tbuckley/cabot-search huggingface dataset:
A phase III, randomized, open-label, study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy (NHT) in patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Neeraj Agarwal, Arun Azad, Joan Carles, Simon Chowdhury, Bradley Alexander McGregor, Axel Stuart Merseburger, Stephane Oudard, Fred Saad, Andrey Soares, Ashok Panneerselvam, Fong Wang, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2021)

TPS190 Background: Cabozantinib inhibits multiple tyrosine kinases, including MET, VEGFR, RET, and TAM kinases (Tyro3, AXL, MER), involved in tumor growth and angiogenesis, and whose mutations and expression are associated with prostate cancer aggressiveness and poor prognosis. Targeting these kinases with cabozantinib may promote an immune permissive tumor environment and may enhance response to immune checkpoint inhibitors. In the ongoing phase 1b COSMIC-021 study of pts with solid tumors, cabozantinib plus the PD-L1 inhibitor atezolizumab, showed preliminary meaningful clinical activity in soft tissue disease and a tolerable safety profile for 44 pts with mCRPC (Agarwal et al., ASCO 2020; abstract 5564). We present the study design of a phase 3 trial of cabozantinib plus atezolizumab versus second NHT in pts with mCRPC. Methods: This randomized, open-label, controlled phase 3 study (NCT04446117) evaluates the efficacy and safety of cabozantinib plus atezolizumab versus second NHT (abiraterone or enzalutamide) in pts with mCRPC who previously received one NHT to treat metastatic castration-sensitive PC (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC. Additional eligibility criteria include histologically or cytologically confirmed adenocarcinoma of the prostate, measurable visceral disease or measurable extrapelvic adenopathy per RECIST 1.1 by investigator, prostate specific antigen progression and/or soft-tissue disease progression, ECOG 0 or 1, and age ≥18 years. Key exclusion criteria include prior nonhormonal therapy for mCRPC and uncontrolled significant illness. Eligible pts (N = 580) are randomized 1:1 to receive cabozantinib (40 mg PO QD) + atezolizumab (1200 mg IV Q3W) vs abiraterone (1000 mg PO QD) + prednisone (5 mg PO BID) or enzalutamide (160 mg PO QD). Designated NHT will differ from previous NHT taken. Randomization is stratified by: liver metastasis (yes, no), prior docetaxel treatment for mCSPC (yes, no), and disease stage for which the first NHT was given (mCSPC, M0 CRPC, mCRPC). Treatment will continue until there is no longer clinical benefit as determined by the treating investigator, unacceptable toxicity, or consent withdrawal. The multiple primary endpoints are progression-free survival per RECIST 1.1 by blinded independent radiology committee (BIRC) and overall survival. Additional endpoints include objective response rate per RECIST 1.1 by BIRC, safety, correlation of biomarkers with outcomes, quality of life and pharmacokinetics. Patient enrollment is ongoing. Clinical trial information: NCT04446117.
Abstract 13300: Prediction of Re-Hospitalization in Patients With Acute Decompensated Heart Failure by the Use of Cardiac Acoustic Biomarkers
Authors: Jun Shitara, Takatoshi Kasai, Shoichito Yatsu, Azusa Kurita, Hiroki Matsumoto, Masaru Hiki, Hiroyuki Daida
Journal: Circulation (2019)

Introduction: Cardiac acoustic biomarkers (CABs), which are acoustic and temporal metrics incorporating heart sounds and electrocardiographic signals, can be recorded noninvasively through the ches...
Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation
Authors: Yan Wang, Zunyun Fu, Xutong Li, Yinming Liang, Siyu Pei, Shumeng Hao, Qingchen Zhu, Tao Yu, Yifei Pei, Jia Yuan, Jialin Ye, Jiemeng Fu, Jing Xu, Jin Hong, Ruirui Yang, Hui Hou, Xinfang Huang, Chao Peng, Mingyue Zheng, Yichuan Xiao
Journal: Immunity (2021)
Durable Response to PD-1 Blockade in a Patient With Metastatic Pancreatic Undifferentiated Carcinoma With Osteoclast-Like Giant Cells
Authors: Robert J. Besaw, Adrienne R. Terra, Grace L. Malvar, Tobias R. Chapman, Lauren M. Hertan, Benjamin L. Schlechter
Journal: Journal of the National Comprehensive Cancer Network (2021)

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare and potentially aggressive variant of pancreatic ductal adenocarcinoma. Data on this disease are sparse, and despite genetic similarities to pancreatic ductal adenocarcinoma, UCOGC clinical outcomes can be markedly different. We report on a female patient aged 62 years who presented with UCOGC with pulmonary metastases initially treated with 2 lines of cytotoxic chemotherapy. After rapid disease progression with both cytotoxic treatments, the patient’s tissue was sent for next-generation sequencing, which revealed a high tumor mutation burden (32 mutations per megabase), as well as somatic mutations in BRAF , NF1 , PIK3CA , CDKN2A , TERT , and TP53. Pancreatic cancers have previously demonstrated suboptimal responses to immunotherapeutic approaches. However, given the high tumor mutation burden and distinctiveness of the tumor class, the patient began third-line pembrolizumab monotherapy after palliative radiation to the rapidly progressing and painful abdominal mass from her primary tumor. She had a marked response in her primary UCOGC tumor and metastatic sites, and she remains on pembrolizumab monotherapy with ongoing response after 32 months of therapy. Recent evidence showing significant PD-L1 enrichment on neoplastic cells of undifferentiated carcinomas (including UCOGC) may indicate a role for immunotherapeutic approaches in these patients. Rare cancers such as UCOGC and other undifferentiated carcinomas may benefit from next-generation sequencing to inform treatment decisions when standards of care are absent, as in this report.
ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.
Authors: Ellen Jaeger, Elisa Marie Ledet, Marcus W. Moses, Charlotte Manogue, Brian E. Lewis, Jodi Lyn Layton, Pedro C. Barata, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2021)

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had &gt; 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of &gt; 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction &gt; 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.
Cost of community-based human papillomavirus self-sampling in Peru: a micro-costing study
Authors: Michelle B Shin, José L Fiestas, Enrique M Saldarriaga, Ruanne V Barnabas, Sarah Gimbel, Patricia J Garcia
Journal: The Lancet Global Health (2021)

BackgroundCost is an essential component of economic evaluations and a determinant of implementation feasibility of human papillomavirus (HPV) self-sampling programmes. Yet, reliable evidence that can be used in low-income and middle-income countries, where cervical cancer burden is highest, remains scarce. Here, we estimate the total and unit costs associated with the Hope Project, a community-based HPV self-sampling social entrepreneurship programme in the peri-urban area of Lima, Peru.MethodsWe conducted a micro-costing analysis from the programme perspective to determine the unit costs of: (1) recruitment and training of community leaders (known as Hope Ladies); and (2) Hope Ladies distributing HPV self-sampling kits (named careHPV) in their communities. A procedural manual was used to identify the programme's activities. A structured questionnaire was administered, and in-depth interviews were conducted with three programme administrators to estimate the resource use for each activity and time associated with intervention delivery. Laboratory materials (disposable and durable) and equipment were also costed. We obtained unit costs for each input previously identified from programme budgets and expenditure reports from Nov 1, 2018, to Dec 30, 2019.FindingsThe annual cost per community leader recruited and trained was US$86·21 (2019 USD); cost per HPV self-sampling kit distributed was $39·44. The cost per HPV-positive woman identified was $328·54; and the cost per woman who received the intervention was $49·38. Personnel and laboratory costs represented 47% and 28% of programmatic costs, respectively. During the study period (Nov 1, 2018, to Dec 30, 2019), the programme recruited and trained 62 Hope Ladies, who distributed 4882 HPV self-sampling kits to women in their communities. Of the screened women, 586 (12%) tested positive for HPV.InterpretationCommunity-based HPV self-sampling appears to be a feasible way to improve cervical cancer screening coverage. These findings can be used as the basis for economic evaluations, such as a cost-effectiveness analysis, or to model the scaling of the intervention.FundingThomas Francis Jr Fellowship.
Evaluating the role of stereotactic body radiation therapy with respect to androgen receptor signaling inhibitors for metastatic prostate cancer.
Authors: Victoria Brennan, Alexander Spektor, Christopher Sweeney, Atish Dipankar Choudhury, Dana E. Rathkopf, Mark Pomerantz, Lauren Michelle Hertan, Neil E. Martin, Paul L. Nguyen, Tracy A. Balboni, Mai Anh Huynh, Martin T. King
Journal: Journal of Clinical Oncology (2021)

121 Background: Outcomes of stereotactic body radiation therapy (SBRT) with respect to androgen receptor signaling inhibitors (ARSI) have not been characterized for metastatic prostate cancer. Our purpose is to characterize prostate specific antigen (PSA) response and progression free survival (PFS) following SBRT among men who have received ARSI in castration sensitive and resistant settings. Methods: A single institution retrospective analysis was performed for men treated with SBRT and ARSI and categorized into 4 groups: 1) oligometastatic castration-sensitive prostate cancer (omCSPC), 2) ARSI-sensitive (ARSI-s) oligometastatic castration-resistant prostate cancer (omCRPC), 3) ARSI-resistant (ARSI-r) omCRPC, and 4) polymetastatic CRPC (pmCRPC). We calculated the PSA reduction greater than 50% (PSA50) and median PFS (PSA or radiographic progression) as determined by routine care. We also used Cox regression analysis to determine factors influencing PFS for ARSI-r disease. Results: 73 men with 126 lesions were treated with SBRT and followed for a median of 14.4 months. The percentages of men who achieved a PSA50 for omCSPC, ARSI-s omCRPC, ARSI-r omCRPC and pmCRPC were 100%, 90%, 62.9%, and 16.7%, respectively. Respective median PFS values were: not reached, 17.3, 9.0, and 1.6 months. For the 35 men with ARSI-r omCRPC, incomplete ablation (defined as the presence of untreated lesions after SBRT or prior palliative external beam radiation therapy (EBRT)) (HR 3.51 [1.36, 9.06]; p = 0.01) was associated with worse PFS on multivariable analysis. For the subgroup of 22 men with ARSI-r omCRPC without prior palliative EBRT or untreated metastases, the median PFS was 13.1 months. Conclusions: SBRT may augment the efficacy of ARSI, particularly among men with ARSI-r omCRPC, provided that all lesions received ablative radiation doses. Future prospective study of SBRT for men receiving ARSI is warranted.
Association of reductions in PSA screening across states with increased metastatic prostate cancer in the United States.
Authors: Vidit Sharma, Abhishek Venkataramana, W. Scott Comulada, Mark S. Litwin, Christopher Saigal
Journal: Journal of Clinical Oncology (2021)

228 Background: While PSA screening was found to reduce prostate cancer metastasis and mortality in a large European randomized trial, PSA screening has also resulted in over-treatment of prostate cancer with significant quality-of-life implications. As a result, the US Preventive Services Task Force (USPSTF) did not recommend PSA screening in 2008 and 2012. It is unknown if reductions in PSA screening were responsible for increased metastatic prostate cancer in the United States. We test this hypothesis by associating longitudinal variations across individual states in PSA screening with their incidence of metastatic prostate cancer at diagnosis from 2002 to 2016. Methods: Age-adjusted incidences of metastatic prostate cancer at diagnosis per 100,000 men were obtained from the North American Association of Central Cancer Registries in 2002 – 2016 for each state. Survey-weighted PSA screening estimates for each state were extracted from the Behavioral Risk Factor Surveillance System, which collects this information for men at least 40 years of age every 2 years from 2002 onward. PSA screening and metastasis data were collated as a multi-panel time series and then analyzed using a random-effects linear regression model with random effects at the state level. Results: There was significant variation between states in the percent of men age &gt;40 years who reported ever receiving PSA screening (range 40.1% to 70.3%) and in the age-adjusted incidence of metastatic prostate cancer at diagnosis (range 3.3 to 14.3 per 100,000). From 2008 to 2016, the mean percentage of men screened decreased (61.8% to 50.5%) whereas the mean incidence of metastatic prostate cancer at diagnosis increased (6.4 to 9.0 per 100,000; Bonferroni adjusted p &lt; 0.001 for both). A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were associated with increased metastatic prostate cancer (regression coefficient per 100,000 men: 14.9, 95% CI 12.3 – 17.5, p &lt; 0.001). This indicated that states with larger declines in PSA screening had larger increases in the incidence of metastatic prostate cancer at diagnosis. Variation in PSA screening explained 27% of the longitudinal variation in metastatic prostate cancer within states. Conclusions: In the context of randomized trial data demonstrating a metastasis reduction with PSA screening, our study strengthens the epidemiologic evidence that reductions in PSA screening may explain some of the recent increase in metastatic prostate cancer at diagnosis in the United States. The trend of rising metastatic disease at diagnosis is a worrisome consequence that needs attention. Thus, we support shared-decision making policies, such as the 2018 USPSTF update, that may optimize PSA screening utilization to reduce the incidence of metastatic prostate cancer in the United States.
Choices in a Crisis — Individual Preferences among SARS-CoV-2 Vaccines
Authors: Daniel B. Kramer, Douglas J. Opel, Efthimios Parasidis, Michelle M. Mello
Journal: New England Journal of Medicine (2021)

Choices in a Crisis As experience with SARS-CoV-2 vaccination accumulates, meaningful differences among vaccines may emerge, making the question of whether individual vaccinees should be able to ch...
Association Between COVID-19 Lockdown Measures and Emergency Department Visits for Violence-Related Injuries in Cardiff, Wales
Authors: Jonathan P. Shepherd, Simon C. Moore, Abigail Long, Laura M. Mercer Kollar, Steven A. Sumner
Journal: JAMA (2021)

This study investigates emergency department visits for violence-related injuries occurring at home and outside the home in Cardiff, Wales, before and after COVID-19 lockdown measures were instituted in March 2020.
Abstract 15053: Difference in Survival Outcomes for Out-of-Hospital Cardiac Arrest After 2010 American Heart Association- Emergency Cardiovascular Care Guidelines for Cardio-Pulmonary Resuscitation
Authors: Anusha G Bhat, Deepak K Pasupula, Sudeep K Siddappa Malleshappa, Muhammad B Munir, Amr Barakat, Sandeep Jain, Norman Wang, Aditya Bhonsale, Samir Saba
Journal: Circulation (2019)

Introduction: American Heart Association/ Emergency Cardiovascular Care (AHA/ECC) recommended changes in Advanced Cardiovascular Life Support and Basic Life Support algorithms in 2010 with an aim t...
Presence of a survival benefit of HLA-incompatible living donor kidney transplantation compared to waiting or HLA-compatible deceased donor kidney transplantation with a long waiting time
Authors: Tai Yeon Koo, Ju Han Lee, Sang-Il Min, Yonggu Lee, Myung Soo Kim, Jongwon Ha, Soon Il Kim, Curie Ahn, Yu Seun Kim, Jayoun Kim, Kyu Ha Huh, Jaeseok Yang
Journal: Kidney International (2021)
Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics
Authors: Peter Garred, Andrea J. Tenner, Tom E. Mollnes
Journal: Pharmacological Reviews (2021)

The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. <h3>Significance Statement</h3> The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.
Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19
Authors: Abby Basalely, Shari Gurusinghe, James Schneider, Sareen S. Shah, Linda B. Siegel, Gabrielle Pollack, Pamela Singer, Laura J. Castellanos-Reyes, Steven Fishbane, Kenar D. Jhaveri, Elizabeth Mitchell, Kumail Merchant, Christine Capone, Ashley M. Gefen, Julie Steinberg, Christine B. Sethna
Journal: Kidney International (2021)

This study describes the incidence, associated clinical characteristics and outcomes of acute kidney injury in a pediatric cohort with COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C). We performed a retrospective study of patients 18 years of age and under admitted to four New York hospitals in the Northwell Health System interned during the height of the COVID-19 pandemic, between March 9 and August 13, 2020. Acute kidney injury was defined and staged according to Kidney Disease: Improving Global Outcomes criteria. The cohort included 152 patients; 97 acute-COVID-19 and 55 with MIS-C associated with COVID-19. Acute kidney injury occurred in 8 with acute-COVID-19 and in 10 with MIS-C. Acute kidney injury, in unadjusted models, was associated with a lower serum albumin level (odds ratio 0.17; 95% confidence interval 0.07, 0.39) and higher white blood cell counts (odds ratio 1.11; 95% confidence interval 1.04, 1.2). Patients with MIS-C and acute kidney injury had significantly greater rates of systolic dysfunction, compared to those without (80% vs 49%). In unadjusted models, patients with acute kidney injury had 8.4 days longer hospitalizations compared to patients without acute kidney injury (95% confidence interval, 4.4-6.7). Acute kidney injury in acute-COVID-19 and MIS-C may be related to inflammation and/or dehydration. Further research in larger pediatric cohorts is needed to better characterize risk factors for acute kidney injury in acute-COVID-19 and with MIS-C consequent to COVID-19.
Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates
Authors: Qingju Li, Yinchuan Xu, Kaiqi Lv, Yingchao Wang, Zhiwei Zhong, Changchen Xiao, Keyang Zhu, Cheng Ni, Kan Wang, Minjian Kong, Xuebiao Li, Youqi Fan, Fengjiang Zhang, Qi Chen, Yi Li, Qian Li, Chengjia Liu, Jinyun Zhu, Shuhan Zhong, Jingyi Wang, Yongjian Chen, Jing Zhao, Dan Zhu, Rongrong Wu, Jinghai Chen, Wei Zhu, Hong Yu, Reza Ardehali, Jianyi(Jay) Zhang, Jian’an Wang, Xinyang Hu
Journal: Science Translational Medicine (2021)

Extracellular vesicles containing miR-486-5p augment angiogenesis after MI in mice and nonhuman primates by targeting fibroblastic Mmp19 .