tbuckley/cabot-search huggingface dataset:
First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy
Authors: Jennifer R. Diamond, Valentina Boni, Emerson Lim, Grzegorz Nowakowski, Raul Cordoba, Daniel Morillo, Ray Valencia, Isabelle Genvresse, Claudia Merz, Oliver Boix, Melanie M. Frigault, Joy M. Greer, Ahmed M. Hamdy, Xin Huang, Raquel Izumi, Harvey Wong, Victor Moreno
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. Patients and Methods: Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. Results: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in &amp;gt; 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). Conclusions: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
Clever Hans effect found in a widely used brain tumour MRI dataset
Authors: David Wallis, Irène Buvat
Journal: Medical Image Analysis (2022)

Machine learning is revolutionising medical image analysis, and clearly the future of the field lies in this direction. However, with increasing automation there is a danger of misunderstanding or misinterpreting models. In this paper, we expose an underlying bias in a commonly used publicly available brain tumour MRI dataset. We propose that this is due to implicit radiologist input in the selection of the 2D slices. Through several experiments we show how this bias allows us to achieve a high tumour classification accuracy, even with no information regarding the tumour itself. No other papers that use the dataset mention this bias. These findings demonstrate the importance of understanding machine learning models and their medical context, and the perils of not doing so.
Error in Text
Authors: Frans Van Workum, Moniek Verstegen, Camiel Rosman
Journal: JAMA Surgery (2022)

those reported by de Steur et al, and the rate found in our multicenter study.In our view, these large differences in leak rates should be subject of further study, but we should remain cautious when interpreting results of single-center studies until these techniques have been tested in large high-quality trials.Finally, we fully agree that finding the most optimal surgical technique and consequently spreading knowledge and skills through training, proctoring, and quality-improvement programs will be extremely important in optimizing outcome for patients undergoing minimally invasive esophagectomy.
Acknowledgment to Reviewers
Journal: Blood Cancer Discovery (2022)

The Blood Cancer Discovery editors wish to acknowledge with sincere appreciation the assistance of the following reviewers who have generously contributed their time and effort during the past year1 in the appraisal of manuscripts. These reviewers have been enormously helpful in assessing the merit of original articles: their careful analysis and critique and their constructive recommendations have greatly enhanced the value of manuscripts they have handled. The quality of the journal can be attributed in large measure to the quality of their effort. We are sincerely grateful.Abdelhamed, S.Abdel-Wahab, O.Alizadeh, A.Ansell, S.Aplan, P.Armstrong, S.Bergsagel, P.Bernard, O.Bhalla, K.Biragyn, A.Boise, L.Bosch, F.Boussiotis, V.Bowman, T.Bullinger, L.Byrd, J.Calado, D.Campo, E.Casulo, C.Cellot, S.Cerchietti, L.Chapuy, B.Cohen, A.Colditz, G.Colonna, M.Constantinescu, S.Crispino, J.Croce, C.Croucher, P.Dang, C.Daver, N.Davies, F.de Bock, C.De Leval, L.de Miranda, N.de The, H.DeGregori, J.Dhodapkar, M.Diehn, M.Duy, C.Ebert, B.Elemento, O.Elenitoba-Johnson, K.Ernst, P.Falini, B.Ferrando, A.Figueroa, M.Flowers, C.Fry, T.Gandhi, M.Garfall, A.Gertych, A.Giuliani, N.Goodell, M.Gottschalk, S.Green, M.Gruber, T.Gurbuxani, S.Gutierrez, A.Handgretinger, R.Hasserjian, R.Herranz, D.Huang, A.Huntington, N.Husby, S.Iwama, A.Jain, N.Jamieson, C.Jardin, F.Johnson, P.Jones, C.June, C.Kantarjian, H.Kats, L.Kochenderfer, J.Kreso, A.Kroemer, G.Küppers, R.Landau, D.Langdon, W.Le Beau, M.Lee, S.Levine, R.Ley, T.Licht, J.Look, A.Maciejewski, J.Majeti, R.Martin, T.Maura, F.Mazzarella, L.Meijerink, J.Melnick, A.Miller, C.Miller, J.Minden, M.Mullally, A.Mullighan, C.Munshi, N.Nadel, B.Nangalia, J.Nutt, S.Obeng, E.Ogawa, S.Oh, S.Orentas, R.Orlowski, R.Palomero, T.Pasqualucci, L.Philips, M.Pietras, E.Pui, C.Rajewsky, K.Rampal, R.Rau, R.Rezvani, K.Riddell, S.Rossi, D.Ruella, M.Ruland, J.Rutella, S.Sanda, T.Savona, M.Schimmer, A.Schwenger, E.Shah, N.Shannon, K.Shipp, M.Sipkins, D.Slany, R.Smith, E.So, C.Sotillo, E.Speck, N.Staudt, L.Steidl, C.Steidl, U.Stock, W.Sulis, M.Sung, P.Tyner, J.Vago, L.Verma, A.Verneris, M.Viny, A.Vyas, P.Walker, B.Walter, M.Weiner, G.Weinstock, D.Wiita, A.Wu, C.Zeidner, J.
Effectiveness of transarterial chemoembolization combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma.
Authors: Fei Cao, Yi Yang, Tongguo Si, Jun Luo, Hui Zeng, Zhewei Zhang, Yi Chen, Jiaping Zheng
Journal: Journal of Clinical Oncology (2022)

414 Background: Combination therapies have been explored for the treatment of hepatocellular carcinoma (HCC) with favorable results, including PD-1 inhibitors plus lenvatinib and transarterial chemoembolization (TACE) plus lenvatinib. However, triple therapy with TACE combined with lenvatinib plus PD-1 inhibitors has not been investigated for patients with unresectable HCC. This study therefore aimed to investigate the effectiveness and safety of TACE combined with lenvatinib plus sintilimab in patients with advanced HCC. Methods: A single-arm retrospective study based on medical records and imaging data from 60 patients diagnosed with HCC using noninvasive methods or biopsy at the Cancer Hospital of the University of Chinese Academy of Sciences and the First Hospital of Medical University between January 2019 and March 2021. Eligible patients had received lenvatinib 12 mg (bodyweight &gt;60 kg) or 8 mg (bodyweight &lt;60 kg) orally once daily 2 weeks before TACE. Subsequently, sintilimab was administered at a dose of 200 mg intravenously on day 1 of a 21-day treatment cycle following TACE. The TACE procedure was repeated 4-6 weeks later and the chemotherapy regimens used included oxaliplatin (75 mg/m 2 ) and iodized oil mixed with epirubicin (30-50 mg/m 2 ). Objective response rate (ORR) and duration of response (DOR) were the primary endpoints and were assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: The analysis included data from 52 patients; 86.4% were male, 76.7% were aged ≤65 years, 13.5% and 86.5% had an ECOG performance status (PS) of 0 and 1, respectively and 88.5% and 11.5% had a Child-Pugh score of A and B, respectively. All patients were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage B (25%) or C (75%) disease. After a median follow-up of 12.5 months (95% confidence interval (CI), 9.1–14.8), the ORR was 46.7% (28/60: complete response, n=4; partial response, n=24). Twenty-three patients had stable disease, and nine had progressive disease. The median DOR for confirmed responders was 10.0 months (95% CI, 9.0–11.0). The median progression-free survival and overall survival were 13.3 months (95% CI, 11.9–14.7) and 23.6 months (95% CI, 22.2–25.0), respectively. In total, 84.6% (n=44) of patients had adverse events (AEs) of any grade. The most common treatment-related AEs were fatigue (30.8%), hypertension (25.0%), diarrhea (19.2%), decreased appetite (23.0%), and palmar-plantar erythrodysesthesia (21.1%). Conclusions: TACE combined with lenvatinib plus sintilimab is a promising and tolerable therapeutic regimen for patients with unresectable HCC.
Large scale proteomics of circulating extracellular vesicles to reveal novel biomarkers for pancreatic cancer.
Authors: Bruno Bockorny, Lakshmi Muthuswamy, Ling Huang, Marco Hadisurya, Leo Tsai, Ritu R. Gill, Jesse Wei, Andrea J. Bullock, Joseph Elan Grossman, Robert J. Besaw, Christine Maria Lim, Supraja Narasimhan, Sofia Perea, Mandeep Sawhney, W. Andy Tao, Steven Freedman, Manuel Hidalgo, Anton Iliuk, Senthil Muthuswamy
Journal: Journal of Clinical Oncology (2022)

523 Background: Robust biomarkers are urgently needed to assist in diagnosing pancreatic cancer. Earlier cancer diagnosis could increase survival rates by an estimated 5-fold and more reliable and real-time assessment of treatment effects in patients with cancer could improve quality of life and reduce healthcare costs. Isolation of circulating extracellular vesicles (cEVs) as ‘liquid biopsies’ offers an advantageous approach to diagnose and monitor disease status. Methods: We conducted a comprehensive proteomics study of cEVs from plasma samples to identify EV proteins that may be used as biomarkers for the diagnosis and prognosis of pancreatic cancer. Patients with pancreatic ductal adenocarcinoma (PDAC) of various tumor stages, chronic pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and age-matched controls were enrolled. EVs were isolated directly from plasma samples using the affinity-based EVTrap method then subject to quantitation by liquid chromatography-tandem mass spectrometry. Results: A total of 124 patients (93 with PDAC, 12 with chronic pancreatitis, 8 with IPMN and 11 controls) were included in the discovery cohort. The isolation of EVs with EVtrap allowed the identification on average of 912 EV proteins per 100µL of sample. Principal component analysis of the cEV proteome showed clear separation between PDAC and benign pancreatic diseases. Individuals with IPMN were more closely related to controls, whereas chronic pancreatitis cases were more related to PDAC. At the functional level, we noted that cytokeratin, protein folding chaperons, and actin dynamics regulators were among protein clusters more highly altered in the cEV of patients with PDAC. We further identified new cEV markers associated with metastatic disease, such as PSMB4, RUVBL2, and ANKAR, as well as other EV proteins with strong correlation to prognosis, such as CRP, RALB, and CD55. Finally, we validated a 7-protein PDAC EV signature in a validation cohort of 36 separate patients (24 with PDAC, 6 with chronic pancreatitis and 6 with IPMN) which yielded an 89% prediction accuracy for the diagnosis of PDAC. Conclusions: This study provides a valuable resource to the scientific community with a comprehensive catalog of novel proteins on circulating EVs that may assist in the development of novel biomarkers and improve the outcomes of patients with pancreatic cancer.
Cyclin dependent kinase 9 inhibition as a potential treatment for hepatocellular carcinoma.
Authors: Yu Yun Shao, Hung-Wei Hsu, Rita Robin Wo, Han-Yu Wang, Ann-Lii Cheng, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2022)

425 Background: Composite cyclin dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. Methods: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, on cell viability and apoptosis in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. Results: Both BAY1143572 and AZD4573 exhibited potent antiproliferative activities in HCC cell lines including HuH7, HLE, and HepG2, regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1, survivin, Bim EL , and the X-linked inhibitor of apoptosis protein. Reduction of CDK9 expression through siRNA knockdown also reduced the phosphorylation of RNA polymerase II and the colony formations of HuH7 and HLE cells. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited a significantly lower tumor growth rate than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving BAY1143572 also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Conclusions: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.
Abstract P151: Comparison of Standard Definitions and Sagittal Abdominal Diameter as a Measure of Excess Adiposity When Defining Metabolic Syndrome in Adolescents
Authors: Symielle A Gaston, Nicolle S Tulve, Tekeda F Ferguson
Journal: Circulation (2017)

Introduction: Metabolic syndrome (MetS) is the cluster of several clinical symptoms that together represent the strongest risk factor for cardiovascular disease. The prevalence of MetS in adolescents is difficult to estimate given that there are several, but no agreed upon definition of MetS for this age group. It is important to estimate MetS and identify at-risk adolescents early in order to provide effective interventions prior to the development of diabetes and coronary heart disease. Objective: Study objectives are to: (1) estimate the prevalence of MetS in U.S. adolescents using three widely adopted definitions and (2) compare changes in prevalence of MetS when utilizing sagittal abdominal diameter (SAD) as a component of MetS. Methods: Data from U.S. adolescents ages 12-19 years (N=970) in the NHANES (2011-2014) were analyzed. MetS standard definitions developed by Cook et al. (2003), deFerranti et al. (2007), and the International Disease Federation (IDF, 2007) were applied to estimate the sex-stratified, weighted prevalence of MetS and its individual components (i.e., high waist circumference (WC), hypertension, blood lipid abnormalities, and high fasting blood glucose (FBG)). The definitions were modified by substituting SAD for WC, and weighted MetS prevalence was re-estimated. Results: Regardless of gender and definition, abnormal blood lipids and high WC were the most prevalent MetS components. For both sexes, estimated prevalence of components varied greatly by definition (e.g., boys’ prevalence of high fasting blood glucose: IDF-27.2% vs. Cook and deFerranti-both 2.7%). MetS prevalence in boys using standard and SAD-modified definitions were 4.5% and 5.0%; 10.6% and 9.4%; and 4.6% and 3.3% for the Cook, deFerranti, and IDF definitions, respectively. Among girls, the standard-defined and SAD-modified MetS prevalence were 2.4% and 2.4%; 8.5% and 8.2%; and 4.3% and 2.8% for the Cook, deFerranti, and IDF definitions, respectively. Conclusions: Though the most prevalent MetS components were similar, the estimated prevalence values of individual components varied greatly across MetS definitions. With the risk of false positives, the deFerranti definition of MetS may identify the greatest number of adolescents at potential risk for MetS. Cook and deFerranti definitions may miss the identification of adolescents who could benefit from additional health promotion programs. Compared to WC, use of SAD resulted in similar yet slightly attenuated estimated MetS prevalence.
Why Eat Raisins?
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Composite Metric for Benchmarking Site Performance in Transcatheter Aortic Valve Replacement: Results From the STS/ACC TVT Registry
Authors: Nimesh D. Desai, Sean M. O’Brien, David J. Cohen, John Carroll, Sreekanth Vemulapalli, Suzanne V. Arnold, John K. Forrest, Vinod H. Thourani, Ajay J. Kirtane, Brian O’Neil, Pratik Manandhar, David M. Shahian, Vinay Badhwar, Joseph E. Bavaria
Journal: Circulation (2021)

Transcatheter aortic valve replacement (TAVR) is a transformative therapy for aortic stenosis. Despite rapid improvements in technology and techniques, serious complications remain relatively common and are not well described by single outcome measures. The purpose of this study was to determine whether there is site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure.We performed a retrospective cohort study using data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry to develop a novel ranked composite performance measure that incorporates mortality and serious complications. The selection and rank order of the complications for the composite was determined by their adjusted association with 1-year outcomes. Sites with risk-adjusted outcomes significantly more or less frequent than the national average based on a 95% probability interval were classified as performing worse or better than expected.The development cohort consisted of 52 561 patients who underwent TAVR between January 1, 2015, and December 31, 2017. Based on associations with 1-year risk-adjusted mortality and health status, we identified 4 periprocedural complications to include in the composite risk model in addition to mortality. Ranked empirically according to severity, these included stroke, major, life-threatening or disabling bleeding, stage III acute kidney injury, and moderate or severe perivalvular regurgitation. Based on these ranked outcomes, we found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better than expected site performance was observed in 25/301 (8%) sites, performance as expected was observed in 242/301 sites (80%), and worse than expected performance was observed in 34/301 (11%) sites. Thirty-day mortality; stroke; major, life-threatening, or disabling bleeding; and moderate or severe perivalvular leak were each substantially more common in sites with worse than expected performance as compared with other sites. There was good aggregate reliability of the model.There are substantial variations in the quality of TAVR care received in the United States and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine structural, process-related, and technical factors associated with high- and low-performing sites.
Economics
Authors: Carl J. Schramm
Journal: JAMA (1990)

Spurred by customer demands for greater control of medical care expenses, commercial insurers began during the 1980s to transform their business—from claims payer to manager of health care delivery systems. At the turn of the decade, employers did not generally regard rising health insurance costs as a major problem.<sup>1</sup>However, as the energy-driven inflation of the 1970s cooled in the early 1980s, annual increases in health benefit plans accelerated to more than 20% (unpublished data from the Employer Cost Index of the Bureau of Labor Statistics). Businesses began to support insurance companies' efforts to take a more active role in improving the value employers received for their health care dollars. Insurers responded by undertaking the arduous process of examining the delivery systems their claims were supporting and constructing techniques and programs to manage the care provided. As the programs have developed, different insurers have defined "managed care" differently. Some
More on Medical Students and Their Schools
Journal: JAMA (1969)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Isn't Androgen Deprivation Enough? Optimal Treatment for Newly Diagnosed Metastatic Prostate Cancer
Authors: Alicia K. Morgans, Himisha Beltran
Journal: Journal of Clinical Oncology (2022)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.