tbuckley/cabot-search huggingface dataset:
New Migraine Drug Gains Approval
Authors: Rebecca Voelker
Journal: JAMA (2020)

Juliana H. VanderPluym, MD; Rashmi B. Halker Singh, MD; Meritxell Urtecho, MD; Allison S. Morrow, BA; Tarek Nayfeh, MD; Victor D. Torres Roldan, MD; Magdoleen H. Farah, MBBS; Bashar Hasan, MD; Samer Saadi, MD; Sahrish Shah, MBBS; Rami Abd-Rabu, MBBS; Lubna Daraz, PhD; Larry J. Prokop, MLS; Mohammad Hassan Murad, MD, MPH; Zhen Wang, PhD
To Make a Living
Authors: Michelle Tong
Journal: JAMA (2020)

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Endoscopic retrieval through a lumen-apposing metal stent of a biflanged metal stent that had been released into a peripancreatic fluid collection
Authors: Edoardo Troncone, Giovanna Del Vecchio Blanco, Carmelina Petruzziello, Benedetto Neri, Michelangela Mossa, Giovanni Monteleone, Alberto Larghi
Journal: Endoscopy (2020)

We report a 60-year-old woman with a previous history of an endoscopically treated walled-off necrosis that developed 12 months after an 80-mm recurrent symptomatic pancreatic body pseudocyst. Drainage was attempted using a 16 × 20-mm biflanged metal stent (Nagi), but the stent was mistakenly released inside the collection. A rescue attempt was made to retrieve the stent and avoid surgical intervention.
Hepatic Deficiency of Augmenter of Liver Regeneration Predisposes to Nonalcoholic Steatohepatitis and Fibrosis
Authors: Sudhir Kumar, Alok K. Verma, Richa Rani, Akanksha Sharma, Jiang Wang, Shimul A. Shah, Jaideep Behari, Rosa Salazar Gonzalez, Rohit Kohli, Chandrashekhar R. Gandhi
Journal: Hepatology (2020)

Background and Aims The augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high‐fat/high‐carbohydrate (HF/HC) diet–induced nonalcoholic fatty liver disease (NAFLD) in wild‐type (WT), hepatocyte‐specific ALR‐knockout (ALR‐H‐KO), and ALR‐heterozygous (ALR‐H‐HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH‐induced cirrhosis (serum and liver). Approach and Results HF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR‐H‐HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR‐H‐KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element‐binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC‐fed mice developed insulin resistance, the magnitude being lower in ALR‐H‐KO mice. HF/HC‐fed ALR‐H‐HET mice were more resistant to glucose challenge than WT or ALR‐H‐KO mice. The frequency of tumor necrosis factor alpha–producing, interleukin 6 (IL6)–producing, and IL17‐producing cells was greater in ALR‐H‐KO than ALR‐H‐HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR‐H‐KO mice, and the increase in ALR‐H‐HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25–positive (CD25 + ) forkhead box P3–positive CD4 + regulatory T‐cell frequency was lower in ALR‐H‐HET than WT mice and further reduced in ALR‐H‐KO mice; HF/HC reduced regulatory T‐cell frequency only in WT mice. HF/HC‐fed ALR‐H‐HET, but not WT, mice developed fibrosis; and ALR‐H‐KO mice progressed to cirrhosis. White adipose tissue of HF/HC‐fed ALR‐deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH‐cirrhosis. Serum ALR was also significantly lower in patients with NASH. Conclusions Hepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.
Inspiratory vocal cord closure in COPD
Authors: Paul Leong, Laurence E. Ruane, Debra Phyland, Joo Koh, Martin I. MacDonald, Malcom Baxter, Kenneth K. Lau, Kais Hamza, Philip G. Bardin
Journal: European Respiratory Journal (2020)

During normal inspiration, vocal cord movements are limited, although mild abduction (widening) can occur [1]. Inspiratory closure is characteristic of vocal cord dysfunction (VCD), a condition that can cause refractory breathlessness [1, 2]. VCD may occur in otherwise healthy individuals and 20–40% of stable asthma patients [3], however, abnormal inspiratory vocal cord activities and putative VCD have not been investigated in other obstructive lung diseases. It is therefore of interest to determine whether inspiratory closure occurs in COPD. Inspiratory vocal cord closure is surprisingly prevalent in COPD <http://bit.ly/2TVHMn0> The authors would like to thank Paul Finlay and Kathy Low for their contribution to this study.
Identification of the optimal patients for trifluridine/tipiracil (FTD/TPI) treatment in mCRC: A Spanish real-world analysis.
Authors: Ana Fernandez Fernandez Montes, Francisca Vazquez Rivera, Nieves Martinez Lago, Marta Covela Rúa, Antia Cousillas Castiñeiras, Paula Gonzalez Villarroel, Juan De la camara, Carlos Méndez Méndez, Mercedes Salgado Fernandez, Sonia Candamio Folgar, Margarita Reboredo Lopez, Marta Carmona Campos, Elena Gallardo Martin, Monica Jorge Fernandez, Maria Luz Pellon Augusto, Jesus Garcia Gomez
Journal: Journal of Clinical Oncology (2020)

146 Background: FTD/TPI has demonstrated significantly overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies. Nevertheless, data regarding the pt profile that benefits most from this FTD/TPI is scarce. Some reports have shown optimal benefit for pts with low tumor burden indolent disease, ECOG PS 0-1, and no liver metastasis. Methods: We conducted a retrospective, multicenter, observational study of pts treated with FTD/TPI at eight hospitals from the Galician Research Group on Digestive Tumours (GITuD). Data were analyzed for a correlation between prognostic characteristics (good prognostic characteristics (GPC) vs. poor prognostic characteristics (PPC)), clinicopathological characteristics and survival. The GPC group was composed of pts who have one or two metastatic sites and time from diagnosis of 1st metastases to treatment ≥ 18 months. Results: Between January 1, 2017 and August 20, 2018, 160 pts were included in the study, of which 85 pts (53.1%) were classified as PPC and 75 pts (46.9%), as GPC. Pts with PPC were associated with younger age (60.5 vs. 63.7 years, p=0.034), higher presence of liver metastases (83.5% vs. 60%, p=0.001) and lower incidence of primary tumor resection (34.1% vs. 17.3%, p=0.019), without differences in ECOG PS, RAS mutation, tumor stage at diagnosis, lung metastases and sidedness. In the whole population of pts median OS and PFS were 7.63 months and 2.75 months, respectively. However, in the GPC and PPC groups mPFS were 2.64 vs. 2.33 months, respectively (p=0.311). Also, median OS was 8.23 months for GPC and 6.75 months for PPC, respectively. Interestingly,the mOS reached 10.5 months in those patients in the GPC group without liver metastasis. OS according ECOG PS 0/1/2 were 10.9 vs. 7.8 vs. 4.4 months, respectively (p=0.004) in the GPC group of pts. Conclusions: We have identified a subgroup of pts who most benefit from FTD/TPI, characterized by ECOG PS 0, low tumor burden, indolent disease and no liver metastasis.
A real-world analysis of non-small cell lung cancer patients treated with pembrolizumab or pembrolizumab in combination with pemetrexed and platinum.
Authors: Himani Agg, Katherine B. Winfree, Yajun Emily Zhu, Catherine Muehlenbein
Journal: Journal of Clinical Oncology (2020)

53 Background: Pembrolizumab (Pembro) is used in first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) as monotherapy and in combination with pemetrexed and platinum agent (Pembro+Pem+Plat). Pembro monotherapy is approved for patients whose tumors express PD-L1 Tumor Proportion Score (TPS) ≥ 1% while triplet therapy is approved regardless of PD-L1 TPS. These 2 regimens have not been compared in a head-to-head trial, and real world (RW) treatment pattern data are lacking. This study used RW data to describe patients who received Pembro or Pembro+Pem+Plat and associated overall survival (OS). Methods: This retrospective observational study selected adult patients with diagnosis of advanced NSQ NSCLC who started first-line treatment with Pembro or Pembro+Pem+Plat between Mar. 2015- Aug. 2018 in Flatiron Health’s electronic health record-derived database. Patient characteristics were summarized descriptively, and the Kaplan-Meier survival method was used (unadjusted). Results: A total of 1137 patients received Pembro (median age 72 years) and 1068 patients received Pembro+Pem+Plat (median age 67 years). Patient characteristics are shown in the Table. Median OS was 11.9 months for the Pembro cohort and 14.3 months for the Pembro+Pem+Plat cohort. Median OS by PD-L1 TPS was TPS &lt; 1%: 8.8 months for Pembro and 9.5 months for Pembro+Pem+Plat, TPS 1-49%: 8.9 months for Pembro and not reached (NR) for Pembro+Pem+Plat, and TPS ≥50%: 13.4 months for Pembro and NR for Pembro+Pem+Plat. Conclusions: These RW data seem to suggest baseline differences between the population with Pembro and Pembro+Pem+Plat with regard to age, PS, disease stage, as well as PD-L1 status. Those baseline differences may play a role in the clinicians’ choice of the two treatment options for the NSCLC patients. [Table: see text]
<i>APOE</i> genotype regulates pathology and disease progression in synucleinopathy
Authors: Albert A. Davis, Casey E. Inman, Zachary M. Wargel, Umber Dube, Brittany M. Freeberg, Alexander Galluppi, Jessica N. Haines, Dhruva D. Dhavale, Rebecca Miller, Fahim A. Choudhury, Patrick M. Sullivan, Carlos Cruchaga, Joel S. Perlmutter, Jason D. Ulrich, Bruno A. Benitez, Paul T. Kotzbauer, David M. Holtzman
Journal: Science Translational Medicine (2020)

Apolipoprotein E (
MAIT Cells Are Enriched and Highly Functional in Ascites of Patients With Decompensated Liver Cirrhosis
Authors: Christian E. Niehaus, Benedikt Strunz, Martin Cornillet, Christine S. Falk, Ansgar Schnieders, Benjamin Maasoumy, Svenja Hardtke, Michael P. Manns, Anke R.M. Kraft, Niklas K. Björkström, Markus Cornberg
Journal: Hepatology (2020)

Background and Aims Patients with advanced liver cirrhosis have an increased susceptibility to infections. As part of the cirrhosis‐associated immune dysfunction, mucosal‐associated invariant T (MAIT) cells, which have the capacity to respond to bacteria, are severely diminished in circulation and liver tissue. However, MAIT cell presence and function in the peritoneal cavity, a common anatomical site for infections in cirrhosis, remain elusive. In this study, we deliver a comprehensive investigation of the immune compartment present in ascites of patients with decompensated liver cirrhosis, and focus especially on MAIT cells. Approach and Results To study this, matched peripheral blood and ascites fluid were collected from 35 patients with decompensated cirrhosis, with or without spontaneous bacterial peritonitis (SBP). MAIT cell phenotype and function were analyzed using high‐dimensional flow cytometry, and the obtained data were compared with the blood samples of healthy controls (n = 24) and patients with compensated cirrhosis (n = 11). We found circulating MAIT cells to be severely decreased in patients with cirrhosis as compared with controls. In contrast, in ascites fluid, MAIT cells were significantly increased together with CD14 + CD16 + monocytes, innate lymphoid cells, and natural killer cells. This was paralleled by elevated levels of several pro‐inflammatory cytokines and chemokines in ascites fluid as compared with plasma. Peritoneal MAIT cells displayed an activated tissue‐resident phenotype, and this was corroborated by increased functional responses following stimulation with E. coli or interleukin (lL)‐12 + IL‐18 as compared with circulating MAIT cells. During SBP, peritoneal MAIT cell frequencies increased most among all major immune cell subsets, suggestive of active homing of MAIT cells to the site of infection. Conclusions Despite severely diminished MAIT cell numbers and impaired phenotype in circulation, peritoneal MAIT cells remain abundant, activated, and highly functional in decompensated cirrhosis and are further enriched in SBP. This suggests that peritoneal MAIT cells could be of interest for immune‐intervention strategies in patients with decompensated liver cirrhosis and SBP.
The relationship between chemotherapy-induced peripheral neuropathy and heart rate variability.
Authors: Aelee Jang, Dong Uk Kim
Journal: Journal of Clinical Oncology (2020)

820 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication related to chemotherapeutic agents and dose accumulation. Initial symptoms are known to be sensory including numbness and pain whereas autonomic symptoms are the latest. Autonomic dysfunction is related to heart rate variability (HRV) change which may precede the symptoms. But, the relationship between CIPN and heart rate variability is not fully evaluated. Therefore, we aimed to evaluate the HRV with CIPN-related questionnaires in patients underwent chemotherapy. Methods: Fifty-five patients with gastrointestinal cancers were enrolled in this cross-sectional cohort study. Patients have received chemotherapeutic agents such as paclitaxel, cisplatin, and oxaliplatin. CIPN was diagnosed using National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI-CTCAE version 4.03). We evaluated the quality of life, CIPN symptom scale, and HRV. Results: Forty-two patients were male (76.4%) and mean age was 63.2 years old. Thirty-nine patients (71.0%) had CIPN of more than grade I according to NCI-CTCAE. Patients with CIPN represented lower physical and role functions. The standard deviation of all normal R-R intervals (SDNN) was decreased in the CIPN group. Parasympathetic tone (high frequency band) were decreased, but sympathetic activity (low frequency band/high frequency band) were increased in CIPN. Conclusions: CIPN affected the quality of life in gastrointestinal cancer patients underwent chemotherapy. HRV was related to CIPN. Further study may be needed to check the feasibility of HRV as early biomarkers for detecting CIPN. [Table: see text]
Role of para-aortic lymph node sampling for patients with potentially resectable biliary cancer.
Authors: Hiromichi Ito, Yoshihiro Ono, Takafumi Sato, Yosuke Inoue, Yu Takahashi
Journal: Journal of Clinical Oncology (2020)

540 Background: While paraaortic lymph node (PALN) metastasis has been known as poor prognostic indicator for patients with biliary cancer and is regarded as distant metastasis in AJCC staging system. However, preoperative diagnosis of PALN metastasis by current imaging studies is not accurate and the incidence of PALN metastasis among patients with potentially resectable biliary cancer and its impact on their long-term outcomes remain unclear. Methods: The patients who underwent exploratory laparotomy with PALN sampling for potentially resectable biliary cancer at our institution from 2006 through 2018 were included. All patients were appropriately staged preoperatively with CT/MRI and patients with suspected PALN metastasis preoperatively were not considered resectable disease, and thus, such patients were not included. The incidence of PALN metastasis and long-term outcomes (recurrence-free and overall survivals [RFS, OS]) for patients with/without PALN metastasis were compared. Results: Total 383 patients with three types of biliary cancers (164 perihilar cholangiocarcinoma [PHCC], 115 distal cholangiocarcinoma [DCC] and 104 gallbladder cancer [GBCA]) were included. The median age was 71 years and 65% were man. Majority of them (362 patients [95%]) completed planned resection and 9 patients (2%) died of post-operative complications. PALN metastasis was confirmed on 33 patients (9%) among the entire cohort; the yield of positive PALN sampling was the highest in the patients with GBCA (14%), followed by 9% in those with PHCC and 4% in those with DCC. Among 33 patients with positive PALN, 20 underwent tumor resection. Median RFS and OS following resection for the patients with PALN metastasis were 11 months and 22 months, respectively, compared to 46 months and 56 months for those without, respectively ( p&lt; 0.001 for both RFS and OS). There were no survivors beyond 5-years among those with PALN metastasis. Conclusions: The yield of routine intraoperative PALN sampling is not small even among patients with potentially resectable biliary cancer and positive PALN indicates poor long-term outcomes. This procedure can provide the opportunity to avoid morbid operation for patients who unlikely benefits.
Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): Results from the multicohort, phase II KEYNOTE-158 study.
Authors: Aurelien Marabelle, Philippe Alexandre Cassier, Marwan Fakih, Tormod Kyrre Guren, Antoine Italiano, Steven Chuan-Hao Kao, Dorte Nielsen, Paolo Antonio Ascierto, Giovanni M. Bariani, Armando Santoro, Manisha H. Shah, Jamil Asselah, Anthony B. El-Khoueiry, Kristen Renee Spencer, Shunji Takahashi, Arkendu Chatterjee, Fan Jin, Kevin Norwood, Jean-Pierre Delord
Journal: Journal of Clinical Oncology (2020)

1 Background: For patients (pts) with ASCC, second-line or later treatment options have been limited. Pembrolizumab (pembro), an anti-PD-1 monoclonal antibody, has demonstrated antitumor activity in several tumor types (including ASCC) in the multicohort phase 1b KEYNOTE-028 study. KEYNOTE-158 (NCT02628067) is an open-label, phase 2, multicohort study that evaluates antitumor activity and safety of pembro in pts with previously treated advanced cancer. Results from the ASCC cohort are presented. Methods: Eligible pts were ≥18 y with histologically/cytologically documented metastatic and/or unresectable ASCC with prior treatment failure on or intolerance to standard first-line therapy, measurable disease per RECIST v1.1, ECOG PS of ≤1, and evaluable tissue sample for PD-L1 and biomarker analysis. PD-L1 expression was assessed by the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). Pts received pembro 200 mg Q3W until disease progression, unacceptable AE, or completion of 35 cycles. The primary endpoint was ORR per RECIST v1.1 (assessed every 9 wk for 12 mo, then every 12 wk thereafter) by independent central review. Secondary endpoints were DOR, OS, PFS and safety. Results: 112 pts with ASCC were enrolled (81.3% women; median age, 61 y [range 32–79]; ≥2 prior therapies, 73.2%). At database cutoff (Dec 6, 2018) 10 pts (8.9%) had completed 35 cycles and 102 discontinued; median follow-up was 12.0 mo (range, 0.8–33.0) Five pts had CR and 8 had PR; ORR was 11.6% (95% CI, 6.3–19.0). Median DOR was not reached (range, 6.0+ to 29.1+ mo). Responses occurred in 11/75 pts (14.7%) with PD-L1 combined positive score (CPS) ≥1 and 2/30 pts (6.7%) with PD-L1 CPS &lt; 1. Among all pts, median OS was 12.0 mo (95% CI, 9.1–15.4), and median PFS was 2.0 mo (95% CI, 2.0–2.1). 68 (60.7%) pts had treatment-related AEs, including 21 (18.8%) who had grade 3–5 events; there were no treatment-related deaths. 4 pts (3.6%) discontinued due to treatment-related AEs. 27 pts (24.1%) had immune-mediated AEs/infusion reactions. Conclusions: Pembro demonstrated antitumor activity and manageable toxicity in pts with heavily pretreated advanced ASCC, regardless of PD-L1 status. Clinical trial information: NCT02628067.
Avelumab flat dose regimen: Justification for use in advanced renal cell carcinoma (aRCC).
Authors: John B. A. G. Haanen, Joanna C. Masters, Bo Huang, Toni K. Choueiri, Robert J. Motzer, Akash Khandelwal, Haiqing (Isaac) Dai, Alessandra di Pietro, Satjit Brar, Brian I. Rini, Laurence Albiges, James M. G. Larkin
Journal: Journal of Clinical Oncology (2020)

32 Background: Avelumab, an anti–PD-L1 monoclonal antibody, was recently approved for the treatment of aRCC in combination with axitinib and was previously indicated for the treatment of metastatic Merkel cell carcinoma (MCC) and platinum-treated advanced/metastatic urothelial carcinoma (UC). Although avelumab was approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), it was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (popPK), exposure-efficacy and exposure-safety modeling and simulations in MCC and UC (Novakovic AM, et al. Clin Pharmacol Ther. 2019). The justification for the recommended flat-dose regimen for avelumab as combination therapy with axitinib in aRCC is presented. Methods: Simulated exposure metrics (eg, area under the curve) from the previous popPK model (data from 1,827 patients with solid tumors across 3 clinical trials) for both weight-based and flat-dose regimens were compared with the exposure metrics obtained from treatment-naive patients with aRCC enrolled in 2 clinical studies (N = 488 from NCT02493751 and NCT02684006) who received avelumab (10 mg/kg Q2W) + axitinib (5 mg orally twice daily). Avelumab exposure-response relationships for safety and efficacy were also analyzed. Endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs) and immune-related (ir)AEs, and progression-free survival (PFS) by independent review. Results: The administration of weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to simulated reference exposures of the flat-dose regimen in the solid tumor population. Avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or IRRs, although there was a weak association with an increased probability of any-grade irAEs. Conclusions: The similar exposures observed for both avelumab dosing regimens in aRCC, and in prior studies in the MCC and UC populations, suggest that the 800 mg Q2W flat-dose regimen will maintain the benefit-risk ratio for avelumab + axitinib for treatment-naive patients with aRCC. Clinical trial information: NCT02493751 . Clinical trial information: NCT02684006.