tbuckley/cabot-search huggingface dataset:
Gls-010, a novel anti-PD-1 mAb in Chinese advanced gastrointestinal tumor: Result of a phase Ib clinical trial.
Authors: Shen Lin, Jifang Gong, Yingying Xu, Xiaotian Zhang, Zhi Peng, Changsong Qi, Guochun Li, Haijin Meng, Zhen Liu, Hui Wang, Chris Chen, Jing Li, Yong Zheng, Johnathan Lee, Yan Zhang, Qiang Zhang, Ge Jin, Yining Yang, Guodong Zhao
Journal: Journal of Clinical Oncology (2019)

125 Background: GLS-010 is a novel fully human anti-PD-1 mAb. Phase Ia exhibited good result of tolerance and 240mg fixed dose was selected. Phase Ib is to explore efficacy and biomarkers in different types of advanced cancer. Here we report the preliminary result in Chinese gastrointestinal (GI) tumor patients (pts) from the phase Ib. Methods: All pts enrolled received GLS-010 240mg every 2 weeks. Tumor response was assessed by RECIST 1.1 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Several biomarkers were evaluated, including PD-L1 by IHC, tissue tumor mutation burden (tTMB) by whole exome sequencing (WES) from FFPE tissue, blood TMB (bTMB) by the multi-gene panel based next-generation sequencing (NGS) from blood ctDNA. Results: Until September 2018, 23 pts (including 10 gastric cancer or GC, 10 esophagus cancer or EC, and 3 biliary tract cancer or BTC) were enrolled in the phase 1b. The median dosing number was 4 (range: 1~16). The most common treatment related AEs included haemoglobin decreased (16/23, G1-2), leukopenia (6/23, G1-2), fever (4/23, G1), blood bilirubin increased (4/23, G1-3), ALT increased (3/23, G1), etc. Treatment–related grade 3-5 AEs include 1 multiple organ dysfunction syndrome, 1 interstitial lung disease and 1 blood bilirubin increased. 21 pts received response evaluation. Four patients achieved partial response (PR), including 1 GC (1/9), 2 EC (2/10), and 1 BTC (1/2). 2 subjects had stable disease (SD) at Week 8, and were still in treatment. No apparent correlation was observed between treatment response and PD-L1 expression. However, both tTMB and bTMB data obtained from 18 patients support positive correlation to tumor response. The tTMB level of 3 PR pts with valid data is significantly higher than that of 9 PD pts (P = 0.036). The bTMB level of 4 PR pts with valid data is significantly higher than that of 10 PD pts (P = 0.049). Conclusions: GLS-010 showed promising efficacy and acceptable safety in Chinese patients. For Chinese GI tumor TMB may be a useful biomarker to predict the treatment response to PD-1 inhibitor. Comparing to tTMB, bTMB may be of more future value due to its applicability in clinical practice.
Abstract 20480: Channel Pore Mutation of RyR2 Cause Calcium Leak Independent of FKBP12.6-RyR2 and Calmodulin-RyR2 Affinity in R4496C/+ Knock-in Mouse
Authors: Hitoshi Uchinoumi, Ivanita Stefanon, Yi Yang, Mena Said, Xiaoqiong Dong, Rogerio Faustino, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H Wehrens, Wayne S Chen, Takeshi Yamamoto, Yano Masafumi, Donald M Bers
Journal: Circulation (2017)

Introduction and Hypothesis: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited stress-induced arrhythmogenic disease caused by mutations in cardiac ryanodine receptor (RyR2). These mutations cluster in 3 regions of the RyR2 mutable regions (N-terminal, central, and channel pore). Diastolic calcium (Ca) leak via RyR2 can cause lethal arrhythmia such as CPVT. We have reported conformational unzipping within RyR2 reduces calmodulin (CaM)-RyR2 affinity in a central CPVT mouse (R2474S/+). To further understand the pathophysiology of RyR2 mutation on CaM-RyR2 affinity in 3 distinct (N-terminal, central, and channel pore) CPVT knock-in (KI) mice. We tested the hypothesis that RyR2 mutation cause Ca leak by reduced CaM affinity in 3 distinct CPVT KI mice (R176Q/+, R2474S/+, and R4496C/+). Methods and results: Ventricular myocytes was isolated from hearts of 3 KI and wild-type (WT) mice. Fluorescence resonance energy transfer (FRET) between donor-F-FKBP (FK506-binding protein) and accept...
Abstract 16891: Beat-to-beat Systolic as Well as Diastolic Blood Pressure Variability is High in Atrial Fibrillation
Authors: Joakim Olbers, Adam Gille, Jan Östergren, Petter Ljungman, Mårten Rosenqvist, Nils Witt
Journal: Circulation (2015)

Background: Atrial fibrillation (AF) is associated with an increased risk for cardiovascular morbidity and mortality, beyond thromboembolism. The underlying mechanisms for this association are not fully understood but may involve effects on artery walls and endothelial function. High blood pressure (BP) incurs an increased risk of cardiovascular events. The interplay between AF and BP is insufficiently studied. Material and methods: We studied 33 patients, 21 in AF and 13 in sinus rhythm (SR), during coronary angiography. After catheterization of the radial artery invasive BP was recorded four times at three locations (radial artery, brachial artery (twice) and ascending aorta). BP was recorded for a minimum of 15 consecutive beats. BP variability defined as mean beat-to-beat BP difference was calculated for systolic and diastolic BP at each site. Results: There was a significant difference (p&lt;0.001) in mean systolic and diastolic beat-to-beat BP variability between the AF and SR groups at all locations, see figures. No significant difference in BP variability was seen between locations. RA = Radial Artery; BA = Brachial Artery; AA = Ascending Aorta Conclusions: Beat-to-beat BP variability in patients with AF is substantially higher than in patients with SR. Systolic BP variability was almost twice as high and diastolic BP variability was almost seven times as high in AF as compared to SR. Hemodynamic effects of this beat-to-beat variation in BP may have negative effects on vascular structure and function, possibly contributing to the disproportionate increase in cardiovascular morbidity and mortality seen in AF patients.
Safety and efficacy of lenvatinib by starting dose (8 mg or 12 mg) based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT.
Authors: Takuji Okusaka, Kenji Ikeda, Masatoshi Kudo, Richard S. Finn, Shukui Qin, Kwang-Hyub Han, Ann-Lii Cheng, Fabio Piscaglia, Masahiro Kobayashi, Max W. Sung, Minshan Chen, Lucjan Wyrwicz, Jung-Hwan Yoon, Zhenggang Ren, Daniel E. Stepan, Corina E. Dutcus, Toshiyuki Tamai, Min Ren, Seiichi Hayato, Hiromitsu Kumada
Journal: Journal of Clinical Oncology (2019)

316 Background: Lenvatinib (LEN) demonstrated statistical confirmation of noninferiority versus sorafenib (SOR) for overall survival (OS), and improved progression-free survival (PFS), time to progression, and objective response rate (ORR) in pts with uHCC in REFLECT (Kudo M et al, Lancet 2018). We report the efficacy and safety of LEN by starting dose, which was based on body weight (BW). Methods: In REFLECT, a multicenter, open-label, noninferiority trial, pts with uHCC were randomized 1:1 to LEN (BW &lt; 60 kg: 8 mg/d; BW ≥ 60 kg: 12 mg/d; QD) or SOR (400 mg BID). Efficacy was analyzed by intention-to-treat; safety was analyzed in pts who received treatment, in each dose group. Results: Of 478 pts randomized to LEN, 151 (male, 70%; median age, 65 y) and 327 (male, 91%; median age, 62 y) were included in the LEN starting dose groups of 8 mg/d or 12 mg/d, respectively. In the 8-mg group, 14% of pts were from Western regions; 86% from Asia-Pacific. In the 12-mg group, 42% were from Western regions; 58% from Asia-Pacific. Median OS was 13.4 (95% CI: 10.5–15.7) and 13.7 months (95% CI: 12.0–15.6); ORR was 22.2% and 24.9% for pts with BW &lt; 60 kg and ≥ 60 kg, respectively. Median PFS was 7.4 months in both groups. Median duration of treatment: 8-mg group, 5.6 months; 12-mg group, 6.3 months. Mean LEN relative dose intensity: 8-mg group, 87.7%; 12-mg group, 87.5%. Most common any-grade adverse events (AEs; 8-mg vs 12-mg) were hypertension (43% vs 42%), diarrhea (35% vs 40%), decreased appetite (33% vs 35%), weight loss (29% vs 32%), and fatigue (28% vs 31%). Adjusted by treatment duration, AE rates (episodes/patient-year) were similar for 8-mg versus 12-mg: hypertension (0.79 vs 0.78), diarrhea (1.06 vs 0.99), decreased appetite (0.63 vs 0.59), weight loss (0.50 vs 0.51), and fatigue (0.52 vs 0.47). Pharmacokinetic profiles were similar between groups. Conclusions: LEN efficacy was comparable between groups. Exposure to LEN was greater for the 12-mg versus 8-mg group. When AEs were adjusted by treatment duration, no notable differences in the AE profiles between the starting doses were observed. Altogether, these results support the 8-mg and 12-mg starting doses based on BW of &lt; 60 kg and ≥ 60 kg, respectively, in REFLECT. Clinical trial information: NCT01761266.
Real-Life Management of Immune Thrombocytopenia in the Elderly: A Multicentre Study on 526 Patients
Authors: Francesca Palandri, Cristina Santoro, Monica Carpenedo, Cantoni Silvia, Wilma Barcellini, Giuseppe Carli, Valentina Carrai, Elena Rossi, Elena Rivolti, Alessandro Lucchesi, Francesco Rotondo, Giuseppe Auteri, Marco Ruggeri, Alessio Fusco, Erminia Baldacci, Lucia Catani, Daniela Bartoletti, Michele Cavo, Valerio De Stefano, Maria Gabriella Mazzucconi, Francesco Rodeghiero, Nicola Vianelli
Journal: Blood (2018)
E-Selectin Ligand Expression By Leukemic Blasts Is Associated with Prognosis in Patients with AML
Authors: Sylvia S Chien, Jin Dai, John L Magnani, Taylor S Sekizaki, William E Fogler, Helen M Thackray, Kelda Gardner, Elihu H. Estey, Pamela S Becker
Journal: Blood (2018)
Elevated Levels of CD64 MFI on Monocyte Subsets Are Associated with a History of Stroke in Sickle Cell Disease
Authors: Susanna A Curtis, Raisa Balbuena-Merle, Lesley Devine, Daniel Zelterman, John D. Roberts, Jennifer Dearborn-Tomazos, Lauren Sansing, Jeanne E. Hendrickson
Journal: Blood (2018)
Prognostic Value of Circulating Bcl-2/Igh Levels before and after Treatment in 415 Patients with Advanced Follicular Lymphoma Receiving First-Line Immuno-Chemotherapy in 2 Prospective StiL Trials - the Effect of Rituximab Maintenance
Authors: Guido Kobbe, Sabrina Pechtel, Fabian Zohren, Jürgen Barth, Alexander Christoph Burchardt, Christian Buske, Ariane Dienst, Ulrich Germing, Richard Greil, Bernd Hertenstein, Frank Kauff, Michael Koenigsmann, Christian Lerchenmüller, Thomas Michael Schroeder, Rainer Haas, Mathias J Rummel
Journal: Blood (2018)
Augmentation of Extinction and Inhibitory Learning in Anxiety and Trauma-Related Disorders
Authors: Lauren A.M. Lebois, Antonia V. Seligowski, Jonathan D. Wolff, Sarah B. Hill, Kerry J. Ressler
Journal: Annual Review of Clinical Psychology (2019)

Although the fear response is an adaptive response to threatening situations, a number of psychiatric disorders feature prominent fear-related symptoms caused, in part, by failures of extinction and inhibitory learning. The translational nature of fear conditioning paradigms has enabled us to develop a nuanced understanding of extinction and inhibitory learning based on the molecular substrates to systems neural circuitry and psychological mechanisms. This knowledge has facilitated the development of novel interventions that may augment extinction and inhibitory learning. These interventions include nonpharmacological techniques, such as behavioral methods to implement during psychotherapy, as well as device-based stimulation techniques that enhance or reduce activity in different regions of the brain. There is also emerging support for a number of psychopharmacological interventions that may augment extinction and inhibitory learning specifically if administered in conjunction with exposure-based psychotherapy. This growing body of research may offer promising novel techniques to address debilitating transdiagnostic fear-related symptoms.
Outcomes with ibrutinib by line of therapy and post‐ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis
Authors: Susan M. O'Brien, John C. Byrd, Peter Hillmen, Steven Coutre, Jennifer R. Brown, Paul M. Barr, Jacqueline C. Barrientos, Stephen Devereux, Tadeusz Robak, Nishitha M. Reddy, Thomas J. Kipps, Alessandra Tedeschi, Florence Cymbalista, Paolo Ghia, Stephen Chang, Joi Ninomoto, Danelle F. James, Jan A. Burger
Journal: American Journal of Hematology (2019)

Abstract The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first‐line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher‐risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib‐treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single‐agent ibrutinib: RESONATE (PCYC‐1112) in patients with R/R CLL and RESONATE‐2 (PCYC‐1115) in patients with treatment‐naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib‐treated non‐del(17p) patients with CLL (136 TN and 135 R/R). Median progression‐free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow‐up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow‐up 18 months, n = 51) and was not reached in TN patients (median follow‐up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy.
Comparison of HER2 expression by immunohistochemistry and <i>HER2</i> copy number by digital PCR in tumor tissue during treatment with trastuzumab in the prospective cohort of metastatic HER2-positive gastric cancer patients.
Authors: Naoki Takahashi, Satoru Iwasa, Tomohiro Matsushima, Shoichi Miyazawa, Yosuke Kumekawa, Satoshi Shimizu, Takako Yoshii, Masako Asayama, Hiroki Hara
Journal: Journal of Clinical Oncology (2019)

58 Background: Trastuzumab (Tmab) is an active molecular-targeted drug for HER2-positive gastric cancer (GC) patients. HER2 expression is known to change during the treatment of Tmab and HER2 amplification in blood is widely investigated as a new biomarker of the treatment candidate or the monitoring of HER2-target therapy. We evaluated the change of the HER2 expression by immunohistochemistory (IHC) and HER2 copy number by degital PCR during the treatment with Tmab in metastatic HER2-positive GC patients. Methods: Metastatic HER2-positive GC patients treated with Tmab were registered prospectively, and tissues were obtained by biopsy from primary lesions at the following points: (1) pre-treatment, (2) post-treatment, and (3) disease progression during chemotherapy with Tmab. Formalin-fixed paraffin-embedded tissue slides were prepared, and the expression of HER2 expression were scored by IHC and HER2 copy number were evaluated by digital-PCR. Results: Among 20 enrolled patients, HER2 expression was evaluated by IHC in all patients. HER2 copy number was evaluated by digital PCR in 15 patients. A patient was excluded because HER2 expression were not detected by re-evaluation. The median of HER2 copy number of 33 sampling points during the treatment was 6.37 (range: 2.12 - 85.8). The median of HER2 copy number of IHC 3+, IHC 2+, IHC 0-1 were 22.4 (3.37 – 85.8), 2.88 (2.65 – 3.6), 2.37 (2.12 – 3.85), respectively. High level of HER2 copy number was detected in tumor tissues of HER2 IHC 3+ compared with that of IHC≦2+. HER2 expression by IHC was disappeared after treatment of Tmab in 42% of HER2-positive patients. Among these patients, HER2 copy number at pre-treatment were relatively low (2.63 - 3.6). Conclusions: High copy number of HER2 was detected in tumor tissues with HER2 IHC3+ in HER2-positive GC patients during the treatment of Tmab. In addition, low copy number of HER2 in tumor tissues at pre-treatment may be associated with the loss of HER2 expression after treatment of Tmab. Further research by large number of patients to confirm our results is required.
Expression and Functional Analysis of CST1 in Intractable Nasal Polyps
Authors: Yukinori Kato, Tetsuji Takabayashi, Masafumi Sakashita, Yoshimasa Imoto, Takahiro Tokunaga, Takahiro Ninomiya, Taiyo Morikawa, Kanako Yoshida, Emiko Noguchi, Shigeharu Fujieda
Journal: Journal of Allergy and Clinical Immunology (2019)
GP is suspended after failing to take proper histories and order necessary tests for patients
Authors: Clare Dyer
Journal: BMJ (2019)

A GP who failed to take proper histories and order necessary tests for patients has been suspended for nine months by a medical practitioners’ tribunal.

Kevin Newley, who ran a single handed practice in Leicester with a list of 2800 patients, was accused of failings in the care of eight patients, several of whom were older men who were later diagnosed with prostate cancer at hospital.

After a hearing that spanned nearly two years, with several long adjournments, the tribunal found failings in the care of seven patients. In one patient’s case no failings were proved.

The failures included lapses in taking and recording patient histories, in advising patients, …
Comparison of biomarkers among 34855 GI cancer samples shows heterogeneity of tumor types.
Authors: Shaheenah S. Dawood
Journal: Journal of Clinical Oncology (2019)

217 Background: Recent data indicate that biomarker driven use of targeted therapy and I/O-therapy among patients with GI cancer is associated with improved outcome. The presence of biomarkers varies broadly between different GI tumor types, highlighting the importance of comprehensive molecular profiling. To analyze the presence of various alterations in GI cancer samples of a large database, comparing congruency between various tumor types. Methods: A retrospective data analysis of 34855 GI cancer patients profiled at CARIS Life Sciences obtained from Jan 1, 2010 till Sep 14, 2018 was performed. GI tumors were classified as CRC, esophageal/gastric/GIST, small intestine, pancreatic/hepatobiliary/liver. Technologies used to analyze the biomarkers: IHC for PD-L1, MMR and Her2, and DNA-NGS for EGFR, BRAF, KRAS, NRAS, MET-CNV, TMB, MSI, POLE and BRCA1/2. Results: Median age was 61 range (18-89 years). 51.5% was CRC (n=18047), 15.5 % was esophageal/Gastric/GIST (n=5470), 3% was small intestinal cancer (n=886) and 30% was pancreatic/hepatobiliary/liver cancer (n=10452). Information on biomarkers was available from 2931 cases for MET amplification to 28536 for RAS mutation. Overall, the most common finding was a pathogenic RAS-mutation in 7650 cases (26.81%), the rarest one was a mutation in EGFR in 12 cases (0.06%). Higher rate of HER2 amplification was observed among pts with esophageal/gastric/GIST tumors (6.5%) in comparison to tumors at other GI sites ( ~1.5%). High TMB was seen among patient with CRC and small intestine tumors (~7%) while it was lowest among pancreatic cancer (1.8%). Compared to other GI sites lower MSI /MMR deficiency rates were observed in pancreatic /hepatobiliary tumors, significantly higher PD-L1 positivity was observed in gastrooesophageal cancer types, increased MET-amplifications in gastrooesophageal and small intestinal cancer types and lower RAS-mutation rate in gastrooesophageal cancer. Conclusions: Molecular profiling analyzing druggable biomarkers can help identify patients with increased likelihood for benefit from immune-checkpoint-inhibitors and targeted therapies. Further investigations are needed to evaluate the different findings in various GI cancer types.
Peroral endoscopic myotomy with fundoplication: are we there yet!
Authors: Nageshwar Reddy
Journal: Endoscopy (2019)

Peroral endoscopic myotomy (POEM) has revolutionized the endoscopic management of achalasia cardia. After almost a decade of "poetry," there is ample evidence to suggest that POEM is a safe and effective treatment modality for esophageal achalasia. Major adverse events are rare, and the procedure can be safely accomplished in an endoscopy suit.
Outcomes following liver SBRT for metastatic pancreatic cancer.
Authors: Oluwadamilola Temilade Oladeru, Eugene J Vaios, Christine Eyler, Bridget N. Noe, Carlos Fernandez Del-Castillo, Colin D. Weekes, Cristina Ferrone, Keith D Lillemoe, Motaz Qadan, Aparna Parikh, Jeffrey W. Clark, David P. Ryan, Jill N Allen, Theodore Sunki Hong, Jennifer Y Wo
Journal: Journal of Clinical Oncology (2019)

418 Background: Traditionally, the role of localized therapy for metastatic pancreatic cancer (MPC) has been limited. However, with more effective systemic therapies, recent studies have explored a potential role for local therapies. We aimed to report outcomes following SBRT (stereotactic body radiation therapy) for liver metastases (LM) in setting of MPC and to identify predictors of response. Methods: 41 patients who underwent ablative RT to LM for MPC (2005-17) were retrospectively identified. Median RT dose was 50 Gy (range: 8-60 Gy), delivered in 5-6 fractions. Kaplan Meier method was used to calculate local control (LC), progression-free survival (PFS) and overall survival (OS). Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were used to identify predictors of clinical outcomes. Results: Median follow up was 14.6 months. This cohort included 19 men and 22 women. 61% of pts had metachronous LM, 39% had synchronous LM. At time of RT, the treated lesion was stable /responding to chemotherapy (CTX) in 36.6% of pts; 46.3% were progressing with mixed response; 17% were off/refused CTX. Median number of prior CTX regimens was 2 (range: 0-5). Median number of LM was 1 (range: 1-4). Median pre-RT CEA was 7 ng/mL, median pre-RT CA19-9 was 354 U/ml. The 12-month outcomes were 75.8% LC, 16.5% PFS, and 36.3% OS. 8/41 (20%) patients were off CTX for ≥ 4 months. On UVA for LC, pre-RT CA19-9 (log10 scale) was associated with LC (HR 2.28, p = 0.03). Timing of LM, CTX response of LM, number of lesions, RT dose and CEA did not predict LC. On UVA for PFS, extrahepatic disease at time of RT was associated with worse PFS (HR: 2.47, p = 0.04), and response to CTX (progressive vs. stable/responding) approached significance (HR 1.83, p = 0.10). On UVA for OS, lower pre-RT CEA (HR 1.009, p = 0.03), lower pre-RT CA19-9 (HR 1.67, p = 0.01), and response to CTX (HR 6.42, p &lt; 0.001) were associated with improved OS. On MVA for OS, response to CTX at time of liver RT remained significant for OS. Conclusions: SBRT of LM for MPC offers high rate of LC. In a small subset of patients, SBRT to LM may offer prolonged duration off systemic therapy. Lower pre-RT CA 19-9 and CEA, absence of extrahepatic disease, and stability/response of CTX at time of liver RT may select for patients most likely to benefit.
Association Between History of Epinephrine Use and Dose-Related Adverse Event Rates During Oral Immunotherapy
Authors: Alexandra Scheiber, R. Sharon Chinthrajah, Andrew J. Long, Divya Kumar, Stacey Skura Zedeck, Melanie Shojinaga, Hyojin Min, Andres Alvarez, Maria I. Garcia Lloret, Kari C. Nadeau, Sayantani B. Sindher
Journal: Journal of Allergy and Clinical Immunology (2019)