tbuckley/cabot-search huggingface dataset:
Efficacy, Safety, and Biomarkers of Toripalimab in Patients with Recurrent or Metastatic Neuroendocrine Neoplasms: A Multiple-Center Phase Ib Trial
Authors: Ming Lu, Panpan Zhang, Yanqiao Zhang, Zhongwu Li, Jifang Gong, Jie Li, Jian Li, Yan Li, Xiaotian Zhang, Zhihao Lu, Xicheng Wang, Jun Zhou, Zhi Peng, Weifeng Wang, Hui Feng, Hai Wu, Sheng Yao, Lin Shen
Journal: Clinical Cancer Research (2020)

Patients with recurrent or metastatic neuroendocrine neoplasms (NEN) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat second-line metastatic melanoma in China in 2018.The multiple-center phase Ib trial enrolled patients with NENs (Ki-67 ≥ 10%) after failure of first-line therapy received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole-exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), and progression-free survival and overall survival.Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 <10% (50.0% vs. 10.7%, P = 0.019) and TMB-low patients (75.0% vs. 16.1%, P = 0.03). Three of 8 (37.5%) responders harbored ARID1A mutations, whereas only 1 of 27 nonresponders had mutations (P = 0.03). Of note, 1 exceptional responder with TMB-L, microsatellite stable (MSS), and PD-L1-negative had multiple genomic arrangements with high prediction score for neoantigens.Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%), and/or microsatellite instable (MSI-H) might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.
Impairments to Consolidation, Reconsolidation, and Long-Term Memory Maintenance Lead to Memory Erasure
Authors: Josué Haubrich, Matteo Bernabo, Andrew G. Baker, Karim Nader
Journal: Annual Review of Neuroscience (2020)

An enduring problem in neuroscience is determining whether cases of amnesia result from eradication of the memory trace (storage impairment) or if the trace is present but inaccessible (retrieval impairment). The most direct approach to resolving this question is to quantify changes in the brain mechanisms of long-term memory (BM-LTM). This approach argues that if the amnesia is due to a retrieval failure, BM-LTM should remain at levels comparable to trained, unimpaired animals. Conversely, if memories are erased, BM-LTM should be reduced to resemble untrained levels. Here we review the use of BM-LTM in a number of studies that induced amnesia by targeting memory maintenance or reconsolidation. The literature strongly suggests that such amnesia is due to storage rather than retrieval impairments. We also describe the shortcomings of the purely behavioral protocol that purports to show recovery from amnesia as a method of understanding the nature of amnesia.
Abstract 14737: National Physician Survey for Nonvalvular Atrial Fibrillation (NVAF) Anticoagulation Comparing Knowledge, Attitudes and Practice of Cardiologist to Primary Care Providers (PCPs)
Authors: Haseeb Saeed, Ujala Bokhary, Anastasia Jermihov, Kristine Kuchta, Kamila Lepkowska, Victoria Bauer, Marcia Wright, Scott Glosner, Margaret Frazer, Andres Quintero, Patrick Hlavacek, Jack Mardekian, Alfonso Tafur, Mark Metzl, Jorge Saucedo
Journal: Circulation (2018)

Introduction: NVAF is estimated to affect between 6.4 and 7.4 million Americans in 2018, and increases the risk of stroke five-fold. To mitigate this risk, guidelines recommend anticoagulating AF p...
Transperineal prostate biopsies without antibiotic prophylaxis: Safety evaluation of the first 65 patients.
Authors: Tobias Kohl, Kai-Peter Schuster, Konrad Lang, Alexandra Blanckenberg, Timur H. Kuru, Jürgen Zumbé, Daniel Porres
Journal: Journal of Clinical Oncology (2020)

355 Background: There is an ongoing trend towards perineal prostate biopsies for the detection of prostate cancer. For many reasons the issue of antibiotic prophylaxis in prostate biopsies is becoming more important, especially with quinolone antibiotics being excluded from this indication and an increasing antibiotic resistance. Considering that the perineal biopsy is a sterile procedure, not giving antibiotics for prophylaxis seems to be an alluring approach. Methods: At the General Hospital Leverkusen, transperineal (TP) MRI TRUS fusion biopsies are performed using the Ginsburg Protocol with a template and software-guided approach in general anesthesia. Patients received single dose antibiotics (Ciprofloxacine 500 mg) two hours prior to surgery from Jan 2019 to Aug 2019 (group 1). Starting in Sep 2019, no antibiotics were used for prophylaxis (group 2). Surgical disinfection using Povidone-iodine was performed ahead of every procedure. In this study, postoperative infection rates were assessed. Patients were followed up by telephone interview at least two weeks after biopsy and were asked about the need for postoperative antibiotics to treat regular UTI, fever, prostatitis or for readmission to other hospitals. Results: A total of 180 TP biopsies were performed with a median of 22 cores (min 18, max 28). Out of 115 cases with antibiotic prophylaxis, no patient was readmitted to the hospital due to infection or fever. Group 2 included 65 patients. No one was readmitted with fever or prostatitis. At the time of abstract admission 45 out of 65 patients in this group were followed up by telephone interview. None needed antibiotics and none was readmitted to a hospital elsewhere. Conclusions: The study shows an infection rate of 0 % for perineal prostate biopsies with or without antibiotic prophylaxis. The results argue in favor of perineal prostate biopsies and challenge the dogma of prostate biopsies needing an antibiotic prophylaxis irrespective of the approach. However, a larger prospective multicenter study should be initiated to ensure patient safety.
Efficacy and toxicity according to hormone therapy used in the CHHiP trial.
Authors: Alison Tree, Clare Griffin, Emma Hall, David P. Dearnaley
Journal: Journal of Clinical Oncology (2020)

316 Background: CHHiP (CRUK/06/016) is a multicentre randomised controlled trial which investigated the use of moderately hypofractionated radiotherapy (RT) dose schedules for treatment of localised prostate cancer. 97% of participants (pts) had concurrent androgen deprivation therapy (ADT). Luteinising Hormone Releasing Hormone analogues (LHRHa) and bicalutamide 150mg (BIC) daily were permitted. This exploratory analysis investigates whether both ADT regimens show similar efficacy and whether BIC has the propensity to preserve erectile function. Methods: In CHHiP, 2700 pts received LHRH and 403 BIC, median duration 5.6 months. The primary endpoint was biochemical or clinical failure (BCF). ADT groups were compared with Cox regression adjusted forage, NCCN risk group, Gleason score,T-stage and stratified by RT dose. A key secondary endpoint was erectile function assessed by clinicians (LENTSOM subjective erectile function for vaginal penetration score) and pts (single items within UCLA-PCI and EPIC-50 questionnaires) at 2 years. 195/875 (22%) pts were excluded from this toxicity analysis as they had erectile dysfunction pre-ADT (grade (G) 3/4 LENTSOM). A chi square trend test compared ADT regimens. Results: Baseline demographics were similar except BIC pts were significantly younger (median 67 years BIC, 69 years LHRHa). With a median follow-up of 9.2 years, there was no evidence of a difference in BCF with an adjusted hazard ratio 0.95 (95% CI 0.75-1.20), p = 0.657. Eight year BCF rates were 80.7% (95%CI 79.0-82.2) and 80.3% (95%CI 75.8-84.0) for LHRHa and BIC pts respectively. At two years, LENTSOM erectile function was significantly worse (p &lt; 0.0001) for LHRHa pts with 93/585 (16%), 95/585 (16%) and 125/585 (21%) G2, G3 and G4, compared to 3/68 (4%), 5/68 (7%) and 9/68 (13%) in BIC. At 2 years, the ability to have an erection, as reported by pts, was graded poor and very poor in 73/278 (26%) and 57/278 (21%) LHRHa pts and 5/23 (22%) and 4/23 (17%) in BIC pts (p = 0.584). Conclusions: There was no evidence of a difference in efficacy according to ADT received. BIC preserved clinician assessed (LENTSOM) erectile function at 2 years but patient reported outcomes did not show statistically significant differences with type of ADT. Clinical trial information: 97182923.
Delay in Diagnosis of Food Protein-Induced Enterocolitis Syndrome Evidenced at Three Academic Medical Centers in Upstate and Western New York State
Authors: Jennifer Pier, Theresa Bingemann, Jasdeep Badwal, Daniel Rosloff, Muhammad Pasha, Kirsi Jarvinen-Seppo, Jeanne Lomas
Journal: Journal of Allergy and Clinical Immunology (2020)
Perioperative chemoimmunotherapy with durvalumab (Durva) in combination with cisplatin/gemcitabine (Cis/Gem) for operable muscle-invasive urothelial carcinoma (MIUC): Preplanned interim analysis of a single-arm phase II trial (SAKK 06/17).
Authors: Richard Cathomas, Ulf Petrausch, Stefanie Hayoz, Martina Schneider, Julian Andreas Schardt, Roland Seiler, Andreas Erdmann, Sacha Rothschild, Stefanie Aeppli, Nicolas Mach, Raeto Strebel, Boris A. Hadaschik, Dominik R. Berthold, Miklos Pless, Deborah Zihler, Mathias Schmid, Christine Biaggi Rudolf, Martin Spahn
Journal: Journal of Clinical Oncology (2020)

499 Background: Cisplatin-based neoadjuvant chemotherapy followed by surgery is the standard of care for patients (pts) with MIUC but relapse rates remain high. Immune checkpoint inhibitors have demonstrated efficacy in advanced urothelial carcinoma (UC). We hypothesize that the integration of the PD-L1 inhibitor durvalumab into perioperative management of MIUC improves outcome. Methods: SAKK 06/17 is an open label single arm phase II study including 61 pts. Operable MIUC cT2-T4a cN0-1 pts without contraindication for Cis were eligible. Four cycles of preoperative Cis/Gem q3w are administered in combination with 4 cycles Durva 1500mg q3w starting at cycle 2. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival at 2 years. We report a preplanned interim analysis of the secondary endpoints safety, pathological complete remission ypT0 N0 (pCR,) and pathological response rate (PaR, defined as ≤ypT1N0) on the first 30 resected pts. Results: Among 34 eligible pts (27M, 7F; median age 70, range 41-81 years) included from 07/18 – 02/19, 33 pts (97%) had primary bladder cancer and 1 pt had upper tract UC. Clinical T2, T3, T4 and TxN1 stage were present at diagnosis in 68%, 18%, 15% and 15%, respectively. Four cycles of chemo-immunotherapy were completed per protocol in 34 pts (100%). No tumor progression was noted at preoperative restaging. AE related to Durvalumab were G3 in 5 pts (15%) and G4 in 3 pts (9%). Surgery was performed as planned in 30 pts (88%), 3 pts refused surgery and 1 pt had a frozen pelvis. Operation technique was open in 20 pts (67%) and laparoscopic/robot-assisted in 10 pts (33%). Postoperative complications included Clavien-Dindo III in 6 pts (20%) and IV in 2 pts (7%) with infections being most common (5 pts, 17%). pCR was found in 9 pts (30%) and additional 6 pts (20%) had ypT1/ypTis for a PaR of 50%. Conclusions: The combination of Cis/Gem and Durva as neoadjuvant treatment for MIUC is feasible with manageable toxicities and pCR and PaR rates in the expected range. The rate of postoperative complications warrants further close follow up. Clinical trial information: 2017-003565-10.
A novel method of triple stenting in patients with malignant hilar biliary obstruction: triple stenting abreast method
Authors: Masanari Sekine, Junichi Fujiwara, Hirosato Mashima
Journal: Endoscopy (2020)

An 85-year-old woman visited our hospital with obstructive jaundice. Contrast-enhanced computed tomography (CT) showed a gallbladder tumor, multiple liver tumors, and intrahepatic bile duct dilatation ([Fig. 1]). Hepatic tumor biopsy showed adenocarcinoma. The final diagnosis was gallbladder cancer, multiple liver metastases, and malignant hepatic hilar biliary obstruction (MHBO) due to liver invasion. She underwent endoscopic retrograde cholangiopancreatography with placement of self-expandable metal stents (SEMS) for obstructive jaundice because she hoped for best supportive care ([Video 1]).
Ceramide/sphingosine‐1‐phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma
Authors: Seung‐Hyun Kim, Hae‐Won Jung, Minji Kim, Ji‐Young Moon, Ga‐Young Ban, Su Jung Kim, Hyun‐Ju Yoo, Hae‐Sim Park
Journal: Allergy (2020)

Abstract Background Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features. Methods To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC‐MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype. Results In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs ( P &lt; .05 for all). Cellular markers (CD66 + neutrophils, platelet‐adherent eosinophils) and SL metabolic markers (C16:0 and C24:0 ceramides) for uncontrolled asthma were also identified; higher levels were observed in uncontrolled asthma compared to controlled asthma ( P &lt; .05 for all). Asthmatics patients with higher levels of CD66 + neutrophils had lower FEV1(%), higher ACQ (but lower AQLO) scores, and higher sphingosine and C16:0 ceramide levels compared to those with low levels of CD66 + neutrophils. Asthmatics patients with higher levels of platelet‐adherent eosinophils had higher S1P levels compared to those with lower levels of platelet‐adherent eosinophils. Patients carrying TT genotype of ORMDL3 had more CD66 + neutrophils; those with AG/ GG genotypes of SGMS1 exhibited higher platelet‐adherent eosinophils. Conclusion Patients with uncontrolled asthma possess distinct inflammatory phenotypes including increased CD66 + neutrophils and platelet‐adherent eosinophils, with an imbalanced ceramide/S1P rheostat, potentially involving ORMDL3 and SGMS1 gene polymorphisms. Ceramide/S1P synthesis could be targeted to control airway inflammation.
TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA).
Authors: Johann S. De Bono, Niven Mehra, Celestia S. Higano, Fred Saad, Consuelo Buttigliero, Marielena Mata, Hsiang-Chun Chen, Cynthia G. Healy, M. Luisa Paccagnella, Akos Czibere, Karim Fizazi
Journal: Journal of Clinical Oncology (2020)

119 Background: Phase 2 and 3 studies with poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated antitumor activity in patients (pts) with mCRPC with DDRmut who were previously treated with novel hormonal therapy (NHT). We report the first IA of a Phase 2 study of TALA, a potent inhibitor and trapper of PARP. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRmut likely to sensitize to PARPi (including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) and progressed on ≥1 NHT (enzalutamide/abiraterone acetate). Pts receive oral TALA 1 mg/d (moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is objective response rate (ORR; blinded independent review). Secondary endpoints are time to OR, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell (CTC) count conversion (to CTC = 0 and &lt;5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival (rPFS), overall survival, safety, pt-reported outcomes, and pharmacokinetics. A planned IA of safety and efficacy was performed after 20 pts with BRCA1/2 mutations were on treatment for ≥8 wks. Results: 81 pts received TALA as of June 5, 2019; 43 pts enrolled by Feb 12, 2019 were evaluable for the primary endpoint (20 BRCA1/2, 2 PALB2, 14 ATM, 7 other). All had received docetaxel and 49% prior cabazitaxel. Overall ORR (95% CI) was 25.6% (13.5–41.2), ORR BRCA1/2 50.0% (27.2–72.8), ORR ATM 7.1% (0.2–33.9). Overall median (95% CI) rPFS was 5.6 months (mo) (3.5–8.2), rPFS BRCA1/2 8.2 mo (5.6–NE), rPFS ATM 3.5 mo (1.7–8.1). Most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and platelet count decreased. Conclusions: TALA monotherapy demonstrates encouraging antitumor activity in docetaxel-pretreated mCRPC pts, especially those with BRCA1/2mut, and was generally well tolerated. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03148795.
Appropriate Dose Modification in Induction Therapy Is Essential for the Treatment of Infants with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).
Authors: Daisuke Tomizawa, Akio Tawa, Tomoyuki Watanabe, Akiko Moriya Saito, Kazuko Kudo, Takashi Taga, Shotaro Iwamoto, Akira Shimada, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hisato Kigasawa, Yoshiyuki Kosaka, Hayato Miyachi, Keizo Horibe, Tatsutoshi Nakahata, Souichi Adachi
Journal: Blood (2012)
Development and Internal Validation of a Web-based Tool to Predict Sexual, Urinary, and Bowel Function Longitudinally After Radiation Therapy, Surgery, or Observation
Authors: Aaron A. Laviana, Zhiguo Zhao, Li-Ching Huang, Tatsuki Koyama, Ralph Conwill, Karen Hoffman, Michael Goodman, Ann S. Hamilton, Xiao-Cheng Wu, Lisa E. Paddock, Antoinette Stroup, Matthew R. Cooperberg, Mia Hashibe, Brock B. O’Neil, Sherrie H. Kaplan, Sheldon Greenfield, David F. Penson, Daniel A. Barocas
Journal: European Urology (2020)
The efficacy and safety of radical prostatectomy and radiotherapy in high-risk prostate cancer: A systematic review and meta-analysis.
Authors: Zhipeng Wang, Yuchao Ni, Junru Chen, Guangxi Sun, Xingming Zhang, Jinge Zhao, Xudong Zhu, Haoran Zhang, Sha Zhu, Jindong Dai, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2020)

369 Background: The optimal treatment for patients with high-risk prostate cancer (PCa) remains debate and selection of patients to receive proper therapy is still an unsettled question. This systematical review was to compare the effectiveness of prostatectomy (RP) and radiotherapy (RT) in patients with high risk prostate cancer (PCa) and to select candidates for optimal treatment. Methods: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. We extracted hazard ratios (HRs) and 95% CI of included studies. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS); the secondary outcomes were biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS) and clinical recurrence-free survival (CRFS). The meta-analysis was performed using Review Manager 5.3. Subgroup analyses were conducted according to GS, T stage and RT types. Quality of life (QOL) was compared with these two treatments. Results: A total of 25 studies were included. Overall, RP showed more survival benefits than RT on CSS (P=0.003) and OS (P=0.002), while RT was associated with a better BRFS (P=0.002) and MFS (P=0.004). Subgroup analyses showed RT was associated with similar or even better survival outcomes compared to RP in patients with high GS, high T stage or received external beam radiotherapy plus brachytherapy (EBRT+BT). As for QOL, RP was associated with poorer urinary and sexual function but better performance in the bowel domain. Conclusions: RP could prolong the survival time of patients with high risk PCa; however, RT could delay disease progression, and combined RT (EBRT+BT) even brought better CSS and similar OS than RP. RT might be the prior choice for patients with high T stage or high GS. RP could lead to poorer urinary and sexual function, while brought better performance in the bowel domain.
Cyclin pathway genomic alterations across 5,356 prostate cancers.
Authors: Denis Leonardo Fontes Jardim, Sherri Z. Millis, Michele Sue-Ann Woo, Jeffrey S. Ross, Siraj Mahamed Ali, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2020)

179 Background: The cyclin pathway is comprised of possible targetable alterations as well as resistant alterations that affect treatment, including hormonal agents. We describe the landscape of cyclin genomic alterations in prostate cancer. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation sequencing (315 genes, &gt;500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition) and androgen receptor ( AR). Results: Alterations in any cyclin pathway genes were found in 9.7% of the 5,356 tumors analyzed. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Frequencies were substantially different according to prostate cancer histology (Table). The majority of alterations were copy number changes. Alterations in possible resistance genes, RB1 and CCNE1 were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, while AR alterations were seen in 20.9% (up to 27.3% in anaplastic). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alterations in cyclin activating and resistance pathway (odds ratio (OR), 0.44, p&lt;0.001). Conversely, we detected a higher likelihood of co-occurrence between AR and cyclin alterations (OR 1.79, p&lt;0.001). Conclusions: Cyclin pathway genomic abnormalities were observed in about 10% of prostate cancer tumors, and are more frequently associated with concomitant AR alterations and absence of co-alterations associated with resistance to cyclin inhibition.[Table: see text]
Coexistence Of Nasal Reactivity To Allergens With And Without IgE-Sensitization In Allergic Rhinitis Patients
Authors: Adriana Ariza Veguillas, MarÃa Salas, Ruben Fernández-Santamaría, Almudena Testera-Montes, Ibon Eguiluz-Gracia, Ana Prieto del Prado, Paloma Campo, Maria Torres Jaen, Cristobalina Mayorga, Carmen Rondon Segovia
Journal: Journal of Allergy and Clinical Immunology (2020)