tbuckley/cabot-search huggingface dataset:
Evaluation of the Number-Needed-to-Biopsy Metric for the Diagnosis of Cutaneous Melanoma
Authors: Kelly C. Nelson, Susan M. Swetter, Kathylynn Saboda, Suephy C. Chen, Clara Curiel-Lewandrowski
Journal: JAMA Dermatology (2019)

To date, no concerted effort has been made to date to evaluate the literature on number-needed-to-biopsy (NNB) metrics, particularly to account for the differences in clinician type and melanoma prevalence in certain geographic locations.To review and synthesize worldwide data for NNB for the diagnosis of cutaneous melanoma.MEDLINE, Embase, and PubMed databases were searched for English-language articles published worldwide from January 1, 2000, to November 28, 2018.A total of 46 studies were included that addressed NNB for at least 3681 clinicians worldwide and included 455 496 biopsied tumors and 29 257 melanomas; primary care practitioner (PCP) data were only available from Australia.Articles were screened for eligibility, and possible overlapping data sets were resolved. Data extracted included clinician specialization, use of dermoscopy, geographic region and location-specific health care system, study design, number of benign tumors, number of melanomas, and NNB. The review followed the PRISMA guidelines.The NNB for the diagnosis of cutaneous melanoma.A total of 46 studies were included that addressed NNB for at least 3681 clinicians worldwide and included 455 496 biopsied tumors and 29 257 melanomas; primary care practitioner (PCP) data were only available from Australia. The reported NNB ranged from 2.2 to 287, and the weighted mean NNB for all included publications was 15.6. The exclusion of publications structured as all biopsied tumors, owing to variable data characterization, resulted in reported NNB ranging from 2.2 to 30.5, with a global weighted mean NNB of 14.8 for all clinicians, 7.5 for all dermatologists, 14.6 for Australian PCPs, and 13.2 for all US-based dermatological practitioners, including dermatologists and advanced practice professionals. The summary effect size (ES) demonstrates that a mean 4% of biopsies demonstrated melanoma for study stratum A (all biopsied skin tumors, ES, 0.04; 95% CI, 0.03-0.05), and a mean 12% of biopsies demonstrated melanoma for study strata B (melanocytic tumors on pathology review, ES, 0.12; 95% CI, 0.10-0.14) and C (clinical concern for melanoma, ES; 0.12; 95% CI, 0.09-0.14).The existing NNB for cutaneous melanoma appeared to vary widely worldwide, lacking standardization in the metric and its reporting, and according to clinician characteristics as well; the NNB of US-based clinicians may warrant further exploration.
Reply to Jon Mikel Inarritu, Daniele Castellani, and Jeremy Y.C. Teoh's Letter to the Editor re: Agustina Bessa, Steven Maclennan, Deborah Enting, et al. Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method. Eur Urol 2019;76:260–1
Authors: Agustina Bessa, Steven Maclennan, Deborah Enting, Richard Bryan, Christel Häggström, Mieke Van Hemelrijck
Journal: European Urology (2019)
Methylated DNA in Pancreatic Juice Distinguishes Patients With Pancreatic Cancer From Controls
Authors: Shounak Majumder, Massimo Raimondo, William R. Taylor, Tracy C. Yab, Calise K. Berger, Brian A. Dukek, Xiaoming Cao, Patrick H. Foote, Chung Wah Wu, Mary E. Devens, Douglas W. Mahoney, Thomas C. Smyrk, Rahul Pannala, Suresh T. Chari, Santhi Swaroop Vege, Mark D. Topazian, Bret T. Petersen, Michael J. Levy, Elizabeth Rajan, Ferga C. Gleeson, Barham Abu Dayyeh, Cuong C. Nguyen, Douglas O. Faigel, Timothy A. Woodward, Michael B. Wallace, Gloria Petersen, Hatim T. Allawi, Graham P. Lidgard, John B. Kisiel, David A. Ahlquist
Journal: Clinical Gastroenterology and Hepatology (2019)
The Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure (DAPA‐HF) trial: baseline characteristics
Authors: John J.V. McMurray, David L. DeMets, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Anna Maria Langkilde, Felipe A. Martinez, Olof Bengtsson, Piotr Ponikowski, Marc S. Sabatine, Mikaela Sjöstrand, Scott D. Solomon
Journal: European Journal of Heart Failure (2019)

Background The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure (DAPA‐HF) trial, (ii) compare DAPA‐HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre‐diabetes and a normal glycated haemoglobin (HbA1c) in DAPA‐HF. Methods and results Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N‐terminal pro‐B‐type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA‐HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre‐diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c &lt; 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre‐diabetes and 33% normal HbA1c. Overall, DAPA‐HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor, 96% beta‐blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co‐morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non‐insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%. Conclusions Patients randomized in DAPA‐HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose‐lowering therapy. Consequently, DAPA‐HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03036124
A phase Ib trial of cabozantinib in combination with durvalumab (MEDI4736) in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (CAMILLA).
Authors: Anwaar Saeed, Devin Koestler, Stephen K. Williamson, Joaquina Celebre Baranda, Weijing Sun, Raed Moh'd Taiseer Al-Rajabi, Anup Kasi, Mazin Francis Al-Kasspooles, Dharmalingam Subramaniam, Shrikant Anant
Journal: Journal of Clinical Oncology (2019)

TPS56 Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US &amp; globally. The current standard upfront therapy has &lt; 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received &gt; 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, &amp; ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis &amp; immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.
Anthropometric Characterization of Impaired Fetal Growth
Authors: C G Victora, J Villar, F C Barros, L C Ismail, C Chumlea, A T Papageorghiou, E Bertino, E O Ohuma, A Lambert, M Carvalho, Y A Jaffer, D G Altman, J A Noble, M G Gravett, M Purwar, I O Frederick, R Pang, Z A Bhutta, S H Kennedy
Journal: JAMA Pediatrics (2015)
Treatment patterns in patients with multiple myeloma (MM): A retrospective study using Medicare data.
Authors: Peggy L. Lin, Dominick Latremouille-Viau, Medha Sasane, Patrick Gagnon-Sanschagrin, Hozefa A. Divan, Edward Joseph Drea, Annie Guerin, Parameswaran Hari
Journal: Journal of Clinical Oncology (2019)

e19506 Background: MM is characterized by repeated relapses and refractoriness and is managed by successive lines of therapies (LT) each typically resulting in shorter response duration over prior LT. This study describes current MM treatment (tx) landscape in US clinical practice. Methods: Adult MM patients (pts) with continuous Medicare Part A, B, and D coverage initiated on 1 st LT (1L), without stem cell transplant, were identified in the Medicare Research Identifiable Files (2012-2016). Claims for any MM tx within 60 days of the 1 st tx constituted the tx regimen of an LT. End of LT was defined as a claim for a new MM tx &gt; 60 days post LT initiation (tx augmentation or switch), discontinuation of all tx in a regimen for &gt; 90 consecutive days, end of Medicare coverage/data or death. From 1L to 3L, overall survival (OS), LT duration (DoT), tx regimens and sequences were assessed. Results: 8374 MM pts with 1L (median [med] age = 76 years at 1L; 55% female) were analyzed. Over a med follow-up of 20 months (mos) from 1L (med 1L DoT = 5.6 mos), 2849 pts received a 2L (med 2L DoT = 5.6 mos) and 978 received a 3L (med 3L DoT = 4.7 mos). The most prominent tx regimens were bortezomib/corticosteroids (CS; VD) in 1L, and lenalidomide/CS (RD) in 2L and 3L. The most prevalent tx sequence was 1L VD, 2L RD and 3L VD. The 1- and 2-year OS rates were 81% [95% confidence interval: 81-82] and 68% [67-69] from 1L initiation, 80% [78-82] and 64% [61-66] from 2L, and 73% [69-76] and 55% [51-60] from 3L initiation, respectively. Conclusions: MM Medicare pts mainly cycle through bortezomib- or lenalidomide-based regimens in front LT; newer agents gain more usage in later LT. A better understanding of tx options and sequencing is warranted to prolong survival. [Table: see text]
<i> <scp>CFTR</scp> </i> gene variants: a predisposition factor to aquagenic palmoplantar keratoderma
Authors: C. Raynal, E. Girodon, M.P. Audrezet, F. Cabet, A. Pagin, M.P. Reboul, F. Dufernez, P. Fergelot, A. Bergougnoux, P. Fanen, C. Ferec, T. Bienvenu
Journal: British Journal of Dermatology (2019)
David A Hamburg: psychiatrist, researcher, and humanitarian who sought to prevent global violence
Authors: Ned Stafford
Journal: BMJ (2019)

Carnegie Corporation New York

In 1975 David A Hamburg, a professor of psychiatry at Stanford University in California, was confronted with a life or death crisis that would change the course of his life. At the time 49 years old, Hamburg was highly regarded for his pioneering research into stress and anxiety as well the biology of mental illness.

The crisis—the kidnapping of four of his students in Africa—caused Hamburg to rethink his life. He decided to change his focus and use his medical background to help shape global policy towards prevention of hatred, violence, and human suffering—or, as he once put it, “the prevention of rotten outcomes.”

In 1982, seven years after the crisis, Hamburg was appointed president of the Carnegie Corporation of New York, the influential philanthropic foundation established by Andrew Carnegie in 1911.

“I feel I have been building toward this all my life,” Hamburg told the New York Times at the time.1

Hamburg was Carnegie president until 1997, when he stepped down at the age of 72; he served as president emeritus for the rest of his life. Under Hamburg’s leadership, the Carnegie Corporation intensified its efforts to tackle critical societal challenges in education, health, scientific advancement, and international peace and security.

“David Hamburg was a respected scholar and a visionary leader who left a rich legacy of promoting peace, democracy, child and adolescent development, and education for all,” said Vartan Gregorian, president of the foundation.

In 1996 Hamburg was awarded the US Presidential Medal of Freedom, the nation’s highest civilian honour. In a ceremony at the White House, Bill Clinton, the president at the time, said: “Physician, scientist, and educator, David Hamburg has devoted his life to understanding human behaviour, preventing violent conflict, and improving the health and wellbeing of our children.”

Hamburg’s life changing crisis began in …
Mechanisms and consequences of gut commensal translocation in chronic diseases
Authors: Rebecca L. Fine, Silvio Manfredo Vieira, Michael S. Gilmore, Martin A. Kriegel
Journal: Gut Microbes (2019)

Humans and other mammalian hosts have evolved mechanisms to control the bacteria colonizing their mucosal barriers to prevent invasion. While the breach of barriers by bacteria typically leads to overt infection, increasing evidence supports a role for translocation of commensal bacteria across an impaired gut barrier to extraintestinal sites in the pathogenesis of autoimmune and other chronic, non-infectious diseases. Whether gut commensal translocation is a cause or consequence of the disease is incompletely defined. Here we discuss factors that lead to translocation of live bacteria across the gut barrier. We expand upon our recently published demonstration that translocation of the gut pathobiont Enterococcus gallinarum can induce autoimmunity in susceptible hosts and postulate on the role of Enterococcus species as instigators of chronic, non-infectious diseases.
Infographic: Mental health in elite athletes. An IOC consensus statement
Authors: Claudia L Reardon, Brian Hainline, Cindy Miller Aron, David Baron, Antonia L Baum, Abhinav Bindra, Richard Budgett, Niccolo Campriani, João Mauricio Castaldelli-Maia, Alan Currie, Jeffrey Lee Derevensky, Ira D Glick, Paul Gorczynski, Vincent Gouttebarge, Michael A Grandner, Doug Hyun Han, David McDuff, Margo Mountjoy, Aslihan Polat, Rosemary Purcell, Margot Putukian, Simon M Rice, Allen Sills, Todd Stull, Leslie Swartz, Li Jing Zhu, Lars Engebretsen
Journal: British Journal of Sports Medicine (2019)
Abstract 16677: Lipid-overload Impairs Cardiomyocyte Autophagosome Turnover by Activating a Protein kinase C (PKC)-NADPH oxidase 2 (NOX2) Pathway
Authors: Bharat P Jaishy, Jin-Ha Kim, E. Dale Abel
Journal: Circulation (2013)

Obesity regulates autophagy in a tissue-dependent manner to influence tissue homeostasis in beneficial or deleterious ways. The regulation of cardiomyocyte autophagy in obesity is incompletely unde...
Genomic landscape and its correlations with tumor mutational burden, PD-L1 expression, and immune cells infiltration in Chinese lung squamous cell carcinoma
Authors: Tao Jiang, Jinpeng Shi, Zhengwei Dong, Likun Hou, Chao Zhao, Xuefei Li, Beibei Mao, Wei Zhu, Xianchao Guo, Henghui Zhang, Ji He, Xiaoxia Chen, Chunxia Su, Shengxiang Ren, Chunyan Wu, Caicun Zhou
Journal: Journal of Hematology & Oncology (2019)

To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates. Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database. The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8+ TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8+ TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8+ TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors. The combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.
Abstract 396: Regulation of Cardiomyocyte Proliferation by the Hippo Pathway and Dystrophin Complex
Authors: Yuka Morikawa, John Leach, Todd Heallen, Ge Tao, James F Martin
Journal: Circulation Research (2016)

Regeneration in mammalian hearts is limited due to the extremely low renewal rate of cardiomyocytes and their inability to reenter the cell cycle. In rodent hearts, endogenous regenerative capacity exists during development but is rapidly repressed after birth, at which time growth is by hypertrophy. During the developmental and neonatal periods, heart regeneration occurs through proliferation of pre-existing cardiomyocytes. Our approach of activating heart regeneration is to uncover the mechanisms responsible for repression of cardiomyocyte proliferation. The Hippo pathway controls heart size by repressing cardiomyocyte proliferation during development. By deleting Salv , a modulator of the Hippo pathway, we found that myocardial damage in postnatal and adult hearts was repaired both anatomically and functionally. This heart repair occurred primary through proliferation of preexisting cardiomyocytes. During repair, cardiomyocytes reenter the cell cycle; de novo DNA synthesis, karyokinesis, and cytokinesis all take place. The dystrophin glycoprotein complex (DGC) is essential for muscle maintenance by anchoring the cytoskeleton and extracellular matrix. Disruption of the DGC results in muscular dystrophies, including Duchenne muscular dystrophy, resulting in both skeletal and cardiac myopathies. Recently the DGC was shown to regulate cardiomyocyte proliferation and we found that the DGC and the Hippo pathway components directly interact. To address if the DGC and the Hippo pathway coordinately regulate cardiomyocyte proliferation, we conditionally deleted Salv in the mouse model of muscular dystrophy, the mdx line. We found that simultaneous disruption of both the DGC and Hippo pathway leads an increased de novo DNA synthesis and cytokinesis in cardiomyocytes after heart damage. Our findings provide new insights into the mechanisms leading to heart repair through proliferation of endogenous cardiomyocytes.
Correction to: Migalastat: A Review in Fabry Disease
Authors: Emma H. McCafferty, Lesley J. Scott
Journal: Drugs (2019)

The article Migalastat: A Review in Fabry Disease, written by Emma H. McCafferty, Lesley J. Scott, was originally published Online First without open access. After publication in volume 79, issue 5, pages 543–554 [funder] requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by [funder]. The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
Impact of biomarkers in predictivity of the efficacy and toxicity of a combination of panitumumab plus FEC 100 followed by docetaxel in a phase II neoadjuvant trial for triple-negative breast cancer (TNBC) patients.
Authors: Jean-Marc A. Nabholtz, Marie-Melanie Dauplat, Catherine Abrial, Beatrice E. Weber, Marie-Ange Mouret-Reynier, Joseph Gligorov, Olivier Tredan, Laurence Vanlemmens, Thierry Petit, FranÃƒÂ§oise Mayer, Christelle Jouannaud, Nicole Tubiana-Mathieu, Fabrice Kwiatkowski, Anne Cayre, Nassera Chalabi, Philippe J. M. Chollet, Frederique Penault-Llorca
Journal: Journal of Clinical Oncology (2012)

1051 Background: We evaluated the combination of a standard chemotherapy with panitumumab as neoadjuvant therapy of operable TNBC. Complete pathologic response (pCR) was the primary endpoint, with toxicity and biologic ancillary studies as secondary endpoints. Methods: Sixty patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 (500/100/500 mg/m 2 ) q.3 weeks followed by 4 cycles of T (100 mg/m 2 ) q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Paraffin-embedded samples and frozen samples have been systematically realised before and after neaodjuvant treatment in order to evalutate the biological profile of the tumor. Patients characteristics are : median age 50 ; median tumor size : 40 mm ; invasive ductal carcinoma : 96% ; Scarff-Bloom-Richardson Grade III : 70%, grade II : 30%, ki-67-positive : 100%, EGFR-positive : 78%, cytokeratine5-6-positive : 48% and p53-positive : 59%. Pathological response showed a pCR according to Sataloff’s classification of 52.38% and according to Chevallier’s classification of 46.52%. Skin toxicity was the main side-effect : Cutaneous toxicity grade IV : 5%, grade III : 30%, grade II : 20%. Neutropenia grade IV : 27% ; febrile neutropenia : 5%. Infection : 0%. Hand-foot syndrome grade III : 3.3%. Ungueal toxicity grade III : 1.6%, grade II : 20%. Results: We have tested the predictive value of ki-67, EGFR, cytokeratine 5-6 and p53. Only ki-67 is predictive of a pCR according to Chevallier’s classification (p=0.026), with a cut-off of 40% of positive cells (ROC curve): 62% of pCR if ki-67&gt; 40% versus 23% if not (relative risk : 2.7). Low EGFR, high p53, and high cytokeratine 5-6 tended to be associated with poor reponse. No correlations were found between cutaneous toxicities and these biomarkers. The cutaneous toxicities were not predictive. Conclusions: HighKi-67 is predictive of more pCR. High EGFR, low p53 and low cytokeratine 5-6 tended to be associated with better response, but the data are not significant.