this past August, free from all signs of disease.

[Negotiating cancer: Tips from one whos done it ]

The small trial in Baltimore was pivotal, and not only for the young marketing professional. It showed that immunotherapy could attack colon and other cancers thought to be unstoppable. The key was their tumors genetic defect, known as mismatch repair (MMR) deficiency akin to a missing spell-check on their DNA. As the DNA copies itself, the abnormality prevents any errors from being fixed. In the cancer cells, that means huge numbers of mutations that are good targets for immunotherapy.

The treatment approach isnt a panacea, however. The glitch under scrutiny which can arise spontaneously or be inherited is found in just 4percent of cancers overall. But bore in on a few specific types, and the scenario changes dramatically. The problem occurs in up to 20percent of colon cancers and about 40percent of endometrial malignancies cancer in the lining of the uterus.

In the United States, researchers estimate that initially about 15,000 people with the defect may be helped by this immunotherapy. That number is likely to rise sharply as doctors begin using it earlier on eligible patients.

Joho was among the first.

***

Even before Joho got sick, cancer had cast a long shadow on her family. Her mother has Lynch syndrome, a hereditary disorder that sharply raises the risk of certain cancers, and since 2003, Priscilla Joho has suffered colon cancer, uterine cancer and squamous cell carcinoma of the skin.

Stefanies older sister, Vanessa, had already tested positive for Lynch syndrome, and Stefanie planned to get tested when she turned 25. But at 22, several months after she graduated from New York University, she began feeling unusually tired. She blamed the fatigue on her demanding job. Her primary-care physician, aware of her mothers medical history, ordered a colonoscopy.

When Joho woke up from the procedure, the gastroenterologist looked like a ghost, she said. A subsequent CT scan revealed a very large tumor in her colon. Shed definitely inherited Lynch syndrome.

She underwent surgery in January 2013 at Philadelphias Fox Chase Cancer Center, where her mother had been treated. The news was good: The cancer didnt appear to have spread, so she could skip chemotherapy and follow up with scans every three months.

[More than two-thirds of cancer mutations are due to random DNA copying errors, study says]

By August of that year, though, Joho started having relentless back pain. Tests detected the invasive tumor in her abdomen. Another operation, and now she started chemo. Once again, in spring 2014, the cancer roared back. Her doctors in New York, where she now was living, switched to a more aggressive chemo regimen.

This thing is going to kill me, Joho remembered thinking. It was eating me alive.

She made it to Jesss college graduation in Vermont that May. Midsummer, her oncologist confessed he was out of options. As he left the examining room, he mentioned offhandedly that some interesting work was going on in immunotherapy. But when Joho met with a hospital immunologist, that doctor told her no suitable trials were available.

Joho began planning to move to her parents home in suburban Philadelphia: I thought, Im dying, and Id like to breathe fresh air and be around the green and the trees.

Her younger sister wasnt ready for her to give up. Jess searched for clinical trials, typing in immunotherapy and other terms shed heard the doctors use. Up popped a trial at Hopkins, where doctors were testing a drug called pembrolizumab.

***

Pembro is part of a class of new medications called checkpoint inhibitors that disable the brakes that keep the immune system from attacking tumors. In September 2014, the treatment was approved by the FDA for advanced melanoma and marketed as Keytruda. The medication made headlines in 2015 when it helped treat former president Jimmy Carter for melanoma that had spread to his brain and liver. It later was cleared for several other malignancies.

Yet researchers still dont know why immunotherapy, once hailed as a game changer, works in only a minority of patients. Figuring that out is important for clinical as well as financial reasons. Keytruda, for example, costs about $150,000 a year.

By the time Joho arrived at Hopkins, the trial had been underway for a year. While an earlier study had shown a similar immunotherapy drug to be effective for a significant proportion of patients with advanced melanoma or lung or kidney cancer, checkpoint inhibitors werent making headway with colon cancer. A single patient out of 20 had responded in a couple of trials.

Why did some tumors shrink and others didnt? What was different about the single colon cancer patient who benefited?

Drew Pardoll, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Hopkins, and top researcher Suzanne L. Topalian took the unusual step of consulting with the cancer geneticists who worked one floor up.

This was the first date in what became the marriage of cancer genetics and cancer immunology, Pardoll said.

[A consumers guide to the hottest field in cancer treatments immunotherapy]

In a brainstorming session, the geneticists were quick to offer their theories. They suggested that the melanoma and lung cancer patients had done best because those cancers have lots of mutations, a consequence of exposure to sunlight and cigarette smoke. The mutations produce proteins recognized by the immune system as foreign and ripe for attack, and the drug boosts the systems response.

And that one colon-cancer patient? As Vogelstein recalls, We all said in unison, He must have MMR deficiency! because such a genetic glitch would spawn even more mutations. The abnormality was a familiar subject to Vogelstein, who in the 1990s had co-discovered its role in the development of colon cancer. But the immunologists hadnt thought of it.

When the patients tumor tissue was tested, it was indeed positive for the defect.

The researchers decided to run a small trial, led by Hopkins immunologist Dung Le and geneticist Diaz, to determine whether the defect could predict a patients response to immunotherapy. The pharmaceutical company Merck provided its still-experimental drug pembrolizumab. Three groups of volunteers were recruited: 10 colon cancer patients whose tumors had the genetic problem; 18 colon cancer patients without it; and 7 patients with other malignancies with the defect.

The first results, published in 2015 in the New England Journal of Medicine, were striking. Four out of the 10 colon cancer patients with the defect and 5 out of the other 7cancer patients with the abnormality responded to the drug. In the remaining group, nothing. Since then, updated numbers have reinforced that a high proportion of patients with the genetic feature benefit from the drug, often for a lengthy period. Other trials by pharmaceutical companies have shown similar results.

The Hopkins investigators found that tumors with the defect had, on average, 1,700 mutations, compared with only 70 for tumors without the problem. That confirmed the theory that high numbers of mutations make it more likely the immune system will recognize and attack cancer if it gets assistance from immunotherapy.

The studies were the foundation of the FDAs decision on Tuesday to green-light Keytruda to treat cancers such as Johos, meaning malignancies with certain molecular characteristics. This first-ever site-agnostic approval by the agency signals an emerging field of precision immunotherapy, Pardoll said, one in which genetic details are used to anticipate who will respond to treatments.

***

For Joho, now 27 and living in suburban Philadelphia, the hard lesson from the past few years is clear: The cancer field is changing so rapidly that patients cant rely on their doctors to find them the best treatments. Oncologists can barely keep up, she said. My sister found a trial I was a perfect candidate for, and my doctors didnt even know it existed.

Her first several weeks on the trial were rough, with an early hospitalization after she cut back too quickly on her fentanyl and went into withdrawal. She still has some lasting side effects today joint pain in her knees, minor nausea and fatigue but they are manageable.

I have had to adapt to some new limits, she acknowledged. But I still feel better than I have in five years.

The FDAs decision last week was an emotional moment. Diaz, now at Memorial Sloan Kettering Cancer Center in New York, immediately texted her. We did it! he exulted.

I got chills all over my body, Joho said. To think that I was at the end of the road, with no options, and then to be part of such a change.

Her experience has prompted her to drop plans to go back into marketing. Now she wants to help patients navigate the new cancer landscape. Become an expert on your cancer is her message. Dont be passive. She encourages patients to try clinical trials.

As a cancer survivor with Lynch syndrome, Joho will be closely watched; if she relapses, she is likely to be treated again with immunotherapy. And if her mother relapses, Keytruda might now be her best chance.

Coming out the other side, I feel really lucky, Joho said. Shes also grateful for something else: A few years ago, her sister Jess was tested for the disorder that has so affected their family. She was negative.

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'This is not the end': Using immunotherapy and a genetic glitch to give cancer patients hope - Washington Post

Philadelphia downtown cityscape on Broad Street at City Hall.

Philadelphia views itself as a city that should be able to compete more effectively with the likes of New York and Boston as an innovation hub, particularly in the realm of life sciences and healthcare. But it doesnt have enough serial entrepreneurs, capital, or talent, at least compared with other cities. A Brookings Institution assessment team reached these and other conclusions and made a series of recommendations of how to better position Philly as an innovative city.

It recommended that Philadelphia should focus on building its reputation in precision medicine by making the most of itsresources here.

The Emerging Innovation District Pilot Study, which was produced by the Anne T. and Robert M. Bass Initiative on Innovation and Placemaking, also highlighted digital health and industries tied to the states natural gas exploration as opportunities for the city tobuild an edge. Its the product of an 18-month research initiative to answer the question of how University City and Center City can help Philadelphia excel on a global stage and improve its role as a regional economic hub.

Some of the 10 institutions that worked with the institution included Comcast, Drexel University, the Childrens Hospital of Philadelphia, Independence Blue Cross, the University City Science Center, the University of Pennsylvania as well as the University of Pennsylvania Health System, and investment manager Vanguard.

Another recommendation from the report was the formation of an Innovation Council with the influence and authority to bring a diverse group of key industry, public and civic stakeholders together around a common vision and narrative. The members of this council would identify a set of strategies and initiatives to grow the regional innovation economy, and to identify the organizations best poised to lead each of them.

On the topic of precision medicine, the report noted:

Given the regions public and private strengths in the life sciences, its broad clinical care capabilities, its large catchment of patients, and the depth of bio-specimens (which support future scientific discoveries), we recommend that the council focus its initial efforts on creating a Precision Medicine Catalyst Initiativea central organizing force that has the ability to pool resources and capture the full value of the regions research and commercialization capacity in gene therapy. The purpose of the initiative would be to both coordinate existing institutions that specialize in the cluster and connect them with the citys entrepreneurs and business support servicesincluding law and business programs and industry partners in these areaswith the goal of developing regional expertise in the wrap-around services that the cluster will demand.

The report offered some more specific recommendations for mapping out this precision medicine initiative:

Penn, for example, has a gene therapy collaboration with Novartis through the Novartis-Penn Center for Advanced Cellular Therapeutics and Childrens Hospital of Philadelphia spinout Spark Therapeutics, a gene therapy company, IPOd in 2015. Collectively, Philadelphias academic institutions generate about $640 million in research funding from the National Institutes of Health. But Philly institutions compete with each other for this funding and other resources. The idea of a citywide collaboration sounds ideal but it ignores the larger reality of the diverse corporate cultures of these groups. If it were so easy to collaborate on a large scale, wouldnt this have happened years ago? Instead, there are lot of smaller collaborations to promote startups and entrepreneurship.

Still, members of Brookings made clear in the report that in a world where the federal government is dysfunctional and the state has been absent, cities like Philly have to be more creative, make the most of their own institutions and collaborate in more innovative ways.

Other report recommendations included developing an Anchor Firm Entrepreneurship Initiative that would use the resources of anchor technology firms to strengthen the regions startup landscape. The goal would be to connect the citys startups with customers, support training and mentorship programs, boost access to investment, and help develop physical spaces in which startups can grow.

Education that would zero in on skills needed to foster local talent in support of the anchor industries would be designed to ensure that city residents in a wider number of communities were positioned to benefit from precision medicine and other technology jobs.

Photo: SeanPavonePhoto, Getty Images

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Philly should pool precision medicine resources in Brookings Institution assessment - MedCity News

May 29, 2017

Urinary incontinence in women is common, with almost 50% of adult women experiencing leakage at least occasionally. Genetic or heritable factors are known to contribute to half of all cases, but until now studies had failed to identify the genetic variants associated with the condition. Speaking at the annual conference of the European Society of Human Genetics today (Monday), Dr Rufus Cartwright, MD, a visiting researcher in the Department of Epidemiology and Biostatistics, Imperial College, London, UK, will say that his team's investigations hold out the promise that drugs already used for the treatment of other conditions can help affected women combat this distressing problem.

Pelvic floor disorders, including urinary incontinence, but also faecal incontinence and pelvic organ prolapse, have a devastating effect on quality of life. Most commonly they occur after childbirth, or at menopause, though some women report incontinence dating from childhood. Of the 25% who are affected sufficiently for it to affect their daily lives, most suffer from stress incontinence - the loss of small amounts of urine associated with laughing, coughing, sneezing, exercising or other movements that increase pressure on the bladder. Isolated urgency incontinence - where a sudden pressing need to urinate causes the leakage of urine - affects only around 5% of women, and 5-10% have a combination of both forms.

"25% of adult women will experience incontinence severe enough to impact on their quality of life," says Dr Cartwright. "Finding a genetic cause and a potential treatment route is therefore a priority."

The researchers undertook a genome-wide association study (GWAS) in just under 9,000 women from three groups in Finland and the UK, confirming their findings in six further studies. Genome-wide association studies work by scanning markers across the complete sets of DNA of large numbers of people in order to find genetic variants associated with a particular disease.

Analysis of the study data yielded a risk locus for urinary incontinence close to the endothelin gene, known to be involved in the ability of the bladder to contract. Drugs that work on the endothelin pathway are already used in the treatment of pulmonary hypertension and Raynaud's syndrome, a condition where spasm of the arteries causes reduced blood flow, most usually to the fingers.

"Previous studies had failed to confirm any genetic causes for incontinence. Although I was always hopeful that we would find something significant, there were major challenges involved in finding enough women to participate, and then collecting the information about incontinence. It has taken more than five years of work, and has only been possible thanks to the existence of high quality cohort studies with participants who were keen to help," says Dr Cartwright.

Current treatment for urinary incontinence in women includes pelvic floor and bladder training, advice on lifestyle changes (for example, reducing fluid intake and losing weight), drugs to reduce bladder contraction, and surgery.

However, as the number of identified risk variants for urinary incontinence grows, there will be potential to introduce genetic screening for the condition, and improve advice to pregnant women about the likely risks of incontinence in order that they may make an informed choice about delivery method. "We know that a caesarean section offers substantial protection from incontinence. However, across Europe there are efforts to reduce caesarean section rates, and establishing such a screening programme during pregnancy may run against current political objectives in many maternity care systems.

"Clearly this will need further debate and an analysis, not just of the cost to healthcare systems, but also of the benefit to women who may be spared the distress of urinary incontinence," Dr Cartwright will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle, United Kingdom, said: "This work reveals the first links between urinary incontinence and genetic factors. It provides important insight into the biological mechanisms for incontinence and suggests the potential of identifying women at risk."

Explore further: Urinary incontinence is common also in women who have not given birth

Women who have not given birth often end up under the radar for research on urinary incontinence. In a study of this group, however, one in five women over 45 years say they experience this type of incontinence.

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New genomic analysis promises benefit in female urinary incontinence - Medical Xpress