Category Archives: Genetic medicine

Weight-shaming, or explicit bias towards people with obesity, has significantly reduced in the United States over the past 3 years, suggesting wider acceptance of obesity as a medical problem, according to a new survey conducted in the United States and UK.

However, the US finding is in stark contrast to the UK, where the survey suggests the general public continues to attribute blame to people with obesity.

Exploring attitudes towards weight was the topic addressed by the survey conducted in both countries over the last 3 years.

"This finding is important because it highlights that, in the United States at least, obesity is increasingly considered a medical condition and not a personal failure," said Ted Kyle, MBA, founder of ConscienHealth, an advocacy organization in Pittsburgh, Pennsylvania, who led the work.

He presented the findings as a poster at this year's virtual European and International Congress on Obesity(ECOICO 2020).

The survey shows nearly one in three UK adultsblame people with obesity for their condition and do not believe obesity is a medical problem.

In contrast, over the past 3 years in the United States there has been a 12% increase in respondents who believe obesity is a medical problem. The difference between the two countries was statistically significant.

"There are multiple reasons for this change including that in the US, the fastest growing medical specialty is obesity medicine; the science of obesity has progressed; and culturally, the noise level about so-called 'fat-shaming' as being morally and socially wrong has increased," said Kyle.

"But by no means is the problem solved," he added. "There's still a lot of bias and remember this refers to explicit bias that expressed, which is very different to implicit bias that is internalized and influences a decision before you are aware of it."

Stuart Flint, PhD, associate professor of the psychology of obesity at the University of Leeds, UK, had this to say: "The decline in weight stigma in the US is much needed and encouraging."

But, he told Medscape Medical News, it is important to learn why these changes in attitudes have occurred in the United States to try to disseminate these positive opinions more widely.

"Considering that weight stigma is so perceptive, and in some instances encouraged, this study shows that greater efforts are needed to reduce weight stigma that is high in the UK," he asserted.

Previous research by Kyle (Obes Facts. 2018;11:1-364. Abstract S1.3) suggests thatexplicit weight bias is more common in the UK than in eight other countries including the United States, and that those harsh British attitudes to obesity are hampering efforts to tackle the obesity epidemic. "Reducing weight stigma has been identified as a key target by, for instance, the UK Obesity Policy Engagement Network and the All-Party Parliamentary Group on obesity," added Flint.

"Greater efforts are warranted and required at all levels including policy, health care, and within the community."

The researchers analyzed the responses from a random sample of 6082 adults from the US and UK,half of whom completed ananonymous online Google survey in November 2017 and the other half in May 2020.

The survey asked participants for their opinion ononeof three different statements using a five-point Likert scale (strongly agree to strongly disagree): 1) that obesity is the fault of the person with obesity; 2) that it is not their fault; or 3) that obesity is a major problem because people with obesity are blamed for the disease instead of receiving needed medical help. The results were adjusted for gender, age, country, and year.

In the United States, results showed a considerable drop in the proportion of respondents who agree that obesity is the fault of people with obesity, from 31% (115/372) in 2017 to 25% (93/377) in 2020 (P = .10). By comparison, UK respondents showed a smaller drop from 34% to 30% for the same question (P = .28).

Turning the question around so asking if the respondent thought obesity was not the fault of the person with obesity showed a rise in the proportion of US respondents agreeing with this statement from 11% to 16% (P = .17) between the two time points. But in the UK, there was an insignificant change from 16% to 15% (P = .31).

A significant change was also seen when American respondents were asked whether they agreed with a medical explanation for obesity. US respondents were much more likely to agree with this than those from the UK.

The percentage of US respondents in agreement rose from 30% to 42% between 2017 and 2020 (P = .002), but among UK respondents, that percentage remained unchanged at 31% (P = .8).

In 2018, the Royal College of Physicians in the UK called for obesity to be urgently recognized as a disease by government and the broader health sector, warning that until this happens its prevalence is unlikely to be reduced.

"There was some considerable backlash to this," noted Kyle.

"In the UK, for some people, there just seems to be a stronger impulse to blame people with obesity. It takes time for sentiment to shift on something that's so deeply held," he added.

"In the US where obesity is more common than in the UK it might make it harder to vilify obesity if over 40% of the population have it."

Kyle explained that by weight-shaming and implying people make bad choices or are somehow defective, "People turn in on themselves and they start believing the bad things people say about them. This is internalized stigma and this is known to predict worse medical outcomes."

Kyle also highlighted that obesity is genetic in origin but that the obesogenic environment plays a large part in people becoming obese.

"We can make a choice about how we are going to cope with a bad set of genes or a hostile environment, but we can't make a choice about susceptibility to obesity in our genes."

ECOICO 2020. Presented September 1, 2020. Abstract 1150/LBP-126.

Kyle is a board member for the Obesity Action Coalition. Flint has reported no relevant financial relationships.

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'Fat-Shaming' Drops in US but UK Public Still Apportion Blame - Medscape

The most common genetic cause of alterations in pediatric patients with papillary thyroid cancer (PTC) were fusion genes, which were associated with more aggressive disease, according to a study published in Thyroid.

In this study, several novel rearrangements were identified, and the fusion genes seemed to be a molecular marker number one in this patient population.

Overall, the study included 93 pediatric patients who had undergone thyroid surgery between 2003 and 2019 at the Department of Ear, Nose, and Throat, Second Faculty Medicine, Charles University, and Motol University Hospital in Prague. The mean age of patients at diagnosis was 14.5 3.4 years, and the female to male ratio was 2.6 to 1. Eighty-two patients had a total thyroidectomy and 11 had a subtotal thyroidectomy, where 10 were completed to total thyroidectomy.

The mean tumor size was 22.1 13.7 mm, and the investigators noted that 17 patients had microcarcinoma. Twenty-six patients (29.9%) had PTC of classical variant, 20 (23.0%) had classical and follicular variant, 29 (33.3%) had follicular variant, 3 (3.4%) had solid variant, 3 (3.4%) had a mixture of classical/follicular/solid variant, 2 (2.3%) had diffuse sclerosing variant, 2 (2.3%) had columnar variant, 1 (1.1%) had tall cell variant, and 1 (1.1%) had case clear cell variant.

After a median follow-up was 72 months (range, 2-198), 11 (19.3%) patients had persistent or recurrent disease at least 1 year after surgery or patients who were in remission and later had a malignant object thyroid tissue formed. Sixteen (19.3%) patients only had biochemical evidence of persistent disease, while 56 (67.5%) remained in remission with no evidence of disease. One patient died due to advanced disease. Additionally, 10 patients were not classified because of short-term follow-up, 84 received radioactive iodine (RAI) treatment, and 8 did not receive RAI because of low-risk disease.

More than half (55.9%) of the patients had fusion genes, which included RET, NTRK1, NTRK3, ALK, BRAF, and MET. Additionally, 10 different types of RET fusions were observed in 26 patients, 4 types of NTRK3fusions in 14 patients, 1 ALK fusion in 6 patients, 2 types of NTRK1 fusions in 3 patients, 2 types of BRAFfusions in 2 patients, and 1 type of MET fusions in 1 patient. Overall, 20 types of fusion genes were identified in the study, 11 of which were interchromosomal and 9 were intrachromosomal rearrangements.

Investigators detected 2 co-existing RET fusions in 1 PTC nodule, which included ACBD5/RET fusion with juxtaposition of exon 11 of the ACBD5 gene and exon 12 of RET gene in the first and BBIP1/RET fusion with a juxtaposition of exon 1 of the BBIP1 gene and exon 8 of the RET gene. CCDC6/RET rearrangement was the most common fusion gene, which was observed in 13 patients (14%), while 1 of these patients had a novel isoform including a part of exon 9 of RET gene. Other rearrangements that were observed more commonly included ETV6/NTRK3 in 10 patients (10.8%), NCOA4/RET, and STRN/ALK both in 6 patients (6.5%) and RBPMS/NTRK3 found in 2 patients (2.2%). The remaining fusions were not recurrent.

BRAF fusions with partner genes, CUL1, and OPTN were reciprocal, and the IRF2BP2/NTRK1 fusion gene has 2 isoforms, 1 being a fusion of exon 1 and the second of exon 2 of the IRF2BP2 gene with exon 10 of the NTRK1 gene. Every isoform was found in a different patient, and no patients with fusion genes had a prior history of radiation exposure before their PTC diagnosis.

The investigators also compared the samples positive for the fusion gene to those that did not harbor this mutation. Positive samples were associated significantly with the mixture of classical and follicular types of PTC (P =.025), and the fusion-positive samples were also significantly associated with extrathyroidal extension (P <.001), higher T classification (P =.009), lymph node metastases (P <.001), distant metastases (P =.021), chronic lymphocytic thyroiditis (P =.001), and frequent occurrence of psammoma bodies (P =.004). Patients who were positive for the fusion gene has also received more frequent multiple doses of RAI therapy (P=.008). Borderline statistically significant associations were observed for features such as tumor size larger in fusion gene-positive tumors (P =.057), number of microcarcinomas higher in fusion gene-negative tumors (P=.052), and a higher number of patients who were not given RAI treatment (P =.058).

Samples that were positive for the fusion genes were different from each other as well, according to the fused oncogene involved. A statistical analysis was only able to be performed between RET and NTRK3 fusion gene-positive samples because of the low number of samples in the other fusion groups. RET fusions were significantly associated with lower mean age of patients at diagnosis (P =.035), lymph node metastases (P =.033), distant metastases (P =.020), and frequent occurrence of psammoma bodies (P =.006). The NTRK3fusions were significantly associated with follicular variant PTC (P =.013).

In RET fusion gene-positive group, 11 patients (42.3%) were of prepubertal age (up to age 12) compared with only 1 patient (7.1%) in the NTRK3 fusion-positive group (P =.021).

All patients with distant metastases (n = 10) had the genetic cause of PTC detected, which was HRAS Q61R point mutation in 1 patient, NCOA4/RET in 4, CCDC6/RET in 2, RASAL2/RET in 1, EML4/MET in 1, and co-occurrence of ACBD5/RET with BBIP1/RET in 1.

Point mutations in BRAF, HRAS, KRAS, NRAS, and TERT genes were assessed in all patients, in which 18 (19%) had the BRAF V600E mutation, and the HRAS Q61R and NRAS Q61K was found in 1 patient each. No mutations were found in the KRAS gene or in the promoter region of TERT. Patients with HRAS-positive PTC (n = 1) underwent radiation treatment for Hodgkins lymphoma. The co-occurrence of fusion gene and somatic point alternation was not identified in the study.

These findings demonstrated a point mutation or fusion gene was observed in 72 pediatric patients (77.4%) with PTC, and the oncogenic alteration was unidentified in 21 patients (22.6%). Most tumors were follicular variants of PTC and T1/T2 classification predominated the tumor samples in this study. No patients had experienced recurrence or persistence of structural disease, but 1 patient had biochemical persistence of their disease while almost all of the other patients remained in remission.

Overall, this study demonstrated that fusion genes occurred in 56% of pediatric patients with PTC, and point mutations in the BRAF and RAS genes were observed in 77% of patients. Patients who harbored a fusion gene had more aggressive forms of the disease, which included more frequent extrathyroidal extension, lymph node metastases, distant metastases, and consequently had received more doses of RAI than those without the fusion gene mutations.

Reference

Pekova B, Sykorova V, Dvorakova S, et al.RET, NTRK, ALK, BRAF,andMETfusions in a large cohort of pediatric papillary thyroid carcinomas.Thyroid.Published Online July 1, 2020. doi: 10.1089/thy.2019.0802

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Fusion Genes Associated With More Aggressive Papillary Thyroid Cancer in Pediatric Patients - Targeted Oncology

Obtaining sufficient tumour tissue for oncology testing can be challenging, particularly when there is an insufficient biopsy sample, and invasive procedures pose a health risk to the patients. This is especially true for non-small cell lung carcinoma (NSCLC), where 27%31% of patients are unable to provide a suitable specimen upon diagnosis. One area of active research in oncology testing has been the evaluation of alternative sources of testing material. Liquid biopsy refers to the analysis of any tumour-derived material, circulating in the blood or any other body fluid. The detection of mutations via circulating tumour DNA (ctDNA) found in plasma has been rising in popularity due to its minimal invasiveness.

On 7 August, Guardant Health announced the Food and Drug Administration (FDA) approval of its novel liquid biopsy comprehensive tumour mutation profiling test across all solid cancers. This is a landmark approval for cancer testing as Guardant Healths liquid biopsy is the first of its kind to genetically profile tumours anywhere in the body from a single blood draw. The FDA approval of this test includes its approval as a companion diagnostic for identifying patients with metastatic NSCLC based on the presence of mutations in the EGFR gene. Lung cancer is the current leading cause of cancer-related deaths worldwide with NSCLC comprising 80%90% of all lung cancers. As such, the need for this test is very high.

On 27 August, Foundation Medicine, a Roche company, received FDA approval for its FoundationOne Liquid CDx, a multi-cancer comprehensive liquid biopsy test. Foundation Medicines test is broader than Guardant Healths, covering more than 300 cancer-related genes. In addition to single-gene alterations, Foundation Medicines test also reports on the presence of multi-gene signatures namely microsatellite instability and blood tumour mutational burden, which can help guide the use of cancer immunotherapies.

The genomic analysis of ctDNA has the potential to offer insight across multiple metastatic sites. This is particularly valuable in settings with increased genomic heterogeneity such as in patients with treatment resistance. Some key opinion leaders (KOLs) interviewed by GlobalData have indicated that despite the fact that the test has some sensitivity issues, liquid biopsies are a cheaper alternative and the minimally invasive aspect of the technique improves patient satisfaction. Other KOLs noted the potential for liquid biopsies to integrate the overall cancer burden in patients with numerous metastases in different locations. GlobalData predicts an increased usage of liquid biopsies in the future due to the benefits they offer patients with metastatic recurrence.

Liquid biopsy is revolutionising cancer tests as it is non-invasive, precise and provides faster turnaround time for results compared to traditional solid tumour biopsy. While DNA sequencing methods such as Sanger sequencing have been considered the gold standard for detecting many genetic mutations associated with cancer, these techniques have lower sensitivity, and thus, require samples with a higher percentage of mutated DNA. As such, the use of ctDNA will be important for detecting cancerous mutations where tumours are hard to resect. Furthermore, the use of highly sensitive assays such as next-generation sequencing (NGS) will aid in the detection of cancerous mutations. As sequencing technology like NGS becomes more developed and its costs decrease, GlobalData expects these techniques to be more frequently used to test for mutations in cancer.

GlobalData is this websites parent business intelligence company.

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Liquid biopsies to disrupt the oncology testing market - Medical Device Network

In the past, in order to get tumor cells from a patient, a doctor had to do surgery or biopsy. Now a nurse draws blood from the arm, like what happens in a routine blood test. (Sept. 2017) Video Elephant

Cancer patients often have to endure months of anxiety and side effects before they can schedule a scan or painful biopsy to learn if their treatment is working.

Liquid biopsy tests, which have won federal approval in recent weeks, could make that process faster and less miserable.

The Food and Drug Administration approved Guardant360 CDxin early August for use in a range of solid tumors; Foundation Medicine's FoundationOne Liquid CDx, became available for widespread use as of late last month.

The tests aren't brand new, but the federal approvals will make them more accessible, as Medicare and more insurance companies cover the costs, which can run as much as $6,000.

"I think that liquid biopsies now are coming into their own," said Dr. Matthew Freedman, an oncologist and researcher at the Dana-Farber Cancer Institute in Boston.

The newly approved liquid biopsies can identify the genetic signature of tumors, which then can be used to match patients to treatments or research trials with experimental therapies.

Lung cancer patients who have certain genetic mutations in their tumors, for instance, can double or triple their life expectancy when given a drug targeted to those mutations.

Doctors can also use liquid biopsies a few weeks after starting treatment to see how a tumor is evolving, and perhaps gain insights into why a treatment isn't working, said Helmy Eltoukhy, CEO of Guardant Health, of Redwood City, California, which makes Guardant360 CDx.

"It's better care for patients at lower cost if you test appropriately," he said.

Today, many cancer patients, particularly those with hard-to-reach tumors, get one biopsy with all future treatment decisions based on that one sample. But tumors change over time. "There's almost no other area of medicine where you'd use an old clinical specimen to decide treatment," Eltoukhy said.

Because blood is so easy to access, a liquid biopsy can be done several times to see how the tumor evolves, he said. And patients who live far from an academic medical center can still get cutting-edge recommendations without traveling.

So-called liquid biopsies, recently approved by the FDA, may make it easier for oncologists to track their patients' cancers.(Photo: Guardant Health)

Liquid biopsies are generally seen as not as precise as more typical biopsies, where a needle is inserted directly into a solid tumor. "If one had a choice, the choice would be to look at the biopsies," said Dr. Bert Vogelstein, who has spent years developing liquid biopsy tests as a professor at Johns Hopkins University in Baltimore.

But with some cancers, it's not easy to access the tumor, or there's very little cancerous material that can be withdrawn or seen.

As a tumor begins to spread its tentacles,it's initially invisible on scans. And after successful surgery, there may be no obvious tumor, but residual disease could still be lurking.

Liquid biopsies can fill those crucial gaps.

Scientific advances in recent years have made it possible to identify cancer DNA in the bloodstream tiny needles in the haystack of the bloodstream.

This opens up a lot of possibilities for treatment and diagnosis, Vogelstein said.

Guardant Health is one of two companies that recently received approval for its liquid biopsy tests, intended to make it easier to track cancers.(Photo: Guardant Health)

In colon cancer, for instance, roughly half of Stage 3 patients who otherwise would die can be cured with so-called adjuvant therapy, Vogelstein said. But nearly everyone who has enough metastatic cancer to be visible on an X-ray will die from their disease. "You cure close to 0% with adjuvant therapy," he said.

Adjuvant therapy is terribly toxic, though, so doctors don't want to use it unless they believe the patient is likely to have metastatic disease.

"So, this is a decision that virtually every patient goes through: Should I undergo adjuvant therapy?" said Vogelstein.

Until now, they've only beenable to guess and play the odds. But early research suggests using liquid biopsy to identify if there's residual diseasecan help make that decision easier, Vogelstein said.

Although studies proving the clinical usefulness of liquid biopsies have yet to be completed, he added, "Patients with positive liquid biopsies after surgery nearly always recur, and many that don't have positive liquid biopsy tests don't recur."

Dr. Neal Shore, medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, said he uses liquid biopsies to help him find clinical trials for patients with advanced cancer.

One patient, who only wanted to be identified by his first name, Joel, has been on a clinical trial of a double-drug therapy for two years, after a liquid biopsy identified a genetic mutation in his advanced prostate cancer.

"He looks great," Shore said on a call with Joel and his wife Tracey. "He's done exceptionally well."

Joel said the treatment has been challenging at times. He has trouble swallowing some days, suffers from back pain, and the hormone therapy he still takes gives him hot flashes.

But his wife said his issues are largely manageable with Tylenol and heating pads. "For the most part, he feels pretty good," she said.

Shore, who treats patients with kidney, bladder and prostate cancers, said liquid biopsies are particularly useful when a tissue sample is old or unusable.

"It expands our treatment armamentarium," he said. "This is really exciting for me as a urologist."

The next step, said Cindy Perettie, CEO of Cambridge, Massachusetts-based Foundation Medicine, will be to use liquid biopsies early in the course of someone's treatment.

"We're really focused on taking it from the metastatic setting and moving it to the early setting," she said. "That's where we're going to have the opportunity to really impact (patients)."

Breast cancer patients on maintenance therapy with tamoxifen, for instance, usually have to wait five years to know if their cancer has advanced, she said, but a liquid biopsy could let them know much faster and more often.

"We can look every six months whether they've progressed or not," Perettie said.

Even further into the future, the real potential for liquid biopsies lies in early detection.

For kidney cancer, as well as many other tumors, the earlier the diagnosis, the better the chance of survival, said Freedman of Dana-Farber. He, along with colleagues including Dr. Toni Choueiri, showed in a paper published earlier this summerthey could identify kidney cancer cells in urine at all stages of disease.

If such tumors could be identified when they're just beginning, the prognosis for kidney cancer would vastly improve.

"You want to cure cancer. You don't cure it with third-line chemo. You want to cure it before it happens," Choueiri said.

Today, about 20% of cancers are diagnosed via screening tools like mammography, colonoscopies or stool-based tests. Add liquid biopsies and that figure could jump to 75%. "I think that will be possible within five years or so," said Vogelstein, who is involved in a company, Thrive Earlier Detection, based in Cambridge, Massachusetts, that is working on such a test.

The challenge: the smaller the tumor, the less DNA released from the cancer cells, so the harder it is to detect.

Metastatic cancers that have spread throughout the body might account for 5-10% of the DNA floating in the bloodstream; but DNA from very early tumors may make up just 1-in-10,000 or 1-in-100,000 DNA molecules in blood, Vogelstein said.

Studies have shown it's feasible to find these few needles in a haystackbut not whether it's useful to doctors or patients.

There is also a risk to using liquid biopsies as a screening tool for early tumors, Vogelstein warned. False positives telling people they have cancer when they don't could do a lot of harm.

And a liquid biopsy can only say there's a high likelihood someone has cancer somewhere and that further testing is warranted, he said. Sometimes, something might look like cancer on a CT scan, but it isn't.

"It is essential," he said, "to show that the benefits of early detection outweigh the risks."

Contact Karen Weintraub at kweintraub@usatoday.com

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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'Coming into their own': FDA approval of liquid biopsy tests puts early, less invasive cancer detection in broader reach - USA TODAY

Sept. 4, 2020 23:00 UTC

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, Inc., a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has approved Gavreto (pralsetinib) for the treatment of adults with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. This indication was approved under the FDAs accelerated approval program based on data from the Phase I/II ARROW study. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations.

The FDA approval of Gavreto for RET fusion-positive non-small cell lung cancer is an important step towards our goal of providing an effective treatment option for every person diagnosed with lung cancer, no matter how rare or hard-to-treat their type of disease, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. We remain committed to finding personalized treatment options for people with cancer based on specific genomic or molecular alterations, and we look forward to partnering with Blueprint Medicines to further explore the potential of Gavreto across multiple RET-altered tumor types.

RET-activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and medullary thyroid cancer (MTC), and treatment options that selectively target these genetic alterations are limited. In NSCLC, RET fusions represent approximately 1-2% of patients. Biomarker testing for these fusions is the most effective way to identify people who are eligible for treatment with Gavreto.

The approval is based on the results from the Phase I/II ARROW study, in which Gavreto produced durable clinical responses in people with RET fusion-positive NSCLC with or without prior therapy, and regardless of RET fusion partner or central nervous system involvement. Gavreto demonstrated an overall response rate (ORR) of 57% (95% CI: 46%, 68%) and complete response (CR) rate of 5.7% in the 87 people with NSCLC previously treated with platinum-based chemotherapy, and the median duration of response (DoR) was not reached (95% CI: 15.2 months, not reached). In the 27 people with treatment-nave NSCLC, the ORR was 70% (95% CI: 50%, 86%) with an 11% CR rate. The most common adverse reactions (25%) were fatigue, constipation, musculoskeletal pain and increased blood pressure (hypertension).

Gavreto is now the sixth FDA-approved medicine in Genentechs portfolio of treatments for lung cancer. The FDA granted Breakthrough Therapy Designation to Gavreto for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy and for RET mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments.

The FDA has also granted Priority Review to Gavreto for the treatment of people with advanced or metastatic RET-mutant MTC and RET fusion-positive thyroid cancer, and is expected to make a decision on approval by February 28, 2021. This New Drug Application (NDA) was accepted for review under the FDAs Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.

For those who qualify, Blueprint Medicines will offer patient assistance programs for people prescribed Gavreto by their doctor through YourBlueprint . Please visit http://www.yourblueprint.com or contact 1-888-BLUPRNT for more information.

About the ARROW study

ARROW (NCT03037385) is a Phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability and efficacy of Gavreto, administered orally in people with rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancer and other RET-altered solid tumors. The trial consists of two parts: a dose escalation portion, which is complete, and an expansion portion in people treated with 400 mg of Gavreto, once-daily. ARROW is being conducted at multiple sites across the United States, European Union and Asia.

About lung cancer

According to the American Cancer Society, it is estimated that more than 228,000 Americans will be diagnosed with lung cancer in 2020, and NSCLC accounts for 80-85% of all lung cancers. It is estimated that approximately 85% of lung cancer diagnoses in the United States are made when the disease is in the advanced stages. In NSCLC, RET fusions represent approximately 1-2% of patients.

About Gavreto

Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations, regardless of the tissue of origin. Preclinical data have shown that Gavreto inhibits primary RET fusions and mutations that cause cancer in subsets of patients, as well as secondary RET mutations predicted to drive resistance to treatment. Blueprint Medicines and Genentech are also co-developing Gavreto for the treatment of patients with various types of RET-altered thyroid cancers and other solid tumors.

Gavreto U.S. Indication

Gavreto (pralsetinib) is indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

Gavreto may cause serious side effects, including:

Lung problems (pneumonitis) occurred in 10% of patients who received Gavreto, including 2.7% with Grade 3/4, and 0.5% with fatal reactions. Monitor for pulmonary symptoms indicative of interstitial lung disease (ILD)/pneumonitis. Withhold Gavreto and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue Gavreto based on severity of confirmed ILD.

Increased blood pressure (hypertension) occurred in 29% of patients, including Grade 3 hypertension in 14% of patients. Overall, 7% had their dose interrupted and 3.2% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Gavreto in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Gavreto. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Gavreto based on the severity.

Liver problems (hepatotoxicity): Serious hepatic adverse reactions occurred in 2.1% of patients treated with Gavreto. Increased AST occurred in 69% of patients, including Grade 3/4 in 5.4% and increased ALT occurred in 46% of patients, including Grade 3/4 in 6%. The median time to first onset for increased AST was 15 days (range: 5 days to 1.5 years) and increased ALT was 22 days (range: 7 days to 1.7 years). Monitor AST and ALT prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Gavreto based on severity.

Grade 3 bleeding (hemorrhagic events) occurred in 2.5% of patients treated with Gavreto including one patient with a fatal hemorrhagic event. Permanently discontinue Gavreto in patients with severe or life-threatening hemorrhage.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Gavreto has the potential to adversely affect wound healing. Withhold Gavreto for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Gavreto after resolution of wound healing complications has not been established.

Based on findings from animal studies and its mechanism of action, Gavreto can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Gavreto and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Gavreto and for 1 week after the final dose. Advise women not to breastfeed during treatment with Gavreto and for 1 week after the final dose.

Common adverse reactions (25%) were fatigue, constipation, musculoskeletal pain, and hypertension. Common Grade 3-4 laboratory abnormalities (2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium (corrected) and increased alanine aminotransferase (ALT).

Avoid coadministration with strong CYP3A inhibitors. Avoid coadministration of Gavreto with combined P-gp and strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the Gavreto dose. Avoid coadministration of Gavreto with strong CYP3A inducers. If coadministration cannot be avoided, increase the Gavreto dose.

Please click here to see the full Prescribing Information for Gavreto.

Gavreto, Blueprint Medicines, YourBlueprint and associated logos are trademarks of Blueprint Medicines Corporation.

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have six approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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Genentech Announces FDA Approval of Gavreto (pralsetinib) for the Treatment of Adults With Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer -...

Foodborne pathogens are very common and usually benign, but certain virulent strains of pathogens can result in severe disease and even death. Distinguishing specific strains of pathogens can help scientists better understand them and develop biomarkers to help detect them in patients, expediting diagnosis and treatment.

UB researchers have now completed the genomic analysis of a specific strain of Shiga-toxin E. coli (STEC) that can cause severe disease outbreaks and is increasingly common. The research could play a role in expanding the understanding of STEC infections and, potentially, in developing vaccines against them.

According to the Centers for Disease Control and Prevention, STEC are estimated to cause more than 265,000 infections per yearin the U.S., and are associated with more than 3,600 hospitalizations and approximately 30 deaths.

Published in BMC Genomics last month, the paper describes the genomic analysis completed on a unique STEC strain isolated from an otherwise healthy 2 -year-old child living in Davidson County, Tennessee. The pathogen caused severe illness, including hemolytic uremic syndrome, a condition that destroys red blood cells, lowers platelets and blocks blood vessels in kidneys, resulting in anemia and kidney damage.

The child survived but was hospitalized for a month and sustained severe complications affecting multiple organ systems, including her lungs, heart, kidney, brain, circulatory system and gastrointestinal tract.

The Shiga-toxin producing E. coli she was infected with is a non-0157 STEC. While the pathogens classified as 0157 STEC infections generally are more common and result in more severe disease, the number of emerging, non-0157 STEC pathogens has been on the increase. Some lead to severe disease, creating a growing public health concern, according to the UB researchers.

The paper states that there are more than 400 of these non-0157 STEC strains, and more than a quarter are reported to cause gastrointestinal disease, often presenting first as bloody diarrhea with hemolytic uremic syndrome and if untreated, in rare cases, death.

The specific pathogen the child was infected with was a STEC 0145:H25. Since genomic studies on emerging non-0157 STEC are limited, our studies are significant because they reveal the genetic makeup of emergent STEC 0145:H25 in comparison with other STEC strains, says Oscar G. Gmez-Duarte, corresponding author on the paper, associate professor and chief of the Division of Pediatric Infectious Diseases in the Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences at UB, and a pediatrician with UBMD Pediatrics.

The findings reveal how this emerging STEC causes severe disease and that it may be as virulent, or even more virulent, than more common STEC strains, leading to severe and even deadly disease in susceptible hosts, he says. It also provides information on how this potentially preventable infection continues to affect vulnerable individuals.

A key finding of the study, he says, was that this 0145:H25 serotype leads to particularly severe infection. Moreover, in addition to carrying virulence genes present in 0157 STEC, it has additional genes and new potential virulence genes as compared to other non-0157 strains that have been studied. These findings deserve further analysis to understand the pathogenesis of these emergent STEC infections, Gmez-Duarte says.

The analysis was conducted through a collaboration between the Department of Pediatrics researchers and colleagues at UBs New York State Center of Excellence in Bioinformatics and LifeSciences, whose expertise in bioinformatics and whole genome sequencing analysis allowed the team to uncover the genetic information critical to understanding where these strains are derived from and how they may be traced to unique reservoirs, such as contaminated food products or infected livestock.

Gmez-Duarte is an expert in infectious gastrointestinal diseases and diarrhea in children. He established a global health research program, the International Enteric Vaccines Research Program (IEVRP), dedicated to studying the epidemiology, pathogenesis and vaccine development of childhood gastrointestinal infections within the U.S. and abroad. He has also conducted vaccine development research for pediatric infectious diseases.

UB co-authors are Julio Guerra of the Department of Pediatrics and Jonathan E. Bard and Donald Yergeau of the Genomics and Bioinformatics Core of UBs NYS Center of Excellence in Bioinformatics and Life Sciences. Chengxian Zhang and Natasha Halasa of Vanderbilt University are also co-authors.

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Genomic analysis reveals insights on virulent, emerging foodborne pathogen - UB Now: News and views for UB faculty and staff - University at Buffalo...

Philadelphia, September 3, 2020 New findings from Childrens Hospital of Philadelphia (CHOP) show that some patients with a rare and aggressive form of leukodystrophy may benefit from receiving treatment with a class of targeted therapy drugs that could improve their neurological function. A correspondence about these findings was published today in the New England Journal of Medicine.

Aicardi-Goutires syndrome (AGS) is a rare genetic disorder and type of leukodystrophy that affects the brain and immune system. In patients with AGS, the bodys immune system turns on itself in a destructive way, targeting the brains white matter, causing most children with the disorder to experience mild to severe intellectual or physical impairments. Most children with AGS are unable to walk or talk and have multisystemic complications, including skin inflammation.

Prior studies have linked the activation of interferons signaling proteins that respond to various immune disruptions to exacerbated symptoms in AGS. Researchers at CHOP wanted to explore whether a class of small molecule inhibitor drugs called janus kinase (JAK) inhibitors could be used to block interferon activation in a way that helped these patients.

Because treatment options for AGS are limited and the symptoms that these patients experience are so severe, there is a need to explore a wide variety of options, said senior author Adeline Vanderver, MD, an attending physician in the Division of Neurology, Program Director of the Leukodystrophy Center, and Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at CHOP.

The study was conducted at CHOP with 35 international patients with genetically confirmed AGS. These patients received baricitinib, an oral JAK1 and JAK2 inhibitor, with doses based on each patients renal function, age and symptoms. Patients had their developmental histories evaluated from the onset of the disease to the end of the study, which ranged from 7.4 months to 41.5 months. The study team analyzed a variety of developmental milestones, including head control, sitting, rolling, smiling, babbling, and the use of single words and word combinations.

Before the patients in this study received treatment, 26 of the 35 had stable or declining neurologic function, and 9 of the 35 patients gained one or two of these developmental skills after disease onset. However, during the study, 20 patients met new milestones, and 12 patients gained between two to seven new skills. The improvements were typically observed within three months into the study and persisted. Children who received higher doses of the therapy appeared to achieve more of these milestones.

Some of the AGS patients who received baricitinib were at risk for developing thrombocytosis, leukopenia, and infection and therefore should be monitored closely while taking the drug.

Measuring neurologic improvements in these patients is a complex process, but the results of this study are encouraging, especially because we observed improvements even in patients with severe and long-standing disease, Vanderver said.

Eli Lilly provided the medication for the study and performed the safety laboratory tests. This work was supported by grants NINDS U01 NS106845 and NICHD U01HD082806 and the State of Pennsylvania, Commonwealth Universal Research Enhancement Program, the J.A. Kamens Chair in Translational Neurotherapeutics from CHOP; grant KL2TR001879 from the National Center for Advancing Translational Sciences of the NIH, K23NS114113 the National Institute of Neurological Disorders and Stroke of the NIH, and K08-HL140129 from the Parker B. Francis Foundation; and funding from the Department of Pediatrics at CHOP.

Vanderver et al, Janus Kinase Inhibition in the AicardiGoutires Syndrome. N Engl J Med, online September 3, 2020. DOI: 10.1056/NEJMc2001362.

About Childrens Hospital of Philadelphia: Childrens Hospital of Philadelphia was founded in 1855 as the nations first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Childrens Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

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Existing Class of Drugs May Improve Neurological Function in Patients with Rare, Aggressive Genetic Disorder - Newswise

Researchers have developed a coherent map of genes in the heart and looked at how they may cause heart diseases, which could pave the way for new treatments for these illnesses.

Heart diseases are a complex set of diseases influenced by different genes, and it is challenging to understand which genes are responsible for a particular disease, say experts.

To help scientists unravel the complex web of genes and how they interact, researchers from the National University of Singapore Yong Loo Lin School of Medicine (NUS Medicine) and the National University Hospital created what they said is the first map of the heart's genes and the "switches" between them that control how the genes behave and contribute to heart diseases.

Genes code for specific traits, and the switches are the non-coding portions of DNA between the genes.

Each gene has more than one switch and the switches may be far away from the genes that they control, making it tricky for scientists to match the switches to the genes.

The genetic heart map locates the genes and their switches so that scientists can eventually study them to create targeted treatments, such as gene therapy.

"If we understand how these genes are controlled, then we may find ways to control heart failure itself... and identify new disease-causing genes," said Professor Roger Foo from the university's department of medicine, who led the research team.

Heart diseases, which eventually lead to heart failure, cause one-third of all deaths in Singapore annually.

The researchers are part of the Cardiovascular Disease Translational Research Programme, one of nine new strategic research focus areas that were established at NUS Medicine in July.

The new focus areas, which also include infectious diseases, healthy longevity and precision medicine, aim to create greater synergy and collaboration between basic and clinical scientists within the National University Health System, and to deliver research outcomes that address current clinical and national healthcare issues.

Professor Chng Wee Joo, vice-dean of research at NUS Medicine, said: "We hope that these nine programmes will deliver not just outstanding research, but over the next five to 10 years, make some real impact on how we treat our patients and on the population's health."

BETTER UNDERSTANDING

If we understand how these genes are controlled, then we may find ways to control heart failure itself... and identify new disease-causing genes.

PROFESSOR ROGER FOO, from the National University of Singapore's department of medicine, who led the team that developed the map of genes in the heart.

The development of the gene map was published as two companion publications in the journals Circulation Research and Circulation last month and this month respectively.

The map took about five years to develop, and the researchers studied tissues from 36 healthy hearts and 34 failing hearts to map out the genes and switches.

Prof Foo said some scientists from Singapore and abroad have reached out to them to find out more about various genes from the map.

He also noted that none of the drugs currently used in treating heart disease targets genes, and cardiovascular research is not as well funded compared with other health conditions.

"The place where a lot of gene targeting is happening, I feel, is in cancer. Looking at the progress that cancer treatment has seen in recent years with targeted therapy, this is our dream for cardiovascular disease also, now that we have mapped out all these specific processes," he added.

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NUS team's map sheds light on heart diseases - The Straits Times

Could gene therapy provide a solution to HIV? A new research project aims to find out.

The National Institutes of Health(NIH) has backed researchers at the University of Southern California and the Fred Hutchison Cancer Center with a five-year, $14.6 million grant to develop a gene therapy that could potentially control HIV without the need for daily medications. Most HIV patients take a well-regimented cocktail of medications each day to control the virus. This therapy could change that. According to an announcement from the Keck School of Medicine at USC, the goal will be to develop a therapy that prepares patients for a stem cell transplantation using their own cells with little to no toxicity, engineers their own stem cells to fight HIV and stimulates those cells to quickly produce new and engineered immune cells once they're reintroduced into the patient. The hematopoietic stem cell transplants, also known as bone marrow transplants, have been used to treat some blood cancers. The idea is to infuse an HIV patient withhealthy donor blood stem cells that can grow into any type of blood or immune cell.

The gene therapy strategy has been inspired by three cases where leukemia patients who also had HIV received blood stem cell transplants from donors who also carried a mutation that confers immunity to HIV. The mutation was in the CCR5 gene, which encodes a receptor that HIV uses to infect immune cells and is present in about 1 percent of the population, USC said.

The program will engineer blood cells to remove CCR5 from a patient's own stem cells.That will be combined with other genetic changes so that the progeny of engineered stem cells will release antibodies and antibody-like molecules that block HIV.

In addition to the potential gene therapy treatment, researchers are also assessing whether or not CAR-T treatments will benefit HIV patients. Researchers from Harvard University developed a Dual CAR T-cell immunotherapy that can potentially help fight HIV infection. First reported by Drug Target Review, the HIV-specific CAR-T cell is being developed to not only target and eliminated HIV-infected cells, but also reproduce in vivo to enable the patients to fight off the infection. HIVs primary target it T cells, which are part of the bodys natural immune response.

Todd Allen, a professor of Medicine at Harvard Medical School, said the Dual CAR-T cell immunotherapy has so far provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself.

According to the report, theDual CAR T cell was developed through the engineering of two CARs into a single T cell. Each of the CARs contained a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. As DTR reported, the first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

To protect the CAR-T cells from HIV, the team added the protein C34-CXCR4, which prevents HIV from attaching to and infecting cells. When that was added, the researchers found in animal models that the treatment was long-lived, replicated in response to HIV infection, killed infected cells effectively and was partially resistant to HIV infection.

Still, other researchers are looking to those rare individuals who are infected with HIV but somehow on their own are able to suppress the virus without the need for any treatment. Researchers have sought to replicate what this small percentage of patients can naturally do in other patients who require those daily regimens of medications. Through the sequencing of the genetic material of those rare individuals, researchers made an interesting discovery.

The team discovered large numbers of intact viral sequences in the elite controllers chromosomes. But in this group, the genetic material was restricted to inactive regions, where DNA is not transcribed into RNA to make proteins, MedNewsToday reported.

Now the race is on to determine how this can be replicated and used to treat the nearly 38 million people across the globe who have been diagnosed with HIV.

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New HIV Gene Therapy, CAR-T Treatments Could be on the Horizon for Patients - BioSpace

CHAPEL HILL, N.C., Aug. 20, 2020 /PRNewswire/ -- Columbus Children's Foundation (CCF), a national leading non-profit biotech organization helping children with ultra-rare genetic diseases, announced today that Krystof Bankiewicz, M.D., Ph.D., has been named president and chief executive officer. Bankiewicz will work closely with Executive Director Laura Hameed and CCF's esteemed board of trustee members, the CCF Cures Cabinet, and scientific advisors.

Bankiewicz, founder of multiple biotech companies and tenured professor in the Department of Neurosurgery at The Ohio State University College of Medicine, has been instrumental in the organization's success by developing and delivering multiple life-changing treatments as a CCF founding trustee.

According to CCF Chairman and Chief Science Officer R. Jude Samulski, "Dr. Bankiewicz has been quietly focused on bringing life-saving medicines to children that have shown tremendous therapeutic outcomes. He is a remarkable talent with a sincere focus on using his expertise to change the lives of children with significant unmet medical needs. We're thrilled to see someone with his mindset, expertise, and experience join us in this leadership role. Our organizational mission is aimed at ensuring no children are left behind when science can put cures in reach and Krystof will be a key player in effectuating that mission."

In this new role, Bankiewicz will orchestrate CCF's unique non-profit model for conducting translational research and developing pre-clinical and clinical novel therapeutic programs to advance treatments for children with ultra-rare, and often debilitating, genetic disorders.

"The significant impact Dr. Bankiewicz has had on the field of neuro-restorative medicine and gene therapy raises the Foundation's standing and its ability to accelerate curative solutions will help children around the globe," said Hameed. "Additionally, this innovative approach has the potential to change the market through developing cures while also ensuring equitable and affordable access for treatments. Access to cures without affordability creates tragic equity and access issues and I am thrilled that he has chosen to advance treatments using this innovative model. This approach brings out the best in science and humanity."

"In a world where economics do not add up for large biotech or pharmaceutical organizations to develop genetic medicine for smaller populations of children with ultra-rare conditions, by accelerating these programs in this manner, we can bring the focus needed to give these kids and their families a chance at life," said Bankiewicz. "Achieving the astounding results we are seeing in children who have already been treated and joining the Foundation to expand this impact is one of the most rewarding opportunities of my career. I look forward to doing my part to make a difference in children's lives and advance the ability to impact advancement in gene therapy more broadly."

Recognized in the medical community for groundbreaking accomplishments treating Parkinson's Disease and other conditions affecting the central nervous system, Dr. Bankiewicz pioneered delivery of gene therapeutics directly to the brain to treat neurological disorders. Among his many achievements as an industry and academic leader, he co-founded three companies, invented numerous medical patents and is author to more than 230 peer-reviewed research articles. Bankiewicz is a tenured professor of neurosurgery and Gilbert and Kathryn Mitchell Endowed Chair at The Ohio State University College of Medicine. Prior to that, he served as Kinetics Foundation chair in translational research and tenured professor in residence of neurological surgery and neurology at the University of California San Francisco.

Bankiewicz earned an M.D. from Jagiellonian University in Krakow, Poland, and a Ph.D., D.Sc., from the Institute of Neurology and Psychiatry in Warsaw. He also trained at National Institutes of Health in Bethesda, MD.

About Columbus Children's FoundationFounded in 2017, the Columbus Children's Foundation is a 501(c)3 non-profit in Chapel Hill, N.C. As one of the leading nonprofit biotech organizations, its mission is to help children diagnosed with ultra-rare genetic diseases. The Foundation has a global footprint with a sister Foundation located in Spain. Columbus Children's Foundation is focused on ultra-rare diseases that have lagged behind due to their small populations. Because the pharmaceutical industry tends to focus on more common illnesses with greater commercial potential, ultra-rare diseases are often overlooked, prompting the need for funding from outside the industry and a new model for advancement. The Columbus Children's Foundation also helps ensure that children with such disorders can participate in clinical trials or receive therapy if their families can't afford travel and related costs. For more information, visit the Columbus Children's Foundation or call (612) 437-8836.

Media Contact:Mark Rosenberg[emailprotected](919) 412-7378

SOURCE Columbus Children's Foundation

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Dr. Krystof Bankiewicz--World-Renowned Neurosurgeon and Genetic Medicine Expert--Named President and Chief Executive Officer, Columbus Children's...