tbuckley/cabot-search huggingface dataset:
Retreatment (reTx) of patients (pts) with refractory large B-cell lymphoma with axicabtagene ciloleucel (axi-cel) in ZUMA-1.
Authors: Frederick Lundry Locke, Nancy L. Bartlett, Caron A. Jacobson, Olalekan O. Oluwole, Javier Munoz, Lazaros J. Lekakis, Max S. Topp, Irit Avivi, Jenny J. Kim, Rong Chu, Lianqing Zheng, John M. Rossi, Adrian Bot, Sattva Swarup Neelapu
Journal: Journal of Clinical Oncology (2020)

8012 Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved in the US and EU for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In the ZUMA-1 pivotal study (NCT02348216), the objective response rate (ORR) was 83% (58% complete response [CR] rate; Locke et al. Lancet Oncol. 2019). While axi-cel has demonstrated durable responses in a subset of pts, approximately half of all responders relapsed, and little is known on the viability of reTx with CAR T cell therapy. Here we report outcomes of pts retreated with axi-cel in ZUMA-1. Methods: Pts with progressive disease (PD) were eligible for reTx if there was no evidence of CD19 loss by local review, and if during 1st Tx they did not experience any dose-limiting toxicities, as defined in Phase 1, or comparable toxicities in Phase 2. Pts received the same regimen at reTx as at 1st Tx: 2 × 10 6 CAR T cells/kg after conditioning chemotherapy. Results: Thirteen pts in Cohorts 1 – 4 received axi-cel reTx. Prior to 1st Tx, most pts (69%) had an IPI score 3-4, 85% had disease stage 3-4, and the median number of prior regimens was 3 (range, 2 – 6). At first Tx, 6 pts achieved a CR, 6 achieved partial response (PR), and 1 pt had stable disease (SD) prior to PD. Median duration of first response was 96 days (range, 56 – 274). There was no Grade ≥ 3 cytokine release syndrome (CRS; 6 pts each had Grade 1 and 2). There were no Grade 4 or 5 neurologic events (NEs; 2 pts had Grade 1, 1 had Grade 2, and 7 had Grade 3). Upon reTx, 54% of pts achieved response (4 CR, 3 PR). Response to reTx was more common among pts who achieved CR at 1st Tx (83%; 4/6 CR, 1 PR, 1 SD) than in pts who achieved PR at 1st Tx (33%; 2/6 PR, 1 SD, 3 PD), and no response was observed in the pt with SD at 1st Tx. Median duration of response at reTx was 81 days (range, 1 – 225+). Response with reTx was longer than that with 1st Tx for 2 pts. One pt remains in response 255 days post-reTx. Comparable rates of CRS were observed with reTx as with 1st Tx. Compared with 1st Tx, fewer pts experienced NEs with reTx, and those that did occur were of lower grade: 23% (3 of 13 pts) had Grade 3; 23% (3 of 13 pts) had Grade 1, and 8% (1 of 13 pts) had Grade 2. Peak CAR T cell expansion was lower upon reTx vs 1st Tx (median, 4.3 vs 66.1 CAR gene-marked cells/µL blood). Conclusions: Based on this limited sample size, reTx with axi-cel may have clinical efficacy, although transient, in some pts, especially those who achieve CR with 1st Tx. CAR T cell expansion and severe CRS and NEs may be attenuated at reTx. Further studies with additional pts are needed to confirm these results. Clinical trial information: NCT02348216 .
Impact of SWI/SNF complex mutations in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors: Immuno-oncology biomarker study in LC-SCRUM-Japan (LC-SCRUM-IBIS).
Authors: Kiyotaka Yoh, Shingo Matsumoto, Naoki Furuya, Kazumi Nishino, Shingo Miyamoto, Satoshi Oizumi, Norio Okamoto, Hidetoshi Itani, Shoichi Kuyama, Atsushi Nakamura, Yuichiro Hayashi, Noriko Motoi, Genichiro Ishii, Koichi Goto
Journal: Journal of Clinical Oncology (2020)

9530 Background: The SWI/SNF chromatin remodeling complex is reported to be involved in sensitivity and resistance to immune checkpoint inhibitor (ICI). However, their role in non-small cell lung cancer (NSCLC) remains unclear. We examined the relationship between SWI/SNF complex mutations and clinical outcomes of ICI in patients with NSCLC. Methods: Of 1017 lung cancer patients enrolled in LC-SCRUM-IBIS, 350 patients were analyzable for whole-exome sequencing (WES). WES data were used to analyze the presence of mutations in 29 major subunits of the SWI/SNF complexes. ARID1A and SMARCA4 mutations were also evaluated in a targeted NGS panel (Oncomine comprehensive assay, OCA). PD-L1 expression by 22C3, tissue tumor mutational burden (tTMB) by WES, STK11 and KEAP1 mutations by WES or OCA were also assessed. Durable clinical benefit (DCB) including CR, PR and SD &gt; 6 mos to ICI, progression-free survival (PFS) and overall survival (OS) were compared in status of each of SWI/SNF complex mutations and other factors. Results: At least one mutation in any subunits of the SWI/SNF complex was present in 28% of NSCLC patients. The most common mutated subcomplexes were SMARCA4 (12%), BAF (7%: ARID1A, 4%), non-canonical BAF (3%), PBAF (3%), and SMARCA2 (2%). Of 101 NSCLC patients treated with PD-1/PD-L1 inhibitors, SMARCA4 mutations tended to be associated with lower DCB (16 vs 31%) and shorter median PFS (1.9 vs 3.6 m) and OS (7.4 vs 18.1m). Patients with ARID1A mutations tended to have better clinical outcomes (DCB, 40 vs 28%) compared to those without mutations. No significant associations were found between PD-L1 expression and SMARCA4 or ARID1A mutations. Patients with STK11/KEAP1 mutations had lower rate of PD-L1 expression (TPS &gt; 50%) (18% vs 48%, P = 0.03) and worse clinical outcomes (DCB, 6 vs 33%) compared to those without mutations. There was no significant association between a tTMB status and clinical outcome. Conclusions: SMARCA4 and ARID1A mutations appear to affect clinical outcomes of ICI in NSCLC patients. These findings indicate that SWI/SNF complex mutations may serve as a predictive biomarker for ICI in NSCLC patients.
Impact of STK11 and KRAS co-mutations on outcomes with immunotherapy in non-small cell lung cancer.
Authors: Fahmin Basher, Diana Saravia, Dino Fanfan, Jared Addison Cotta, Gilberto Lopes
Journal: Journal of Clinical Oncology (2020)

e15135 Background: While the use of monoclonal antibodies targeting the PD-1 axis in metastatic non-small cell lung cancer (NSCLC) continues to expand since initial FDA approval in 2015, factors predictive of response still remain to be determined. Mutation status may provide insight as to which subgroups exhibit resistance to checkpoint inhibitor therapy. Methods: We conducted a single center retrospective analysis of patients with metastatic NSCLC treated at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) and identified patients that harbor either STK11 mutation alone (S) or co-mutations with STK11 and KRAS (S/K). Genomic results were obtained from Guardant360 and Foundation One testing in blood and tissue, respectively. Results: We identified 37 S patients and 36 S/K patients and determined no significant differences in progression-free survival (PFS). However, overall survival (OS) was significantly increased in patients with S/K co-mutation (20.3 ± 4.1 months) vs. patients with S alone (11.9 ± 1.9 months, p = 0.028). Furthermore, S/K patients who received immunotherapy had longer OS (20.7 ± 5.6 months) vs. S patients (13.6 ± 3.4 months, p = 0.049). We further investigated any population-specific factors that may contribute to the enhanced survival in the S/K cohort that had received immunotherapy, as previous studies have reported that STK11/KRAS co-mutations may confer a resistance to PD-1 axis-directed therapy. We found that S/K patients were older at diagnosis and were more likely to have received nivolumab (as compared to newer therapies pembrolizumab and atezolizumab). In addition, S/K patients were more likely to have longer smoking histories (81% smoked more than 30 pack-years at diagnosis) vs. S patients (53%, p = 0.01) and also had a higher number of additional targetable mutations found on NGS (4.7 ± 0.4 vs. 2.9 ± 0.3, p = 0.001). The most commonly identified mutations were TP53 (30%), KEAP1 (19%), CDKN2A/B (18%), SMARCA4/BRG1 (16%), and ARID1A (11%). Conclusions: Our study reveals an interesting analysis of potential predictors of resistance to immunotherapy with the utilization of precision medicine in combination with patient characteristics to identify the most appropriate treatment regimens for patients with NSCLC. Further studies will explore whether patients receiving immunotherapy as first line could overcome any inherent resistance to PD-1 axis-directed therapy from non-modifiable factors at diagnosis.
Impact of premature venetoclax (Ven) discontinuation/interruption on outcomes in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Phase III MURANO study results.
Authors: Anthony R. Mato, Jeff P. Sharman, Juliana Biondo, Mei Wu, Yong Mun, Su Young Kim, Kathryn Humphrey, Michelle Boyer, Qian Zhu, John F. Seymour
Journal: Journal of Clinical Oncology (2020)

8028 Background: Ven + rituximab (VenR) has a manageable safety profile and improves survival in patients (pts) with R/R CLL, but discontinuation/interruption is frequent. We present new data from the Phase III MURANO study on the impact of Ven early discontinuation/interruption on outcomes in pts with R/R CLL. Methods: Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of Ven discontinuation/interruption on investigator-assessed PFS and OS. Analyses were performed retrospectively (without type-1 error control) in intent-to-treat pts with R/R CLL from the fixed-duration VenR arm of MURANO (NCT02005471; data cut-off: May 8, 2019). Results: 140/194 pts (72%) in the VenR arm completed 2 years of therapy. Early discontinuation occurred in 54/194 (28%) pts (adverse events [AEs]: 29, disease progression [PD]: 12, withdrawal: 5, physician decision: 3, death: 2, other: 2, non-compliance: 1). Median Ven durations for pts discontinuing due to AEs and PD: 11.3 (0.5–24.6) and 17.1 (4.6–25.1) months, respectively (p = 0.08). Inferior PFS was observed in pts who discontinued Ven early for any reason except PD or due to AEs, versus those who completed therapy (Table). Greater cumulative Ven exposure significantly reduced risk of a PFS/OS event (PFS: HR 0.93, 95% CI 0.88–0.99, p = 0.0168; OS: HR 0.85, 95% CI 0.79–0.92, p &lt; 0.0001). Treatment interruption for AEs occurred in 134/194 (69%) pts, most commonly due to neutropenia (84/194; 43%), per protocol requirements. Median duration of interruption: 9 (1–93) days. Treatment interruption, regardless of duration, had no impact on PFS or OS (Table). 36 (19%) pts with interruptions later discontinued Ven. Conclusions: In MURANO, early Ven discontinuation was associated with suboptimal outcomes; Ven interruption was not. These data highlight the importance of effective control of toxicity to realize the full benefit of VenR treatment. Clinical trial information: NCT02005471 . [Table: see text]
Clinical and molecular features of responders to PD-1 blockade for patients with microsatellite instability high or mismatch repair deficient advanced gastrointestinal tumors.
Authors: Keigo Chida, Akihito Kawazoe, Masahito Kawazu, Yoshiaki Nakamura, Toshihiro Suzuki, Shigehisa Kitano, Tetsuya Nakatsura, Takeshi Kuwata, Kohei Shitara, Masafumi Ikeda, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2020)

e16550 Background: An anti-PD-1 inhibitor pembrolizumab showed a durable response for patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors. However, clinical and molecular features of responders to PD-1 blockade for MSI-H/dMMR advanced gastrointestinal (GI) tumors are not well understood. Methods: Patients with MSI-H/dMMR GI tumors who received anti‒PD-1 monotherapy were enrolled in this study. PD-L1 expression in tumor cells or immune cells as well as combined positive score (CPS) were assessed using the PDL1 IHC 22C3 pharmDx assay. Cancer genome alterations were evaluated by a next generation sequencing-based panel with Oncomine Comprehensive Assay for tumor tissue samples or Guardant360 ctDNA Assay for plasma samples. Results: A total of 43 patients with gastric cancer (n = 19), colorectal cancer (n = 16), cholangiocarcinoma (n = 4), small intestine cancer (n = 2) and pancreatic cancer (n = 2) were analyzed in this study. All patients had measurable lesions and objective response was observed in 20 patients (46%). Objective response rate (ORR) was significantly higher in patients with ECOG PS of 0 than in those with PS of 1 or 2 (64% vs. 22%, p = 0.01) and PD-L1+ in tumor cells than in those with PD-L1- in tumor cells (67% vs. 32%, p = 0.03). ORR was similar according to PD-L1 CPS; 45% in CPS &lt; 1, 47% in CPS ≥1 and 56% in CPS ≥10, respectively. ORR was numerically lower in patients with PTEN mutation than in those with PTEN wild type (29% vs. 56%). Also, durable response rate (objective response lasting continuously ≥6 months) was significantly lower in patients with PTEN mutation than in those with PTEN wild type (0% vs. 52%, p = 0.03). In the overall population, median progression-free survival (PFS) was 10.0 months (95% CI, 4.0-not reached). In univariate analysis, PS (1 or 2 vs. 0) was the strongest clinical factor associated with PFS (3.9 months vs. not reached, HR 3.9; 95% CI 1.7-9.2, p = 0.002). After adjusted by PS, PTEN mutation was only molecular factor associated with shorter PFS (3.4 vs. 24.5 months, HR 3.0; 95% CI 1.1-8.4, p = 0.03). Conclusions: Some clinical and molecular factors were associated with response to PD-1 blockade for MSI-H/dMMR advanced GI tumors. Updated biomarker analysis with whole exome sequencing and multiplex IHC will be presented.
Clinical application of thoracoscopic surgery for esophageal neoplasms in lateral prone position
Authors: Yu-long Hou, Wei Guo, Zhi-jian Yang
Journal: BMJ (2013)

Thirty-three patients with esophageal carcinoma (T3N1M0 or less) underwent thoracoscopic surgery in lateral prone position for esophagectomy from February 2010 to November 2012. Their postoperative outcomes and survivals were retrospectively analyzed. The results confirmed the feasibility and safety of this mini-invasive thoracoscopic procedure in lateral prone position for patients with esophageal carcinoma. A possible advantage of lateral prone technique is that in case of an emergency switch to open surgery, precious time may be saved in changing body position.


Key words: 
Esophageal neoplasms; Posture
Comprehensive analysis of T-cell receptor sequencing in resectable squamous cell lung cancer patients with neoadjuvant therapy of PD-1 inhibitor and chemotherapy.
Authors: Yuan Feng, Shanshan Xiao, Wei Sun, Yuanyuan Ma, Yang Hong, Yue Pu, Rui Lin, Tao Wang, Dongmei Lin, Yue Yang
Journal: Journal of Clinical Oncology (2020)

e21012 Background: Cancer therapies alter the tumor microenvironment such as the infiltration of T cells. Neoadjuvant therapy to squamous cell lung cancer patients using PD-1 inhibitor expands specific T cell clones. However, the T cell clones and diversity in tumors and lymph nodes according to different neoadjuvant settings remain largely unknown. In this study, we used T-cell receptor (TCR) sequencing technology to investigate the TCR clonotypes and diversities in squamous cell NSCLC patients who received neoadjuvant chemotherapy and PD-1 inhibitor plus chemotherapy. Methods: Tumor tissues, non-metastatic lymph nodes (NMLN)s, and available metastatic lymph nodes (MLNs) were collected from two patient groups. Each group enrolled three patients who received either neoadjuvant chemotherapy or PD-1 inhibitor plus chemotherapy. DNA samples were harvested and processed for multiplex PCR for the third complementary determining region (CDR3) of TCR-β chain followed by the next generation sequencing analysis. Differences of the CDR3 clonotypes and clonal diversities were analyzed by bioinformatics tools including the Mixcr software. Results: For all the six patients, TCR clonotypes in the tumor tissues were found to be fewer than those from the lymph nodes in the same patient, consistent with a hypothesis that most of the tumor infiltrated T cells after therapy derive from the lymph nodes. Some clonotypes among the top 10 highest frequencies were found in different samples from the same patient, further supporting the lymph node origin of the tumor infiltrating T cells after therapies. Interestingly, TCR clonal diversity was higher in the NMLNs compared with the MLNs, but clonotype overlap with tumor tissues was higher in the MLNs than NMLNs; these results could imply that TCR clonotypes in the primary lymph node were more stimulated. Additionally, there were very few clonotypes shared between different patients, indicating the heterogeneity of immune response for different individuals. Due to the limited sample size, we could not find the systemic difference between the two patient groups. Conclusions: TCR sequencing technology can detect the CDR3 clonotypes in tumor tissues and lymph nodes of cancer patients, providing new opportunities for revealing patients' response to chemotherapy and immunotherapy. Further analysis will be performed to investigate TCR clonotype differences caused by immunotherapy.
Dynamic change in serum level of cytokines in patients with multiple organ dysfunction syndrome and its prognostic significance
Authors: 梅雪, 李春盛, 王烁
Journal: BMJ (2006)

目的 检测多器官功能不全综合征(MODS)患者血清促炎和抗炎细胞因子的浓度变化,探讨二者的动态变化规律及其对预后的影响.方法所有符合全身炎症反应综合征(SIRS)诊断标准的入选患者按病情分为MODS组(48例)和非MODS组(30例),按预后分为生存组(37例)和死亡组(41例).采用ELISA法测定促炎和抗炎细胞因子血清浓度,流式细胞仪测定单核细胞HLA-DR表达强度.结果MODS组、死亡组患者血清中促炎因子水平显著高于非MODS组和生存组(P＜0.01),且随着时间推移和病情加重而逐渐增高;抗炎因子及单核细胞HLA-DR的表达强度均不断降低,且随时间的推移最终低于非MODS组和生存组(P＜0.05).白细胞介素-6(IL-6)、HLA-DR与APECHEⅡ评分有显著相关性.决定系数R2=0.811,可以建立多元回归方程:APECHEⅡ=0.180IL-6-0.868 HLA-DR+22.265(F=49.290,P＜0.01).肿瘤坏死因子-α、HLA-DR及APECHEⅡ评分对预后的预测有显著性意义,可以建立logistic回归方程.结论MODS患者促炎因子持续升高、抗炎因子、单核细胞HLA-DR表达强度持续降低提示预后不良。
Isoform-specific roles of AMPK catalytic α subunits in Alzheimer’s disease
Authors: Fanpeng Zhao, Chunyu Wang, Xiongwei Zhu
Journal: Journal of Clinical Investigation (2020)

AMPK is a heterotrimeric complex that serves as a major sensor of energy status in eukaryotic cells. Accumulating evidence depicts a complex role of dysregulated AMPK signaling in Alzheimer's disease (AD). In this issue of the JCI, Zimmermann et al. report on their investigation of AD-specific differential expression of AMPKα1 and AMPKα2 isoforms of the catalytic subunit and demonstrate that genetic reduction of AMPKα1, but not AMPKα2, rescued cognitive decline in AD mouse models. These findings reveal an isoform-specific role of AMPKα in the pathogenesis of AD, which likely provides a more precise target for future therapeutic development.
Quality of life in patients with locally advanced head and neck cancer undergoing chemoradiation with once-a-week versus once-every-three-weeks cisplatin.
Authors: Nandini Sharrel Menon, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Atanu Bhattacharjee, Devanshi Kalra, Vijayalakshmi Mathrudev, Arti Bhelekar, Kumar Prabhash
Journal: Journal of Clinical Oncology (2020)

12092 Background: This trial was conducted to compare the efficacy of low dose once-a-week cisplatin with once-every-3-weeks cisplatin with radiation in locally advanced head and neck squamous cell carcinoma (LAHNSCC). The current analysis focuses on the quality of life (QoL) of patients in this trial. Methods: In this phase III randomized trial, patients with stage III or IV non-metastatic LAHNSCC were randomized to receive cisplatin 30 mg/m 2 once a week or cisplatin 100 mg/m 2 once every 3 weeks concurrently with curative intent radiotherapy. The primary endpoint was locoregional control. QoL was a key secondary endpoint. QoL was assessed using the EORTC QLQ-C30 (v.3) and EORTC QLQ-H&amp;N35 (v.1). QoL data were assessed at baseline and days 22 and 43 during treatment; at the end of chemoradiation and at each follow-up. The linear mixed effects model was used for longitudinal analysis of QoL domains to determine the impact of treatment (arm) and time on QoL scores. Results: Three hundred patients were enrolled, 150 in each arm. QoL data from 283 patients with at least one assessable questionnaire were analyzed. The pretreatment QoL scores were similar in both the arms in all domains. There was no significant difference in the global health status/QoL with respect to the treatment arm ( P =0.608) or time ( P=0.0544 ). There was no significant difference in the longitudinal QoL scores between the two treatment arms in all domains except the physical function ( P= .0074), constipation ( P= .0326), trouble with social contact ( P= .0321) and sexuality ( P= .0004). There was a decline in the QoL scores in all domains in both arms during treatment. After completion of treatment, the QoL scores started improving steadily up to 1 year and plateaued thereafter in both arms. Conclusions: The use of once-every-three weeks cisplatin significantly improved the locoregional control without adversely impacting the quality of life as compared to once-a-week cisplatin in combination with radical radiotherapy in locally advanced HNSCC. Clinical trial information: CTRI/2012/10/ 003062. .
Pre-therapy visceral metastases in castrate resistant metastatic prostate cancer: Role in tumor progression.
Authors: Kathleen Ruchalski, Hyun J. Kim, Michael Douek, Steven Raman, Maitraya Patel, Antonio Gutierrez, Benjamin D. Levine, Cheryce Fischer, Martin S. Auerbach, Pawan Gupta, Heidi Coy, Bianca Villegas, Jonathan Goldin
Journal: Journal of Clinical Oncology (2020)

e17586 Background: Visceral metastases in castrate resistant metastatic prostate cancer (mCRPC) are known to develop late in the course of disease and portend a poor prognosis. As patients with visceral metastases still derive a clinical benefit to treatment, understanding patterns of progressive disease (PD) may help differentiate important disease phenotypes in mCRPC. The aim of our study was to evaluate the differences in anatomic sites of PD in patients with pretreatment visceral or bone metastases on time to progression (TTP). Methods: A retrospective review of anonymized patients enrolled in phase 2 and 3 clinical trials was performed. Patients were excluded if lacked Tc bone scan or CT chest, abdomen and pelvis (CT CAP) at baseline. Bone disease was defined by automated bone scan lesion area (BSLA) criteria. All CT CAPs per clinical trial protocol were assessed by RECIST 1.1. Soft tissue PD was noted as target, non-target lesion growth and/or presence of new lesions by anatomic site. Bone PD was defined by &gt; 20% increase in BSLA score. Results: Of the 169 subjects that met our selection criterion, visceral disease was present at baseline in 90 patients (53%). Baseline BSLA score was 90474 mm² in visceral and 80348 mm² in non-visceral patients (p = 0.395). Disease progression occurred in 93 patients (55%). With baseline visceral disease, PD was a result of BSLA in 26 (51%) and visceral disease only in 11 (22%) of patient. Lacking visceral disease at baseline resulted in PD by BSLA in 26 (62%) and visceral disease only in 3 (7%) of patients. There was no significant difference in PFS for baseline visceral/non-visceral involvement; median PFS = 4.5 months in visceral; median PFS = 4.34 months in non-visceral (HR = 1.28; p = 0.244). Conclusions: Patients with visceral disease may still derive a similar clinical benefit from treatment to those without. While the presence of baseline visceral disease was associated with higher rates of PD by visceral involvement, PD by bone disease remained the most common cause of PD regardless of presence of baseline visceral metastases.
Abstract 15752: Alarmingly Rising Trends in Cardiovascular Events and Worsening Outcomes Among Adult Hospitalizations With Prediabetes
Authors: Upenkumar Patel, Tarang Parekh, Sandeep Singh, Kishorbhai Gangani, Rupak Desai
Journal: Circulation (2019)

Background: The prevalences of acute myocardial infarction (AMI) and arrhythmia among prediabetics have not been analyzed on a large scale. We assessed the temporal trends in the prevalence of AMI ...