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BOSTON - By analyzing tumors from patients treated with immunotherapy for advanced kidney cancer in three clinical trials, Dana-Farber Cancer Institute scientists have identified several features of the tumors that influence their response to immune checkpoint inhibitor drugs.

The research was presented during the Clinical Science Symposium at the American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in Nature Medicine. The researchers say the study provides important clues about kidney cancer genetics and its interaction with the immune system that may prove to be vital in our ability to predict which patients are likely to benefit from immunotherapy drugs, which have been approved for first- and second-line treatment in the disease, but which don't work in all patients. The study showed that features that are typically linked to immunotherapy response or resistance in other types of cancer don't work the same way in advanced clear cell renal cell cancer (ccRCC).

"Kidney cancer breaks all those rules," said David Braun, MD, PhD, a Dana-Farber kidney cancer specialist and first author of the report. Co-senior authors are Toni Choueiri, MD, Catherine J. Wu, MD, Sachet A. Shukla, PhD, and Sabina Signoretti, MD all of Dana-Farber. Other authors are from the Broad Institute of MIT and Harvard, Bristol Myers Squibb, and Brigham and Women's Hospital.

Clear cell renal cell cancer is the most common form of kidney cancer. There are about 74,000 new cases of kidney cancer in the United States each year, and about 15,000 deaths. Checkpoint inhibitor immunotherapy drugs such as pembrolizumab (Keytruda) and nivolumab (Opdivo) used in advanced kidney cancer work by blocking PD-1, a protein on immune T cells that normally keep these cells from attacking other cells in the body. By blocking PD-1, these drugs boost the immune response against kidney cancer cells.

PD-1 checkpoint inhibitors have brought a powerful new weapon to bear on advanced kidney cancer, which generally doesn't respond to standard chemotherapy. In cancers such as melanoma and lung cancer, checkpoint inhibitors - drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) - tend to be more effective against tumors with a "high mutational burden," that is, their DNA is riddled with many mutations. Advanced clear cell renal cell cancer, by contrast, has a moderate number of mutations yet is relatively responsive to checkpoint inhibitors - and scientists don't know why that is. Another puzzling difference is that in melanoma and some other cancers, tumors that are infiltrated with large numbers of immune CD8 T cells, creating what's termed an inflamed or "hot" environment within the tumor, respond better to PD-1 blockade. But the reverse is true in advanced kidney cancer - high infiltration by CD8 T cells is associated with a worse outcome.

In this study, the scientists analyzed 592 tumors collected from patients with advanced kidney cancer who were enrolled in clinical trials of PD-1 blocking drugs. They used whole-exome and RNA sequencing and other methods to uncover the genomic changes and other factors that were associated with how the patients' tumors responded to the drugs - specifically, the patients' progression-free survival and overall survival.

The study was aimed at determining what features of advanced kidney cancer cells were associated with their response or resistance to PD-1 inhibitors. In analyzing the tumors from advanced ccRCC patients treated with PD-1 inhibitors, the investigators looked for biomarkers - genetic changes, mutations, copy number alterations, and so forth - in the genomes of the kidney cancer cells that might be correlated with patient outcomes - such as progression-free survival and overall survival.

Braun said that some of the most interesting findings were characteristics of the kidney tumors that - unlike with other types of cancer - did not influence responsiveness to PD-1 inhibitor drugs. For example, tumors containing a large number of neoantigens - proteins made by cancer-related DNA mutations that may make the tumors more responsive to immunotherapy, but this proved not to be true of the kidney tumors. Also, even though the kidney tumors were heavily infiltrated by CD8 immune T cells - which causes other kinds of cancer to provoke a strong immune attack against the tumors - this actually led to no difference in outcome for these kidney cancer patients. "To our surprise, the immunologically 'hot' tumors did not respond any better than the 'cold' tumors," said Braun.

Another factor that affects responsiveness in some types of cancer - the specific HLA molecules inherited by individuals that present antigens to the immune system - didn't affect the immune response to advanced kidney tumors. "That surprised us," said Dr. Wu, chief of Division of Stem Cell Transplantation and Cellular Therapies. "We reasonably hypothesized that the potential of the patient's immune system to present and react to a greater diversity of antigens may be associated with better outcomes, but clearly kidney cancer does not fit the standard mold," noted Wu.

"However, we did uncover some factors that may explain the unexpected observations," said Dr. Shukla who leads the computational group at the Dana-Farber Translational Immunogenomics Laboratory. The study uncovered that advanced kidney tumors heavily infiltrated with CD8 T cells did not respond well to immune checkpoint blockers even though they were immunologically "hot" tumors. The scientists, with their comprehensive analysis of changes in the kidney tumors' genomes, found that the tumors were depleted of mutated PBRM1 genes - which are correlated with improved survival with PD-1 blockade therapy - and also had an abundance of deletions of a chromosomal segment known as 9p21.3, which is associated with worse outcomes with PD-1 blockade. "We believe that these two factors may explain why CD8 T cell infiltration of the tumors did not make them responsive to checkpoint blocker therapy," explained Shukla, "while other types of cancer that exhibited CD8 T cell infiltration but did not have those chromosomal changes did respond."

"Our work highlights the importance of integrating genomic data with immunopathologic data generated through painstaking review by expert pathologists," said Dr. Signoretti, professor of pathology at Harvard Medical School. "Our findings reveal that interactions between immune T cell infiltration and alterations in the tumor DNA (such as inactivation of the PBRM1 gene and the abundance of 9p21.3 deletions) can be important influences on tumors' response to PD-1 blockade - perhaps not only in kidney cancer but in other types of tumors as well."

"The current study provides critical insights into immunogenomic mechanisms contributing to response and resistance to immunotherapy in clear cell renal cell cancer," said Dr. Choueiri, director of the Lank Center for Genitourinary Oncology and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. "The detailed clinical, genomic, transcriptomic, and immunopathology data produced by this study will serve as a valuable resource for the cancer immunology community. This work, therefore, will be important for ongoing research in precision medicine and immuno-oncology, helping to identify which patients are likely to respond to current therapies, and providing fundamental information to aid in development of rational combination therapies to overcome resistance in the future."

"One notable thing," said Choueiri, "is the collaboration between multiple disciplines and stakeholders: Immunology, pathology, genetics, computational and clinical expertise all converged on one tumor, while involving academic and industry stakeholders."

What The Study Did: A systematic assessment of deep vein thrombosis among patients in an intensive care unit in France with severe COVID-19 is reported in this case series.

Authors: Tristan Morichau-Beauchant, M.D., of the Centre Cardiologique du Nord in Saint-Denis, France, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.10478)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

Scientists from the University of Maryland School of Medicine (UMSOM) developed an experimental diagnostic test for COVID-19 that can visually detect the presence of the virus in 10 minutes. It uses a simple assay containing plasmonic gold nanoparticles to detect a color change when the virus is present. The test does not require the use of any advanced laboratory techniques, such as those commonly used to amplify DNA, for analysis. The authors published their work last week in the American Chemical Society's nanotechnology journal ACS Nano.

"Based on our preliminary results, we believe this promising new test may detect RNA material from the virus as early as the first day of infection. Additional studies are needed, however, to confirm whether this is indeed the case," said study leader Dipanjan Pan, PhD, Professor of Diagnostic Radiology and Nuclear Medicine and Pediatrics at the UMSOM.

Once a nasal swab or saliva sample is obtained from a patient, the RNA is extracted from the sample via a simple process that takes about 10 minutes. The test uses a highly specific molecule attached to the gold nanoparticles to detect a particular protein. This protein is part of the genetic sequence that is unique to the novel coronavirus. When the biosensor binds to the virus's gene sequence, the gold nanoparticles respond by turning the liquid reagent from purple to blue.

"The accuracy of any COVID-19 test is based on being able to reliably detect any virus. This means it does not give a false negative result if the virus actually is present, nor a false positive result if the virus is not present," said Dr. Pan. "Many of the diagnostic tests currently on the market cannot detect the virus until several days after infection. For this reason, they have a significant rate of false negative results."

Dr. Pan created a company called VitruVian Bio to develop the test for commercial application. He plans to have a pre-submission meeting with the U.S. Food and Drug Administration (FDA) within the next month to discuss requirements for getting an emergency use authorization for the test. New FDA policy allows for the marketing of COVID-19 tests without requiring them to go through the usual approval or clearance process. These tests do, however, need to meet certain validation testing requirements to ensure that they provide reliable results.

"This RNA-based test appears to be very promising in terms of detecting the virus. The innovative approach provides results without the need for a sophisticated laboratory facility," said study co-author Matthew Frieman, PhD, Associate Professor of Microbiology and Immunology at UMSOM.

Although more clinical studies are warranted, this test could be far less expensive to produce and process than a standard COVID-19 lab test; it does not require laboratory equipment or trained personnel to run the test and analyze the results. If this new test meets FDA expectations, it could potentially be used in daycare centers, nursing homes, college campuses, and work places as a surveillance technique to monitor any resurgence of infections.

In Dr. Pan's laboratory, research scientist Parikshit Moitra, PhD, and UMSOM research fellow Maha Alafeef conducted the studies along with research fellow Ketan Dighe from UMBC.

Dr. Pan holds a joint appointment with the College of Engineering at the University of Maryland Baltimore County and is also a faculty member of the Center for Blood Oxygen Transport and Hemostasis (CBOTH).

"This is another example of how our faculty is driving innovation to fulfill a vital need to expand the capacity of COVID-19 testing," said Dean E. Albert Reece, MD, PhD, MBA, who is also Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor, University of Maryland School of Medicine. "Our nation will be relying on inexpensive, rapid tests that can be dispersed widely and used often until we have effective vaccines against this pandemic."

Plasmodium vivax is the most widespread malaria parasite worldwide, with up to two billion people at risk of infection. As well as causing illness and death in its 'active' stage of infection, the parasite can hide as hypnozoites, a dormant stage, in the liver, and is a significant cause of 'relapsing' malaria.

These hypnozoites, undetectable with current diagnostics, can be responsible for >80% of all blood-stage infections. Identifying and targeting individuals with hypnozoites is thus essential for accelerating and achieving malaria elimination. A major gap in the P. vivax elimination toolkit is the identification of individuals carrying clinically silent and undetectable hypnozoites.

This study developed a panel of serological exposure markers capable of classifying individuals with P. vivax infections within the previous 9 months who have a high likelihood of harboring hypnozoites. 1) We measured IgG antibody responses with the AlphaScreen system to 342 P. vivax proteins expressed by a wheat germ cell-free system, invented at Ehime University, in longitudinal clinical cohorts conducted in Thailand and Brazil and identified 60 candidate serological markers of exposure. 2) Candidate markers were validated using samples from year-long observational cohorts conducted in Thailand, Brazil and the Solomon Islands and antibody responses to eight P. vivax proteins classified P. vivax infections in the previous 9 months with 80% sensitivity and specificity. Mathematical models demonstrate that a serological testing and treatment strategy could reduce P. vivax prevalence by 59-69%.

These eight antibody responses can serve as a biomarker, identifying individuals who should be targeted with anti-hypnozoite therapy. The test offers new opportunities for improving malaria control and elimination strategies.

ABSTRACT: #109

HOUSTON -- The targeted therapy pralsetinib appears to have high response rates and durable activity in patients with a broad variety of tumors harboring RET gene fusions, according to results from the international Phase I/II ARROW trial, led by researchers at The University of Texas MD Anderson Cancer Center.

In patients with RET fusion-positive thyroid cancers, pralsetinib achieved an overall response rate (ORR), indicating tumor shrinkage, of 91% and disease control rate (DCR), indicating tumor shrinkage or stable disease, of 100%. For all other tumor types included in the cohort, pralsetinib resulted in a 50% ORR and 92% DCR.

Trial data were shared in an oral presentation at the 2020 American Society of Clinical Oncology Annual Meeting by principal investigator Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics.

"This trial shows that pralsetinib has broad and durable anti-tumor activity across multiple advanced solid tumor types, giving it the potential to address an unmet medical need for patients with RET fusion-positive cancers," said Subbiah. "The recent tumor-agnostic drug approvals have resulted in a paradigm shift in cancer treatment, away from organ-histology specific indications to a biomarker-guided, tumor-agnostic approach. However, until recently, we haven't had any effective targeted therapies targeting RET alterations."

RET fusions occur when a portion of the chromosome containing the RET gene breaks off and joins with a gene on another chromosome, creating a fusion protein capable of fueling cancer development. RET alterations are most common in medullary thyroid cancers (approximately 90% of advanced cases), papillary thyroid cancers (approximately 10-20% of cases) and non-small cell lung cancers (approximately 1-2% of cases).

The presentation included data for 13 patients with RET fusion-positive thyroid cancers and 14 patients with other RET fusion-positive cancers, including pancreatic cancer, cholangiocarcinoma, ovarian cancer, colon cancer and others. Nearly all patients had stage IV disease and had progressed or relapsed on available standard therapies.

Among those patients with RET fusion-positive thyroid cancers, the duration of treatment ranged from three to 22 months, and 70% of responding patients remain on therapy

In other RET fusion-positive cancers, all patients with pancreatic cancer (3) and cholangiocarcinoma (2) in the trial had a partial response from treatment. The duration of treatment ranged from two to 21 months, and 67% of responding patients remain on therapy.

Further, treatment with pralsetinib was well-tolerated across all patients in the cohort, explained Subbiah. "Pralsetinib was consistently safe across the overall population, and the majority of adverse events were low-grade. None of the patients in the basket cohort discontinued therapy due to treatment-related adverse events."

Additional cohorts of the ARROW trial focus on patients with RET fusion-positive non-small cell lung cancers and RET-mutant medullary thyroid cancer. Data from the non-small cell lung cancer cohort, indicating an ORR of 65% and DCR of 93%, also were presented in a poster discussion at the ASCO Annual Meeting. Results from the non-small cell lung cancer cohorts have been submitted to the U.S. Food and Drug Administration for approval of pralsetinib in these patients

"This study stresses the importance of considering genomic testing for all patients regardless of tumor histology, so we can identify those that may benefit from targeted therapies such as pralsetinib," said Subbiah. "It's encouraging to be able to offer effective options to these patients and give them the gift of time."

Results of an Electronic Health Record (EHR) study assessing the most commonly used medications for raising blood pressure in patients with nontraumatic subarachnoid hemorrhage (SAH), a rare type of stroke, have been published in Neurosurgical Focus by scientists at The University of Texas Health Science Center at Houston (UTHealth).

A nontraumatic SAH causes bleeding in the area between the brain and tissue that covers the brain, called the subarachnoid space. Often caused by a ruptured brain aneurysm, this type of stroke can also be linked to malformations in the arteries and veins. Women account for over half (63.9%) of reported cases of nontraumatic SAH. If a patient survives the initial bleeding, they often experience restricted blood flow to the brain, which can lead to death in 40% of patients. In addition, 50% of those who survive have some degree of brain impairment. No clear clinical guidelines currently exist to provide doctors with an optimal drug choice to raise blood pressure in these patients.

"Nontraumatic subarachnoid hemorrhage is a potentially devastating condition with a high death rate," said Hulin Wu, PhD, the study's senior author and the Betty Wheless Trotter Professor and chair in the Department of Biostatistics and Data Science at UTHealth School of Public Health. Wu also holds a joint appointment as a professor at UTHealth School of Biomedical Informatics. "Our research goal was to use EHR data to understand which drug is better for reducing the death rate for these patients."

The research team extracted the data from a nationwide EHR database on three common vasopressors - dopamine, norepinephrine, and phenylephrine- which are commonly administered after a nontraumatic SAH in order to increase the patient's blood pressure and maintain the necessary pressure for blood flow in the brain.

The research team identified 2,634 patients who suffered a nontraumatic SAH at 200 hospitals over 14 years. Of those, 559 (21.2%) were treated with dopamine; 1,342 (50.9%) with phenylephrine; and 733 (27.8%) with nonrepinephrine. Of the 2,634 participants, 59.8% survived and were discharged from the hospital, and 36.5% either died in the hospital or were transferred to hospice care. Another 3.7% had unknown mortality status.

The data revealed that patients who received phenylephrine as the first vasopressor treatment had a mortality rate of 24.5%, while the rates for patients receiving dopamine and norepinephrine were 50.6% and 47.6% respectively. The data also indicated that the decreased mortality rate for phenylephrine held true even when the patient had acute comorbidities such as a heart attack, renal failure, or sepsis.

Previous research on phenylephrine suggested that it was not the optimal vasopressor choice to treat SAH and was associated with worse outcomes. While dopamine and norepinephrine have been recognized as more potent options, they can lead to complications associated with excessively high blood pressure, the researchers noted.

"Doctors have multiple vasopressor options to choose from to treat this disease, but until now there weren't studies to reference in actively comparing the choices and weighing the consequences of each treatment option," said George Williams, MD, the study's first author and an associate professor of critical care medicine in the Department of Anesthesiology at McGovern Medical School at UTHealth.

While the results from this study are based on observational data, future clinical trials could further evaluate the findings of this study and confirm if phenylephrine is the optimal treatment for nontraumatic SAH.

ABSTRACT: #102

HOUSTON -- The adoptive T-cell therapy ADP-A2M4, which is engineered to express a T-cell receptor (TCR) directed against the MAGE-A4 cancer antigen, achieved responses in patients with multiple solid tumor types, including synovial sarcoma, head and neck cancer and lung cancer, according to results from a Phase I clinical trial led by researchers at The University of Texas MD Anderson Cancer Center.

Among 38 patients treated on the trial, the ADP-A2M4 T cells resulted in overall response (OR), or tumor shrinkage, in 9 patients (23.7%) and stable disease in 18 patients (47.4%). Trial data were shared in an oral presentation at the 2020 American Society of Clinical Oncology Annual Meeting by principal investigator David Hong, M.D., professor of Investigational Cancer Therapeutics.

"Thus far, we haven't seen strong responses in treating solid tumors with available cellular therapies, in large part because antigens expressed are not restricted to the tumors," said Hong. "In this trial, I've been encouraged to see durable responses in several patients, and the results suggest there is potential for this emerging TCR-based technology for treating solid tumors."

Adoptive cellular therapy is a form of immunotherapy that modifies immune cells to be more effective in mounting an immune response against cancer. For ADP-A2M4, T cells are isolated from patients and engineered to express a TCR targeting MAGE-A4, a protein normally expressed only in the testis but present in certain cancers.

Unlike chimeric antigen receptor (CAR)-modified T cells, which target surface proteins on cancer cells, TCR T-cell therapies are able to target proteins normally found inside the cell by recognizing protein fragments bound to immune-related proteins on the cell surface.

The Phase I trial was designed as a dose-escalation study to assess the safety, tolerability and antitumor activity of ADP-A2M4 in patients with advanced solid tumors with expression of the MAGE-A4 protein. Patients on the trial included those with synovial sarcoma, ovarian cancer, head and neck cancer, gastric cancer, myxoid/round cell liposarcoma, non-small cell lung cancer, bladder cancer, esophageal cancer and melanoma. Participants had a median of three prior lines of systemic therapy.

The therapy achieved strong responses in particular groups of patients in the trial. Patients with synovial sarcoma saw a 43.8% OR rate and a disease control rate of more than 90%. There also was an additional patient with an unconfirmed response after the data cut-off. Median duration of response in these patients was 28 weeks and median progression-free survival was 20 weeks. Confirmed responses were also seen in patients with lung cancer and head and neck cancer.

Most patients (97.4%) experienced some treatment-related adverse events, with the most common being low blood cell counts (lymphopenia, leukopenia, neutropenia, anemia and thrombocytopenia). Half of patients experienced cytokine release syndrome. Two patients had trial-related deaths, which led to modification of the lymphodepletion regimen and eligibility criteria.

"The side effects seen on the trial were largely consistent with those typically experienced by cancer patients undergoing lymphodepleting chemotherapy and cellular therapy," said Hong. "This study is a nice proof of concept for treating solid tumors and suggests there could be a role for cellular therapies in these indications going forward."

This research is part of an ongoing strategic alliance between MD Anderson and Adaptimmune, designed to expedite the development of novel T-cell therapies for multiple cancer types. Translational research and analyses of related biomarkers continues. Results from this study led to a low-dose radiation sub-study, a Phase II trial of ADP-A2M4 in sarcoma and a Phase I trial of Adaptimmune's next-generation T-cell therapy targeting MAGE-A4, ADP-A2M4CD8.

This study was funded by Adaptimmune. A full list of co-authors and their disclosures can be found here.

Results of the NRG Oncology clinical trial RTOG 1010 indicated that the addition of the monoclonal antibody trastuzumab to neoadjuvant trimodality treatment did not improve disease-free survival (DFS) outcomes for patient with HER2 overexpressing local and locally advanced esophageal adenocarcinoma. These results were recently, orally presented during the virtual Annual Meeting of the American Society for Clinical Oncology.

The Phase III NRG-RTOG 1010 trial evaluated 203 HER2 positive patients with a median follow up of 5 years. The primary aim of the trial was to determine if the addition of trastuzumab could improve DFS when combined with trimodality treatment of chemotherapy, radiotherapy, and surgery for patients who have newly diagnosed esophageal cancer with HER2 overexpression. Patients on the trial had stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving mid, distal, or esophagogastric junction and up to 5 centimeters of the stomach.

Trial participants were randomly assigned to trimodality standard of care with or without trastuzumab.Participants on the standard of care arm received chemotherapy, consisting of paclitaxel and carboplatin weekly, for 6 weeks with radiotherapy (CXRT) then followed by surgery. Participants on the experimental treatment arm received weekly trastuzumab during CXRT and then every 3 weeks following surgery for 13 treatments.

Patients were evaluated for disease every 4 months for 2 years and then annually. DFS rates (95% CI) for patients on the CXRT plus trastuzumab (CXRT+T) treatment arm were 41.8% (31.8%, 51.7%) at 2 years, 34.3% (24.7%, 43.9%) at 3 years, and 33.1% (23.6%, 42.7%) at 4 years. DFS for patients on the CXRT alone arm were 40% (30.0%, 49.9%) at 2 years, 33.4% (23.8%, 43.0%) at 3 years, and 30.1% (20.7%, 39.4%)at 4 years, log-rank p=0.85. The median DFS time DFS in the CXRT+T arm was 19.6 months compared to 14.2 months in the CXRT alone arm. The hazard ratio (95% CI) comparing the DFS of CXRT+T arm to the CXRT alone arm was 0.97 (0.69, 1.36) and there were no statistically significant differences in treatment-related toxicity between arms.

"The strength of the National Cancer Institute's National Clinical Trials Network system was highlighted in this trial, as accrual of this HER2 overexpressing population was successfully completed as projected, allowing this important question to be answered. We will be performing genomic analysis to determine if there was a subset of patients who may still benefit from from the addition of trastuzumab to trimodality therapy in HER2 over expressing esophageal cancer," stated Howard Safran, MD, of The Rhode Island Hospital and Brown University, the lead author of the NRG-RTOG 1010 abstract.

Results of the NRG Oncology phase III clinical trial NRG-GY004 indicated that the addition of the investigational agent cediranib to olaparib and standard platinum-based chemotherapy did not improve progression-free survival (PFS) outcomes for women with platinum-sensitive ovarian cancer;, however, activity between the treatments were similar in patients. These results were recently presented at the virtual Annual Meeting of the American Society of Clinical Oncology (ASCO).

NRG-GY004 was designed to expand upon the findings of a phase II trial that indicated a combination of cediranib and olaparib improved PFS outcomes compared to olaparib alone for women with platinum-sensitive, high-grade serous/endometrioid ovarian cancer, regardless if they had a BRCA mutation. On NRG-GY004, women were randomly assigned to one of three treatment regimens. Participants randomly assigned to the first treatment arm received the standard of care chemotherapy chemotherapy with either carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated lipsomal doxorubicin. The participants on the experimental treatment arms either received olaparib at 300mg twice a day or olaparib at 200mg twice a day with cediranib at 30mg twice a day. The primary endpoint of this study was to assess PFS of cediranib and olaparib treatment compared to chemotherapy for women with platinum-sensitive ovarian cancer.

Between March 2016 and June 2018, 565 patients had enrolled in NRG-GY004 and, of those patients, 528 initiated treatment: 23.7% of the patients had a germline BRCA mutation. At a median follow-up of 29.1 months, the hazard ratio for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) for the combination of cediranib and olaparib compared to chemotherapy treatment. The hazard ratio for PFS was 1.20 (95% CI 0.93-1.54) for olaparib alone compared to chemotherapy treatment. Median PFS for patients was 10.3 months for the standard of care chemotherapy, 8.2 months for olaparib alone, and 10.4 months for patients receiving combination cediranib and olaparib. In a predefined biomarker subset analysis of women with a germline BRCA mutation, the PFS hazard ratio was 0.55 (95% CI 0.73-1.30) for combined cediranib and olaparib compared to chemotherapy and 0.63 (95% CI 0.37-1.07) for olaparib alone versus the standard chemotherapy. In women without a germline BRCA mutation, the PFS hazard ratio was 0.97 (95% CI 0.73-1.30) for combined cediranib and olaparib compared to chemotherapy and 1.41 (1.07-1.86) for olaparib alone versus standard chemotherapy.

"This is the first Phase 3 trial comparing a completely oral non platinum-based therapy regimen to standard of care platinum-based chemotherapy in platinum-sensitive ovarian cancer. While the combination of cediranib and olaparib was not found to improve PFS compared to standard of care chemotherapy, the findings of this study suggest that non-platinum based alternatives have potential in this setting, especially in appropriate biomarker subgroups such as patients with BRCA mutations," stated Joyce Liu, MD, MPH, of the Dana-Farber Cancer Institute and the lead author of the NRG-GY004 abstract.

There were no overall survival differences between the treatment arms. Patients who received cediranib and olaparib in addition to the standard of care did experience a higher frequency of grade 3 or higher gastrointestinal, hypertension, and fatigue adverse events.

This study was supported by the National Cancer Institute grants U10CA180822 (NRG Oncology SDMC), U10CA180868 (NRG Oncology Operations), U24CA180803 (IROC), U24CA196067 (NRG Specimen Bank). , NRG-GY004 was sponsored by National Cancer Institute (NCI), part of the National Institutes of Health. AstraZeneca provided cediranib and olaparib to support the study through a Collaborative Research and Development Agreement with NCI. Olaparib is jointly developed and commercialized by AstraZeneca and Merck & Co. (Merck: known as MSD outside the US and Canada).

Scientific studies suggest that children with birth defects are at increased risk of cancer. However, it has not been assessed whether the type of cancer, the age at which they are diagnosed or the extent of cancer spread at the time of diagnosis, is different for children with birth defects compared to children without birth defects.

In this study led by Baylor College of Medicine and Texas Children's Hospital, researchers compared about 13,000 children with cancer but no birth defects with nearly 1,600 children with cancer and one or more birth defects. The results were published in the journal Cancer.

"We investigated 28 different types of cancer by analyzing data from population-based registries in four U.S. states. For eight cancer types, we saw differences in the frequencies of those cancers when comparing children with birth defects and children without," said first author Dr. Jeremy Schraw, instructor of pediatric oncology and part of the Center for Epidemiology and Population Health at Baylor.

The group of children with birth defects in this study did not include those with syndromes caused by chromosomal or single-gene alterations, such as Down syndrome or neurofibromatosis, whose increased cancer risk has been previously studied.

The researchers found that acute lymphoblastic leukemia (ALL), the most common childhood cancer in the general pediatric population (24.5 percent), constituted a smaller proportion of diagnoses (12.4 percent) in children with birth defects. On the other hand, among children with birth defects, larger proportions of tumors were of embryonic origin, including neuroblastoma (12.5 percent vs. 8.2 percent) and hepatoblastoma (5 percent vs. 1.3 percent).

Regarding the age of diagnosis, the researchers found that the majority of these cancers were diagnosed 1 to 2 years earlier in children with birth defects than in children without.

Schraw and his colleagues also looked at the stage of cancer at diagnosis to address the possibility that cancers were diagnosed earlier in children with birth defects a result of the children getting more medical attention due to their condition, and during checkups cancer was found incidentally. If this were the case, the researchers expected that cancers in children with birth defects would more often be at an earlier stage at diagnosis than cancers in the general pediatric population.

"When we looked at the cancer stage at diagnosis, we found that, for the most part, there was no trend toward earlier stage at diagnosis in children with birth defects," said Schraw, who also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "This suggests that increased medical surveillance alone does not explain the earlier age at diagnosis in children with birth defects."

"We hope that this research can inform future studies that will help us better understand cancer risk in children with birth defects," said corresponding author Dr. Philip Lupo, associate professor of pediatric hematology and oncology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. He also is the director of the Childhood Cancer Epidemiology and Prevention Program at Texas Children's Hospital. "However, it should be noted that while children with birth defects are more likely to develop cancer, their overall risk remains low."

"If we understand better the link between birth defects and cancer, we might be able to identify which of these children have a unique high risk of cancer and need surveillance," said co-author Dr. Sharon Plon, professor of pediatric oncology and of molecular and human genetics at Baylor. She also is a member of the Dan L Duncan Comprehensive Cancer Center.

Rochester Institute of Technology scientists have developed a method they believe will help epidemiologists more efficiently predict the spread of the COVID-19 pandemic. Their new study, published in Physica D: Nonlinear Phenomena, outlines a solution to the SIR epidemic model, which is commonly used to predict how many people are susceptible to, infected by, and recovered from viral epidemics.

The method was created by Nathaniel Barlow, associate professor in RIT's School of Mathematical Sciences, and Steven Weinstein, head of RIT's Department of Chemical Engineering. They say that by using this solution to the model, epidemiologists can quickly forecast many different scenarios of how COVID-19 could spread based on a variety of variables. Projections produced by mathematical models help public officials make policy decisions about when to impose and lift restrictions aimed at flattening the curve of infection rates.

The applied mathematicians who developed the method said they were excited to find a way to apply their skills to help combat the pandemic.

"I was at home thinking that I would like to somehow help with everything going on," said Barlow. "We saw a popular article out there about the SIR model, saw that our method could speed the process up and we quickly wrote the paper. Our goal was to get better tools to the experts who are fighting this disease."

The method was based on solutions they previously developed to very different problems in thermodynamics, fluid mechanics and predicting the trajectories of light around black holes. They have worked extensively with undergraduate students on those problems over the past six years and found that the solution to the SIR epidemic model had a very similar mathematical structure. Although the authors haven't previously worked in the field of epidemiology, their previous work translated seamlessly to this new field.

"Many times, that's what we as applied mathematicians do--work at the boundaries of fields where people are not typically talking," said Weinstein. "We serve an important function to provide algorithms to support scientific inquiry and prediction. The technique we have developed here is general to many different fields."

AURORA, Colo. (May 29, 2020) - Researchers at the University of Colorado College of Nursing and the School of Medicine Department of Anesthesiology at the Anschutz Medical Campus found that the use of nitrous oxide (N2O) as a pain relief option for individuals in labor is safe for newborn children and laboring individual, and converting to a different form of pain relief such as an epidural or opioid is influenced by a woman's prior birth history and other factors.

The study, out today in Journal of Midwifery & Women's Health, surveyed 463 women who used nitrous oxide during labor. The study is the largest and first of its kind in the United States to report rates of side effects from N2O use during labor, as well as reasons for women in labor after cesarean to convert to other forms of pain relief. Of the women who began using N2O as an initial pain relief technique, 31% used only N2O throughout labor and 69% transitioned to another pain relief method such as epidural and/or opioids. "Nitrous oxide is a useful, safe option for labor analgesia in the United States. And for some laboring mothers, that's all the pain relief they need. Understanding predictors of conversion from inhaled nitrous oxide to other forms of analgesia may assist providers in their discussions with women about pain relief options during labor," said lead author and Associate Professor with the University of Colorado College of Nursing Priscilla M. Nodine, PhD, CNM.

The reason most often cited (96%) for converting from N2O to an alternative therapy was inadequate pain relief. The odds of conversion from N2O increased approximately 3-fold when labor was augmented with oxytocin and when labor was induced. Also, those who had a history ofcesarean section and experienced labor post-cesarean had more than a 6-fold increased odds of conversion to neuraxial analgesia or epidural. The odds of conversion to neuraxial analgesia decreased by 63% for individuals who had given birth previously relative to those who were giving birth for the first time.

Approximately 4 million women in the United States give birth each year, and for many, coping with laborp is a significant concern. Epidurals and spinal blocks, also known as neuraxial analgesia, are the most frequently used pain management tools in the United States, with the main alternative being systemic opioids, which can be associated with both maternal and fetal adverse effects. Recently reintroduced as a pain relief option during labor in the United States, N2O has a long history of use in many developed nations and is increasingly available in the US. "While there is a fair body of anecdotal evidence of safety and effectiveness for how nitrous oxide affects pain during labor, few systematic analyses of outcomes are available from US-based cohorts," said Nodine.

People with cancer sickened by COVID-19 have a crude death rate of 13%, according to the largest series of data released thus far from a multinational perspective. The data on more than 900 patients, published May 28 in The Lancet, also revealed cancer-specific factors associated with increased mortality.

The information is the first report from an ongoing international initiative by the COVID-19 and Cancer Consortium (CCC19) to track outcomes within this vulnerable population. The CCC19 registry was built and is maintained as an electronic REDCap database housed at Vanderbilt University Medical Center.

"People with cancer face a great deal of uncertainty in the era of COVID-19, including whether the balance of risks and benefits in the treatment of cancer has shifted in some fundamental way," said Jeremy Warner, MD, MS, associate professor of Medicine and Biomedical Informatics at Vanderbilt University, the study's corresponding author. "The death rate for this group of patients as a whole was 13%, more than twice that reported for all patients with COVID-19 (by the Johns Hopkins Center for Systems Science and Engineering). Certain subgroups, such as patients with active (measurable) cancer and those with an impaired performance status, fared much, much worse."

The data in this first report from CCC19 was gathered from 928 patients in Spain, Canada and the United States.

"CCC19 has been a massive effort to accumulate clinically-relevant data on a large number of patients with COVID-19 infection," said Brian Rini, MD, Ingram Professor of Cancer Research and Chief of Clinical Trials at Vanderbilt-Ingram Cancer Center, one of the study's three senior authors. "This initial report defines some of the major risk factors and outcomes for certain patient subsets, and several other CCC19 projects are ongoing to further expand this knowledge with the goal to inform cancer patients and providers."

The other senior authors are Warner and Gary H. Lyman, MD, MPH, professor of Medicine-Oncology at the University of Washington.

These early data showed no statistical association between 30-day mortality and cancer treatments, suggesting that surgery, adjuvant chemotherapy and maintenance chemotherapy could continue during the pandemic with "extreme caution."

"While older patients and those with major comorbid conditions are at substantially increased risk of dying from COVID-19, our early findings are encouraging news for patients without major medical conditions who receive their cancer therapy within four weeks of their infection. However, more data are needed to reliably assess individual higher risk therapies," said Nicole Kuderer, MD, with the Advanced Cancer Research Group in Seattle, one of the study's lead authors.

The cancer-specific factors associated with increased mortality included having an ECOG performance status of two or worse. ECOG is a grading scale for measuring how cancer impacts a patient's daily living abilities. A score of two designates a patient who is capable of selfcare but unable to work and who is up and about more than 50% during waking hours. Another factor associated with increased mortality was an active cancer status, particularly progressive cancer. The mortality risk also increased with the number of comorbidities, such as hypertension or diabetes, particularly with two or more comorbidities. As is the case with the non-cancer population, mortality increased with age. Mortality was 6% for cancer patients younger than 65, 11% for those 65-74 and 25% for those older than 75. Males also had a higher death rate than females, 17% compared to 9%.

Up to now, women who present with a new diagnosis of breast cancer that is already in an advanced stage (stage IV) face an unanswered question about whether surgery and radiation to the tumor in the breast (local therapy) will prolong survival compared to the traditional treatment of systemic treatment alone. Data from the long-awaited E2108 randomized phase three trial show that the survival experience of the two treatments was the same; local therapy did not improve overall survival. The goal of the E2108 study was to determine whether surgery and radiation should become routine practice for patients with stage IV breast cancer and resolve conflicting data from two earlier randomized trials.

The American Society of Clinical Oncology (ASCO) will highlight the data during the plenary session of its annual meeting to occur virtually from May 29-31 (Abstract LBA2). The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) designed and led this trial, which was conducted in the NCI National Clinical Trials Network (NCTN) with funding from the National Cancer Institute, part of the National Institutes of Health.

"Based on the results of our study, women who present with a new diagnosis of breast cancer already in stage IV should not be offered surgery and radiation for the primary breast tumor with the expectation of a survival benefit," said lead investigator Seema A Khan, MD (Northwestern University). "When making these decisions, it is important to focus energy and resources on proven therapies that can prolong life."

About one in every 20 women diagnosed with breast cancer in the United States each year present with cancer that has already spread beyond the breast to other organs (also called stage IV, advanced, metastatic, or distant breast cancer). Patients with stage IV breast cancer usually receive systemic treatment--drugs that travel through the bloodstream and treat disease throughout the body. Examples of systemic treatments are: chemotherapy to attack cells that grow quickly, targeted therapy that attacks specific proteins on cancer cells, hormonal therapy that either blocks or decreases the level of the body's natural hormones, which sometimes act to promote cancer growth, and, immunotherapy to stimulate the patient's immune system to attack the cancer.

Traditionally, it was thought that because metastases had occurred, local therapy would not provide any additional survival benefit beyond what systemic treatment could offer. Starting about 20 years ago, this approach was questioned based on the idea that the primary tumor could be a source of re-seeding of cancer outside the breast. Several studies suggested that removal of the tumor in the breast with surgery would be beneficial. However, these studies were flawed because women receiving surgery tended to be younger, healthier, and have less severe disease. It became clear that a clinical trial was needed to provide women and their doctors with good information. Further complicating matters, two randomized clinical trials published in the last five years had conflicting results.

In E2108, 390 women with stage IV breast cancer were enrolled. All received the optimal systemic treatment for them based on the number of other organ systems involved and tumor biomarker status. Of those whose disease responded to initial systemic therapy, or stayed stable, 256 women agreed to be randomized to either continue with systemic therapy or to receive surgery and radiation (local therapy) and then continue on with systemic treatment.

The main goal of the E2108 trial was to see if the use of local therapy to the breast tumor would improve survival. The results show that the survival experience of the two groups was identical (half of them alive after 4.5 years).

"When combined with the results of an earlier trial in Mumbai, India (Badwe et al, Lancet Oncol 2015), these results tip the scales against the possibility that local therapy to the breast tumor will help women live longer," said Dr. Khan. "The Indian trial had a similar design to E2108, and also showed similar results between the two treatment groups."

The E2108 trial also compared patient-reported quality of life (depression, anxiety, and well-being for example) between the two groups. It found that there was no quality of life advantage in the group of women who received local therapy to the breast tumor.

"This result was a little surprising since one of the reasons for considering surgery and radiation is the idea that growth of the tumor will impair quality of life," said Dr. Khan. "Instead, we find that the adverse effects of surgery and radiation appear to balance out the gains in quality of life that were achieved with better control of the primary tumor."

"ECOG-ACRIN also conducted TAILORx to help women and their physicians avoid unnecessary chemotherapy treatment and its toxicity for those diagnosed with early stage, hormone receptor positive disease," said ECOG-ACRIN Breast Cancer Committee Chair Antonio C. Wolff, MD (Johns Hopkins University). "Trials like TAILORx, and now E2108, help ECOG-ACRIN, in a partnership with the National Cancer Institute and investigators all over the world, fulfill our mission to identify the best treatments for an individual patient and maximize quality of life."

The benefit of population-based PSA screening for men with an average risk of prostate cancer does not outweigh the harm caused. This is the conclusion drawn by the Institute for Quality and Efficiency in Health Care (IQWiG) in its final report after evaluating the worldwide evidence from studies on the topic. While screening using a PSA test benefits some men by preventing or delaying metastatic prostate cancer, at the same time, however, considerably more men are at risk to become permanently incontinent or impotent due to overdiagnosis and subsequent overtreatment - and this at a relatively young age.

At the hearing on the preliminary report, IQWiG discussed in detail with participants whether and how the harm from PSA screening could be reduced using risk-adapted screening strategies without simultaneously reducing the benefit. IQWiG's Director Jürgen Windeler emphasizes "Measures such as restricting biopsies to men at high risk of progression or using new biopsy methods are promising approaches to improve the benefit-harm ratio of PSA screening in the long term. However, there are currently no studies to prove this." Therefore, the overall assessment of PSA screening remained unchanged in IQWiG's final report.

The most common type of cancer in men

Prostate cancer is the most common cancer in men in Germany, accounting for 23 percent of all new cancer cases and causing approximately 14,000 deaths per year.

The aim of screening is to detect prostate cancer with a high risk of progression at an early stage in order to cure the disease. Two screening tests are currently used: the digital-rectal examination and the test for prostate-specific antigen (PSA). The former is part of the screening programme offered by statutory health insurance for men aged 45 and older, the PSA test is not.

The IQWiG benefit assessment now available is based on the analysis of 11 randomized controlled trials with more than 400,000 participants worldwide. All of these studies compare prostate cancer screening using the PSA test with no screening for prostate cancer.

More harm than benefit in the overall balance

After evaluating the evidence, IQWiG concludes that prostate cancer screening using a PSA test benefits some men with prostate cancer by delaying or preventing metastatic cancer. This advantage only occurs after several years. Moreover, it is unclear whether screening leads to an increase in overall life expectancy in these men.

At the same time, PSA screening harms overdiagnosed men (men with prostate cancer not requiring treatment) and men with a false-positive screening test result (men without prostate cancer). The overdiagnosed men are at risk of treatment-related complications such as incontinence and impotence. Men with a false-positive result may experience harm in the form of a worrying test result that is followed by a prostate biopsy.

Overall, prostate cancer screening using a PSA test harms considerably more men through overdiagnosis than it benefits men through earlier diagnosis of the cancer. In summary, on the basis of the available studies IQWiG therefore concludes that the benefit of PSA screening does not outweigh the harm. The Institute is in good company with this careful consideration: worldwide, almost all national health authorities and professional societies recommend against population-based PSA screening.

Process of report production