tbuckley/cabot-search huggingface dataset:
Association of Germline Genetic Testing Results With Locoregional and Systemic Therapy in Patients With Breast Cancer
Authors: Allison W. Kurian, Kevin C. Ward, Paul Abrahamse, Ann S. Hamilton, Dennis Deapen, Monica Morrow, Reshma Jagsi, Steven J. Katz
Journal: JAMA Oncology (2020)

The increasing use of germline genetic testing may have unintended consequences on treatment. Little is known about how women with pathogenic variants in cancer susceptibility genes are treated for breast cancer.
Safety of perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: An interim safety analysis of the DANTE, a randomized, open-label phase II trial of the German Gastric Group at the AIO and the SAKK.
Authors: Salah-Eddin Al-Batran, Sylvie Lorenzen, Michael Schenk, Peter C. Thuss-Patience, Eray Goekkurt, Ralf Hofheinz, Albrecht Kretzschmar, Claus Bolling, Stefan Angermeier, Andreas Wicki, Alexander Rheinhard Siebenhuener, Ekkehard Eigendorff, Christin Pink, Thomas Jens Ettrich, Harald Schmalenberg, Lisa Waberer, Jonathan Talbot, Claudia Pauligk, Thorsten Oliver Goetze, Nils Homann
Journal: Journal of Clinical Oncology (2020)

398 Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sept 2018; by September 2019, a total of 122 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: perioperative atezolizumab plus FLOT is feasible and safe. The study continued recruitment. Clinical trial information: NCT03421288.
Onset, duration, and clinical impact of immune-related adverse events in Hodgkin lymphoma.
Authors: Alexandra Higgins, Michael D. Richter, Shruti Patel, Kristen Beth McCullough, Thomas Matthew Habermann, Stephen M. Ansell, Carrie A. Thompson, Nabila Nora Bennani, Uma Thanarajasingam, Gita Thanarajasingam
Journal: Journal of Clinical Oncology (2020)

95 Background: The incidence of immune-related adverse events (irAEs) in patients (pts) with Hodgkin lymphoma (HL) treated with PD-1 antibodies (ICI) is reported at 28 - 36%. However, clinically relevant information on irAE onset, duration, or impact on ability to continue therapy in HL is lacking. Additionally, these incidence rates reflect CTCAE definition and grading, and not ASCO Clinical Practice Guidelines irAE-specific criteria (Brahmer et al, JCO 2018). The objectives of this study were to evaluate the rate and severity of irAEs in HL pts using ASCO criteria, to characterize irAE time profile and to assess their impact on continued therapy. Methods: HL pts who received a PD-1 inhibitor for the treatment of HL at Mayo Clinic Rochester between January 1, 2011 and March 1, 2018 were identified. We conducted a detailed, longitudinal retrospective chart review with definition and grading of irAEs in accordance with ASCO guidelines. Results: Fifty-one pts were identified (35% women, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 30 months (range: 1-70). Thirty-one pts (61%) had any irAE. Most common irAEs were inflammatory/bullous dermatoses (23.5%/5.9% any grade/grade3-4; median onset/duration of 81/57 days[d]), followed by thyroiditis (22%/0%; 86/84 d), colitis (14%/8%; 82/106 d), pneumonitis (14%/10%; 241/182 d), and hepatitis (14%/4%; 71/35 d). Fifteen pts (29%) required treatment with steroids. Among the total cohort, ICI was held for an irAE 28 times (50% of 56 total irAEs). Median treatment cycles held was 2.5 and ICI was permanently discontinued due to irAE in 18%. The most common irAE leading to treatment discontinuation was pneumonitis, followed by neuritis (5.9%/3.9%; 179/374 d), colitis, and rash. Conclusions: The rate of irAEs of 61% in this cohort as defined by ASCO consensus criteria was higher than reported in trials. Most irAEs were characterized by delayed onset of several months and prolonged duration, particularly pneumonitis and neuritis. Treatment discontinuation due to irAEs was infrequent overall. Further studies are needed to determine whether the development or duration of irAEs is predictive of treatment outcomes in HL.
Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke
Authors: Yves Werner, Elvira Mass, Praveen Ashok Kumar, Thomas Ulas, Kristian Händler, Arik Horne, Kathrin Klee, Amelie Lupp, Dagmar Schütz, Friederike Saaber, Christoph Redecker, Joachim L. Schultze, Frederic Geissmann, Ralf Stumm
Journal: Nature Neuroscience (2020)
Identification of Cardiovascular Monosodium Urate Crystal Deposition in Patients With Gout Using Dual-Energy Computed Tomography—Reply
Authors: Ethan J. Halpern, Gudrun M. Feuchtner, Andrea S. Klauser
Journal: JAMA Cardiology (2020)

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Abstract 15704: Exploratory Analysis of the Efficacy of β-blockersin Patients With Post-infarction Systolic Dysfunction Plus Atrial Fibrillation
Authors: Violeta González Salvado, Sergio Raposeiras Roubín, Albert Ariza-Solé, Emad Abu-Assi, Guillem Muntané, Alberto Garay, Alfonso Varela Román, José Ramón González-Juanatey
Journal: Circulation (2015)

Introduction: β blocker therapy for patients with acute myocardial infarction (AMI) and reduced left ventricular ejection fraction (LVEF) was instituted after large randomized controlled trials showed a significant reduction in morbidity and mortality rates. Recently, their efficacy in patients with heart failure (HF) and atrial fibrillation (AF) has been questioned, based on the results of a large meta-analysis. We aim to analyze the efficacy of β blocker therapy in patients with post-AMI reduced LVEF and permanent AF. Methods: We studied all consecutive patients discharged with AMI and LVEF ≤ 40% from Hospital of Santiago de Compostela (2004-12) and Bellvitge Hospital of Barcelona (2009-14). The final cohort included 1,056 patients after excluding those without follow-up data. We analyzed the association between β blockers and follow-up (3.0 ± 2.5 years) mortality using Cox regression, adjusting by all confounding variables and by propensity score. Results: 782 patients (74.6%) were treated with β blockers. There were prescribed to 67.1% of patients in sinus rhythm (SR) and to 71.4% in AF. 140 patients (13.2%) had permanent AF at discharge. In SR group, β blockers were associated with lower mortality during follow-up (HR 0.42, 95% CI 0.31-0.53; p&lt;0.001) after adjusting by the confounding variables (HR 0.50, 95% CI 0.32-0.96; p=0.028) and by propensity score (HR 0.68, 95% CI 0.51-0.92; p=0.010), but not in the AF group (HR 0.75, 95% CI 0.45-1.23; P=0.248) after adjusting by the confouding variables (HR 0.67, 95% CI 0.34-1.32; p=0.247) and propensity score (HR 0.81, 95% CI 0.47-1.40; p=0.459). Conclusion: β blocker therapy has no or minimal effect on mortality in patients with post-infarction reduced LVEF and AF, in contrast with its beneficial effects in SR. Thus, we call into question the preferential use of β blockers compared with other rate-control drugs in these patients (1A) and we emphasize the need for further trials to clarify it.
How to improve toxicity evaluation in clinical trials? Testing new metrics from irinotecan or oxaliplatin-based treatments in metastatic colorectal cancer (mCRC): A pooled analysis from 2,349 patients in ARCAD database.
Authors: Christophe Tournigand, Guilherme Lopes, Curtis L. Olswold, Richard Adams, John Raymond Zalcberg, Eric Van Cutsem, Leonard B. Saltz, Richard M. Goldberg, Herbert Hurwitz, Carsten Bokemeyer, Charles S. Fuchs, Benoist Chibaudel, Axel Grothey, Aimery De Gramont, Qian Shi
Journal: Journal of Clinical Oncology (2020)

89 Background: Monitoring of adverse events (AE) is crucial in clinical trials. Maximum grade per patient (pt) is commonly used but better metrics are needed to aid describing and comparing AE profiles. Methods: We developed and evaluated 2 longitudinal AE summary metrics. 1) Onset time of max grade refers to whether a pt has max grade within pre-specified timeframes for an AE, e.g. onset can be defined as “early” (max grade before the 6 th cy) or “late” (≥ 6 th cy). 2) Adverse effect load (AEL) is a longitudinal score of worst grade possible excluding death over the entire treatment for an AE. Higher AEL means worst overall experience of AE. We applied these metrics to real trial data. Pts were from 6 mCRC trials included in ARCAD database and received Irinotecan-based (n = 1,119) or Oxaliplatin-based (n = 1,230) treatments that did not include biologicals. AEs were diarrhea, nausea/vomiting, neutropenia/leukopenia, and neuropathy. We used linear model to AEL and logistic model to the other metrics, adjusting for age, sex, and number of metastases. Results: For nausea/vomiting, pts in Oxali-based chemo showed a higher AEL compared to patients in Iri-based (mean (M) [standard deviation (SD)] = 0.04 [0.06] vs. 0.02 [0.04]; p &lt; 0.001) even though less pts had gr ≥ 3 (10.4% vs. 16.2%, resp.; p &lt; 0.001), suggesting a lower-grade but persistent nausea/vomiting for Oxali-based. Among pts with diarrhea max gr 2, pts in Iri-based had higher AEL than with Oxali-based (M [SD] = 0.11 [0.11] vs. 0.08 [0.09]; p = 0.008), indicating more persistent diarrhea for Iri-based trts even among pts with same max grade. For neutropenia/leukopenia, pts in Oxali-based trts experienced higher AEL (M [SD] = 0.09 [0.13] vs. 0.05 [0.11], p &lt; 0.001), and more pts in Oxali-based trts had gr ≥ 3 (70.1% vs. 64.4%; p = 0.002), suggesting that pts in Oxali-based trts experienced worst overall and max grade neutropenia/leukopenia compared to pts in Iri-based. Conclusions: To improve toxicity assessment in clinical trials, AEL and onset time of max grade are new measures that describe the evolution of adverse events over time. Further validation is warranted.
<i>Artemisia annua</i>‐sublingual immunotherapy for seasonal allergic rhinitis: A randomized controlled trial
Authors: Hongfei Lou, Yanran Huang, Yuhui Ouyang, Yuan Zhang, Lin Xi, Xiaohan Chu, Yang Wang, Chengshuo Wang, Luo Zhang
Journal: Allergy (2020)

Artemisia annua is an important autumnal pollen allergen for seasonal allergic rhinitis (SAR) in northern China. To date, no study has investigated allergen immunotherapy with A annua. We aimed to investigate the efficacy and mechanisms underlying A annua-sublingual immunotherapy (SLIT).This was a randomized, double-blind, placebo-controlled phase III clinical trial involving 71 SAR patients, randomized to SLIT with A annua extract (n = 47) or placebo (n = 24) for 32 weeks. Total nasal symptom score (TNSS; primary clinical end point) was evaluated at baseline (peak pollen phase (PPP) in the previous year), initiation of A annua-SLIT, 1st PPP during SLIT, end of SLIT and 2nd PPP during follow-up. Blood samples and nasal secretions were collected at beginning and after SLIT for assessment of T cells and inflammatory mediators. Safety was assessed according to adverse events (AEs) reported.Artemisia annua-SLIT significantly reduced TNSS to a greater level from baseline (from 9.45 ± 1.68 to 6.16 ± 2.27) than placebo (from 9.29 ± 2.09 to 9.05 ± 2.40) at the 1st PPP (P < .001) and sustained the improvement in symptoms throughout to the 2nd PPP. Preseasonal A annua-SLIT for 16 weeks significantly decreased Th2 cells, increased nTreg and Tr1 cells in blood; and increased cystatin 1 (CST1) in nasal secretion after 16 and 32 weeks compared with pretreatment. Overall, 17/47 patients experienced mild local AEs and 2 patients mild systemic AEs, after A annua-SLIT.Artemisia annua-SLIT is an efficacious and safe treatment in patients with A annua SAR.
Short term association between ozone and mortality: global two stage time series study in 406 locations in 20 countries
Authors: Ana M Vicedo-Cabrera, Francesco Sera, Cong Liu, Ben Armstrong, Ai Milojevic, Yuming Guo, Shilu Tong, Eric Lavigne, Jan Kyselý, Aleš Urban, Hans Orru, Ene Indermitte, Mathilde Pascal, Veronika Huber, Alexandra Schneider, Klea Katsouyanni, Evangelia Samoli, Massimo Stafoggia, Matteo Scortichini, Masahiro Hashizume, Yasushi Honda, Chris Fook Sheng Ng, Magali Hurtado-Diaz, Julio Cruz, Susana Silva, Joana Madureira, Noah Scovronick, Rebecca M. Garland, Ho Kim, Aurelio Tobias, Carmen Íñiguez, Bertil Forsberg, Christofer Åström, Martina S Ragettli, Martin Röösli, Yue-Liang Leon Guo, Bing-Yu Chen, Antonella Zanobetti, Joel Schwartz, Michelle L Bell, Haidong Kan, Antonio Gasparrini
Journal: BMJ (2020)

Abstract Objective To assess short term mortality risks and excess mortality associated with exposure to ozone in several cities worldwide. Design Two stage time series analysis. Setting 406 cities in 20 countries, with overlapping periods between 1985 and 2015, collected from the database of Multi-City Multi-Country Collaborative Research Network. Population Deaths for all causes or for external causes only registered in each city within the study period . Main outcome measures Daily total mortality (all or non-external causes only). Results A total of 45 165 171 deaths were analysed in the 406 cities. On average, a 10 µg/m 3 increase in ozone during the current and previous day was associated with an overall relative risk of mortality of 1.0018 (95% confidence interval 1.0012 to 1.0024). Some heterogeneity was found across countries, with estimates ranging from greater than 1.0020 in the United Kingdom, South Africa, Estonia, and Canada to less than 1.0008 in Mexico and Spain. Short term excess mortality in association with exposure to ozone higher than maximum background levels (70 µg/m 3 ) was 0.26% (95% confidence interval 0.24% to 0.28%), corresponding to 8203 annual excess deaths (95% confidence interval 3525 to 12 840) across the 406 cities studied. The excess remained at 0.20% (0.18% to 0.22%) when restricting to days above the WHO guideline (100 µg/m 3 ), corresponding to 6262 annual excess deaths (1413 to 11 065). Above more lenient thresholds for air quality standards in Europe, America, and China, excess mortality was 0.14%, 0.09%, and 0.05%, respectively. Conclusions Results suggest that ozone related mortality could be potentially reduced under stricter air quality standards. These findings have relevance for the implementation of efficient clean air interventions and mitigation strategies designed within national and international climate policies.
PRRT neuroendocrine tumor response assessment using blood transcript analysis: The NETest.
Authors: Lisa Bodei, Mark A. Kidd, Aviral Singh, Wouter A van der Zwan, Stefano Severi, Ignat A. Drozdov, Anna Malczewska, Richard P. Baum, Dik J. Kwekkeboom, Giovanni Paganelli, Eric Krenning, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2020)

625 Background: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is most effective after treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy, NETest monitors disease. We prospectively evaluated: 1) NETest as a surrogate biomarker for RECIST; 2) Correlation of NETest levels, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n=41; Bad-Berka, Germany: n=44; Meldola, Italy: n=72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable&lt;40; progressive &gt;40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p&lt;0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p&lt;0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels &gt;40 (progressive) vs stable (&lt;40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04, 95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%); 99% accurate positive and 93% accurate negative prediction. NETest significantly ( p&lt;0.0001) decreased in PPQ-predicted responders (-46±3%) and remained increased in PPQ-predicted non-responders (+75±19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06, 95%CI: 0.03-0.12). CgA failed to identify response to PRRT ( p=NS). Conclusions: NETest accurately (98%) monitors PRRT response and is an effective surrogate marker for radiological response (image concordance 98%). A NETest decrease identified responders and correlated (&gt;97%) with the pretreatment PPQ response predictor.
Expansion part of phase I study of E7090 in patients with cholangiocarcinoma harboring FGFR2 gene fusion and with gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression.
Authors: Chigusa Morizane, Makoto Ueno, Tatsuya Ioka, Masahiro Tajika, Masafumi Ikeda, Kensei Yamaguchi, Hiroki Hara, Hiroshi Yabusaki, Atsushi Miyamoto, Satoru Iwasa, Manabu Muto, Tsutomu Takashima, Keiko Minashi, Yoshito Komatsu, Tomohiro Nishina, Takako Eguchi Nakajima, Takatoshi Sahara, Setsuo Funasaka, Masakazu Yashiro, Junji Furuse
Journal: Journal of Clinical Oncology (2020)

538 Background: E7090 is a selective tyrosine kinase inhibitor against FGFR1-3. This first-in-human phase I study has been conducted in Japan and consists of 2 parts. Based on the toxic, pharmacokinetic, and pharmacodynamic profiles in Part 1, dose escalation study, the recommended dose was determined to be 140 mg QD for Part 2, an expansion study part restricted to patients with tumors harboring FGFR gene alterations. Here we provide the interim analysis results of Part 2. Methods: In Part 2, patients with cholangiocarcinoma harboring FGFR2 gene fusion (CCA cohort) and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression (GC cohort) were enrolled. Patients received oral dosing of E7090 until disease progression or unacceptable toxicity. Safety was assessed using CTCAE version 4.03. Tumor response was evaluated by site investigators using RECIST 1.1. Results: As of 31 March 2019, 16 patients including 6 patients in CCA cohort and 10 patients in GC cohort received E7090 in Part2. Median age was 63 years, 25% were female, ECOG PS of 0 and 1 were 50% respectively. 5 patients (83%) in CCA cohort and 1 patient (10%) in GC cohort achieved partial response as the best overall response. The disease control rates were 100% in CCA cohort and 30% in GC cohort, respectively. Median progression-free survivals were 8.3 months in CCA cohort and 2.8 months in GC cohort at the cut-off date. 2 patients with CCA remain on treatment. The most common treatment-related TEAEs occurring in 30% or more of patients in Part 2 were hyperphosphatemia (100%), palmar–plantar erythrodysesthesia syndrome (56%), paronychia (50%), dysgeusia (38%), stomatitis (31%), diarrhea (31%), increased AST (31%) and blood creatinine increased (31%). Grade≥3 treatment-related TEAEs were reported in 2 out of 16 patients (13%); they were increased AST, lipase increased and retinopathy. Conclusions: This study indicated that E7090 has a manageable safety profile in Part 2 and the promising clinical activity in CCA patients with FGFR2 gene fusion.