tbuckley/cabot-search huggingface dataset:
<i>RET</i>-rearranged lung cancers: Immunophenotype and response to immunotherapy.
Authors: Joshua K. Sabari, Michael David Offin, Stephanie L Wu, Ai Ni, Darragh Halpenny, Joseph Montecalvo, Dazhi Liu, Terry K. Pak, Kathryn Cecilia Arbour, Wei-Chu Victoria Lai, Matthew David Hellmann, Gregory J. Riely, Mark G. Kris, Charles M. Rudin, Natasha Rekhtman, Bob T. Li, Josiah David Land, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2018)

9034 Background: In patients with RET-rearranged lung cancers, multikinase inhibitors (e.g. cabozantinib and vandetanib) and specific (e.g. pemetrexed-containing) chemotherapy regimens have documented activity. In contrast, PD-L1 expression, tumor mutational burden (TMB), and the treatment outcomes of immunotherapy are not well characterized in this genomic subset. Methods: Patients with a pathologically confirmed diagnosis of lung cancer harboring a RET rearrangement were identified between January 2012 and December 2017. PD-L1 expression was determined by IHC (E1L3N Clone). TMB was calculated in tumors that underwent NGS (Mutations/Mb, MSK-IMPACT). Objective response rate (ORR) to immunotherapy was evaluated by RECIST. Results: 74 patients with RET-rearranged lung cancers were identified. The median age was 63 (range 34-80 years), 55% were women, and 68% were never smokers. The majority (97%) had adenocarcinoma and 85% had metastatic disease. In patients with sufficient tissue for analysis, tumor PD-L1 expression was as follows: PD-L1 ≥50% in 21% (5/24, 95% CI 5-37%), PD-L1 1-49% in 25% (6/24, 95% CI 8-42%), and PD-L1 0% in 42% (13/24, 95% CI 22-62%). The median TMB of RET-rearranged lung cancers was 3.3 Mt/Mb (range 0.82-9.84, n = 43) and lower than the median TMB of 5.7 Mt/Mb in unselected NSCLCs (n = 1,769, p < 0.001). 12 patients received PD-1/PD-L1 blockade and 1 patient received 2 lines: pembrolizumab (6), nivolumab (4), atezolizumab (2), and durvalumab (1). ORR by RECIST was 0% (0/5 evaluable). The median duration of therapy was 1.4 months (m) (range 0.5-8.7m). Responses were not enriched in those with positive PD-L1 expression (≥1%) nor in those with TMB > median of all NSCLCs. The overall survival of patients who received immunotherapy did not differ from patients who did not receive immunotherapy (n = 51): 18.2 vs 17.9m, p = 0.6. Conclusions: While PD-L1 expression occurs in a substantial proportion of RET-rearranged lung cancers, TMB is lower compared to unselected lung cancers, and response to immunotherapy is poor. RET-directed targeted therapy strategies and platinum doublet chemotherapy should be considered prior to single-agent immunotherapy.
Re: Lindén et al.: Normal-tension glaucoma has normal intracranial pressure: a prospective study of intracranial pressure and intraocular pressure in different body positions (Ophthalmology. 2018;125:361-368)
Authors: Xiangxiang Liu, Diya Yang, Yiquan Yang, Hanruo Liu, Xiaoxia Li, Yuan Xie, Ningli Wang
Journal: Ophthalmology (2018)
Abstract 13830: Senescent CD8+ T Cells Are Increased and Associated With Clinical Outcome in Patients With Heart Failure
Authors: Jong-Chan Youn, Hee Tae Yu, Jaewon Oh, Sungha Park, Sang-Hak Lee, Donghoon Choi, Eui-Cheol Shin, Seok-Min Kang
Journal: Circulation (2015)

Background: The pathogenic role of T cells in heart failure (HF) has been well documented in recent animal studies. However, the existence of T cell driven inflammation in patients with HF has not been confirmed. Therefore, we studied immunologic characterization of T cells from patients with HF. Methods: We compared the frequency of senescent T cells in 23 end-stage HF patients (11 male, mean age 48 ± 13 years), 23 age- and sex-matched healthy control subjects (11 male, mean age 49 ± 12 years) and 17 newly diagnosed acute HF patients (8 male, mean age 59 ± 18 years) by multicolor flow cytometry. Senescent T cells were defined as CD28null or CD57+ cells in CD4+ or CD8+ T cell subset. Primary endpoint was cardiovascular (CV) events defined as CV mortality and rehospitalization due to HF aggravation. Results: The frequency of senescent CD8+ T cells was significantly increased in patients with end-stage HF compared to healthy control (CD8+CD57+ T cell fraction: 46.3 ± 22.3% vs. 29.0 ± 13.1%, p=0.003; CD8+CD28null T cell fraction: 47.7 ± 20.2% vs. 27.8 ± 12.1%, p&lt;0.001). Regarding the newly diagnosed acute HF patients, patients with CV events showed significantly higher CD8+CD57+ T cell fraction compared with those with no CV events (46.5 ± 9.2% vs. 29.9 ± 11.5%, p=0.037). Conclusion: Senescent CD8+ T cells are increased and associated with clinical outcome in patients with HF, suggesting a role for T cell driven inflammation in HF. A more detailed characterization of senescent CD8+ T cells may offer new opportunities for the prevention and treatment of HF.
Deep sequencing of the t-cell receptors for monitoring peripheral CD8<sup>+T</sup> cells in advanced NSCLC Chinese patients treated with anti-PD-L1 antibody.
Authors: Jin Sheng, Xiao Liu, Chao Jin, Pengfei Xu, Hong Pan, Jiawei Shou, Hongsen Li, Xiaoyun Zhou, Weidong Han, Tao Sun, Yong Fang, Hongming Pan
Journal: Journal of Clinical Oncology (2018)

e15025 Background: Atezolizumab, a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody, has dramatically produced clinical benefit for patients with advanced non-small cell lung cancer (NSCLC). However, the biomarker and immunomodulatory effects of PD-L1 blockade in peripheral immunity remains to be illustrated. Methods: In a prospective cohort with twelve Chinese advanced NSCLC patients who received intravenous atezolizumab 1200 mg once every 3 weeks as second-line treatment. Blood samples were obtained prior to and 6 weeks after atezolizumab initiation, and the time when disease progression confirmed. Patients were classified into response or progression group according to their clinical efficacy to atezolizumab. TCRβ chains of CD8+ T cells were analyzed by NGS using TCR profiling system at the deep level (ImmuQuad Biotech, Hangzhou China). Briefly, a 5' RACE unbiased amplification protocol was applied. Sequencing was performed on an Illumina MiSeq system. Meanwhile, fresh PBMCs from patients were stained with anti-human CD3, CD8, and PD1 antibodies for flow cytometry analysis. Results: Clonal expansion with high PD1 expression was detected in all patient peripheral CD8+ T cells before atezolizumab therapy. Unlike progression group, diversity of TCR repertoire and singletons in TCRβ pool, apparently increased overtime with atezolizumab administration and the TCR repertoire showed dynamic changes by calculated with Baroni-Urbani & Buser similarity index in response group. Meanwhile, the frequency of CD8+PD1high terminal exhausted T cells declined in response group after treatment. Conclusions: Results from deep sequencing of the T-cell Receptors highly indicated the existing of tumor antigen-specific T cells with exhaustion phenotype caused by persistent tumor antigen stimulation in Chinese advanced NSCLC patients. Our study demonstrated that an efficient anti-PD-L1 therapy could reshape T-cell repertoire for targeting and adapting to tumor heterogeneity, and reinvigorate the progenitor exhausted T cell population which includes tumor antigen-specific T cells for fighting tumor cells.
Association of the bevacizumab pharmacokinetics with efficacy and toxicity in advanced non-squamous non-small cell lung cancer: Kumamoto Thoracic Oncology Study Group (KTOSG) 1003 study.
Authors: Sho Saeki, Jiichiro Sasaki, Shinya Sakata, Ryo Sato, Koichi Saruwatari, Yasumiko Sakamoto, Megumi Inaba, Hiroto Kishi, Shinji Fujii, Shinsuke Tsumura, Mayu Ouchi, Hideyuki Saito, Akinobu Hamada, Hirotsugu Kohrogi
Journal: Journal of Clinical Oncology (2017)

e20559 Background: Biomarkers predicting the efficacy and toxicity of bevacizumab (Bev) have not yet been established. Therefore we conducted this pharmacokinetic study to elucidate the role of plasma concentration of Bev as a biomarker to predict outcome in the treatment of patients with lung cancer. Methods: This multicenter prospective pharmacokinetic study was conducted among nine centers in Kumamoto Prefecture, Japan. Patients with non-squamous non-small cell lung cancer who were treated using tri-weekly Bev (15mg/kg) with platinum-doublet chemotherapy were enrolled. Plasma samples were collected from all patients before the administration of every dose of Bev until disease progression or treatment discontinuation owing to toxicity. Plasma concentrations of Bev were analyzed via nano-surface and molecular-orientation limited proteolysis coupled with liquid chromatography-mass spectrometry. Results: Between July 2010 and May 2014, 30 patients were enrolled in this study. Majority of the patients received pemetrexed with cisplatin or carboplatin (24 patients, 80%) and others received paclitaxel with carboplatin. The trough concentrations of Bev after first administration (day 22) were 63.19 ± 19.57 μg/mL. Trough concentrations gradually increased until the six cycle of Bev and reached a steady state. Plasma concentrations of Bev did not decrease until disease progression in patients with a long treatment period. Higher mean plasma concentrations of Bev correlated with female sex (p = 0.034) and high serum albumin levels (p = 0.034). Patients who received pemetrexed had higher mean concentrations of Bev (p = 0.038) than those who received paclitaxel. The response rate and progression-free survival did not correlate with the plasma concentration of Bev. Proteinuria (≥Grade 2) correlated with higher concentrations of Bev. Conclusions: Our study demonstrated that various types of chemotherapy influenced the concentrations of Bev, and a higher concentration of Bev may predict the incidence of proteinuria. In addition, clearance of Bev did not change after long treatment period until disease progression. Clinical trial information: 000007630.
Correlation between nivolumab exposure and treatment outcome in NSCLC.
Authors: Stijn L.W. Koolen, Edwin A. Basak, Daan Hurkmans, Marco W.J. Schreurs, Sander Bins, Esther Oomen De Hoop, Annemarie JM Wijkhuis, Ilse Den Besten, Stefan Sleijfer, Reno Debets, Astrid Van Der Veldt, Joachim Aerts, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2018)

9057 Background: Treatment with anti-PD-1 therapy is subject to large inter-individual variation in clinical outcome. This may be influenced partly by differences in nivolumab exposure between patients. The objective of the current analysis was to investigate whether an exposure-response relationship exists for nivolumab-treated NSCLC patients. Methods: 84 patients started nivolumab treatment between May 5th 2016 and August 1st 2017 and were included for prospective collection of serum samples prior to each nivolumab cycle. Clinical data were collected until November 1st 2017. Patients were classified according to best objective response (BOR) according to RECIST v1.1 and the occurrence of grade ≥3 toxicities according to CTCAE v4.03. Geometric mean nivolumab trough concentrations after 2, 4, and 10 weeks of treatment were compared using ANOVA with respect to BOR and t-test with respect to toxicity in patients without dose delays until that particular time point. Results: 76 patients were evaluable for analysis; 4 patients had no follow-up tumor evaluation, and 4 patients had no follow-up blood sample. At each time point, partial responders (PR; n = 15) had higher geometric mean trough concentrations when compared to patients with progression (PD; n = 33): at 2 weeks : 27.4 µg/mL (95% CI: 22.3 – 33.6 µg/mL) vs. 18.7 µg/mL (95% CI: 16.7 – 20.9 µg/mL; p = 0.001; 47% higher), at 4 weeks: 46.2 µg/mL (95% CI: 37.4 – 57.0 µg/mL) vs. 30.2 µg/mL (95% CI: 25.0 – 36.4 µg/mL; p = 0.008; 53% higher), at 10 weeks: 79.4 µg/mL (95% CI: 60.7 – 103.8 µg/mL) vs. 45.8 µg/mL (95% CI: 35.6 – 58.9 µg/mL; p = 0.002; 73% higher). Moreover, PR patients had higher trough concentrations when compared to patients with stable disease (SD; n = 28) at week 2 (p = 0.034) and at week 4 (p = 0.047). Exposure was not significantly related to the occurrence of grade ≥3 toxicity (n = 15) at any time point. Conclusions: This analysis shows that NSCLC patients with an objective response to nivolumab have significantly higher nivolumab exposure than patients with early progressive disease, indicating an exposure-response relationship. Further clinical research is needed to explain and quantify this relation. If confirmed, more rational and individualized dosing-strategies can improve patient outcome.
Association with consolidation chemotherapy after concurrent chemoradiotherapyfollowed by surgery and the disease free survival in patients with stage III non-small cell lung cancer (NSCLC).
Authors: Yuka Kato, Katsuyuki Hotta, Go Makimoto, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Akiko Sato, Masahiro Tabata, Susumu Kanazawa, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2016)

e20053 Background: Surgical resection is a promising therapeutic option for controlling locally advanced stage III non-small cell lung cancer (NSCLC), and the 5-year overall survival rate is 63.6% in patients (pts) with NSCLC harboring mediastinal lymph node metastasis. To determine potential ways to improve the cure rate after concurrent chemoradiotherapy (CCRT) followed by surgery, the association between disease-free survival (DFS) and the pathological effect (pEf) of consolidation chemotherapy (CCT) after CCRT followed by surgery was examined in patients with stage III NSCLC. Methods: Data from 106 stage III NSCLC pts treated in our hospital between January 2011 and October 2015 were examined retrospectively. In total, 60 patients with locally advanced stage III who had received CCRT (cisplatin and docetaxel, total 40-46 Gy). Of the 60 patients that had received CCRT, 54 received subsequent surgery. The pEf was evaluated in the 54 surgery patients, and the patients were categorized according to response: those with complete pathological response (pCR) (Group A) and those without pCR (Group B). DFS was defined as the period between surgery and the day of recurrence. Results: Pts demographics were as follows; 38men; mean age, 60yrs; PS0 before CCRT, 34; stage IIIA/B, 43/11; Adenocarcinoma, 37; never-smoking, 9. We first evaluated the relationship between CCRT pEf and DFS. 14 (25.9%) pts achieved pCR (Group A). Pts in Group A had a better DFS (85% vs. 35% at 36 mo; p < 0.047) than Group B. Multivariate analysis revealed that pCR (Group A vs B) correlated with DFS (HR: 4.51; 95% CI: 0.96 -21.16318; p = 0.056). We next investigated the effect of CCT after CCRT followed by surgery. 24 out of 54 (44%) pts received consolidation chemotherapy (CCT+), while 30 pts did not receive any (CCT-) after CCRT and surgery. There was no statistical difference in DFS after 36 months between CCT+ and CCT- groups (66.5% vs 42.5%, p = 0.29). In Group A, there were no differences between the two groups (CCT+ vs CCT-) (p = 0.18) as well as Group B (p = 0.49). Conclusions: CCT after CCRT followed by surgery does not prolong DFS. However, CCRT pEF affect DFS significantly.
Quality of life (QoL) in a phase III trial of pelvic external beam radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk, early stage endometrial carcinoma: An NRG Oncology/Gynecologic Oncology Group study.
Authors: Vivian Vongruenigen, Helen Q Huang, David Cella, Marcus Randall, Robert S. Mannel, Byoung-Gie Kim, Ritu Salani, James J Burke, Thomas J. Rutherford, Nick Spirtos, Katina Robison, Lari B. Wenzel
Journal: Journal of Clinical Oncology (2018)

5593 Background: In GOG Study 249, VCB/C was not superior to PXRT in overall survival or treatment failure rate (Randall et al, ASTRO, 2017). Here we compare QoL, fatigue, neurotoxicity, and gastrointestinal (GI) symptoms between patients randomized to VCB/C versus PXRT, and examine the association between primary comorbid illness plus obesity on QoL. Methods: The Functional Assessment of Cancer Therapy (FACT) – Endometrial Trial Outcome Index (FACT-En TOI) for QoL, FACIT-Fatigue subscale, FACT/GOG-Neurotoxicity subscale, and 6 items from the FACT-En for gastrointestinal (GI) symptoms were measured at baseline, 4 and 11 weeks, 8 and 14 months post-enrollment. Treatment differences were assessed with a linear mixed model adjusting for pretreatment score, assessment time, and age at enrollment. Results: 540 of 601 eligible patients provided evaluable patient-reported assessments. QOL was not statistically significantly different between treatment arms. However, fatigue and neurotoxicity were significantly worse in the VCB/C group compared to the PXRT group (p < 0.001) especially at 11 weeks. Patients in the PXRT arm, however, reported significantly (p < 0.001) worse GI symptoms when compared with those in VCB/C. Patients with ≥3 comorbid illnesses reported 7.1 points lower (95% CI: 12.0~-2.3; p = 0.004) QOL scores than those with ≤ 2 comorbid illnesses, and 6.5 points lower (95% CI: 2.8~102; p < 0.001) fatigue scores than those with ≤1 comorbid illness. Although obesity status was not associated with the QOL score, patients with morbid obesity (BMI≥40) reported worse fatigue (4.1 points lower; 95% CI: 0.8~7.5; p = 0.008) than other patients. Conclusions: VCB/C was associated with substantially more fatigue and neuropathy; however, PXRT resulted in more GI symptoms. Absent any survival or disease control benefit of VCB/C over PXRT, PXRT remains an effective and appropriate treatment for this patient population. In addition, patients with three or more comorbidities at study entry are likely to have worse QoL and fatigue. Clinical trial information: NCT00807768.
Prognostic factors of recurrence and survival of gastrointestinal stromal tumors: First multicentric study of Mexico.
Authors: Rafael Medrano Guzman
Journal: Journal of Clinical Oncology (2017)

11045 Background: Gastrointestinal stromal tumors are mesenchymal lesions arising from the interstitial cells of Cajal. In GIST the location, size, number of mitosis and risk group are accepted as prognostic factors; some factors in which there are still controversies about their value as prognostic factors include male gender, tumor cellularity, the margins of resection, the presence or absence of p16 or intraperitoneal tumor breakdown. Methods: Observational, retrospective and longitudinal study. Patients admitted to the Oncology Hospital, CMN Siglo XXI of January 1, 1991 to April 30, 2012. Results: We identified 384 patients, the mean follow-up time was 55.86 months, the mean age was 58 years, 80.3% had symptoms and only 4.54% the finding was incidental. The most common site was the stomach (66.6%), followed by small intestine (28.7%) and colon (1.54%). The 7.57% had metastases at diagnosis, 4.54% in liver and 3.03% in the peritoneum. Were expressed by abdominal pain (39.39%) and gastrointestinal bleeding (30.30%), intestinal obstruction in 1.5%. The most common site was the stomach (66.6%), followed by small intestine (28.7%) and colon (1.54%). The 7.57% had metastases at diagnosis. The average tumor size was 10.84 cm (2.2 to 38 cm). Immunohistochemical markers were studied: 94.28% positive for CD117, CD34 74.28%, 11.42% S100 protein, desmin 5.71% and 51.72% for smooth muscle actin (AML). Overall rate at 5 years and 82% rate of recurrence-free survival at 5 years and 61% survival. The location of the tumor (p = 0.0002), size (p = 0.03145), the number of mitosis (p = 0.008), risk group (p = 0.020) and adjuvant treatment with Imatinib showed a statistically significant difference for Survival Recurrence-free. For overall survival, lesion location was the only factor that showed statistical significance with p = 0.0054. Conclusions: The tumor location, size, number of mitosis, the risk group and adjuvant treatment with Imatinib were statistically significant prognostic factors for disease recurrence. The location of the lesion was the only factor that showed statistical significance as a predictor of overall survival.
Comprehensive molecular profiling and analysis of mutual exclusivity of genetic aberrations (MEGA) of intra- and extrahepatic cholangiocarcinomas (IHC and EHC) evaluation of prognostic features and potential targets for intervention.
Authors: Maeve Aine Lowery, Ryan Ptashkin, Emmet Jordan, Michael F. Berger, Ahmet Zehir, Nancy E. Kemeny, Eileen Mary O'Reilly, William R. Jarnagin, James J. Harding, Ronald P. DeMatteo, Michael Ian D'Angelica, Andrea Cercek, Michele LY, Erica Salehi, Jaclyn Frances Hechtman, Nikolaus Schultz, David Michael Hyman, David S. Klimstra, Leonard Saltz, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2016)

4088 Background: Varying driver genetic aberrations have been identified among different anatomic and clinical subtypes of IHC and EHC, with suggestive prognostic and/or predictive benefit and potential therapeutic implications. Methods: Archival FFPE samples from patients who consented prospectively to study were analyzed using the MSK-IMPACT platform, a hybridization capture based next generation sequencing assay for targeted deep sequencing of all exons and selected introns of 410 key cancer genes. Tumor and matched normal libraries were sequenced on an Illumina HiSeq 2500. Sequencing output was processed using a custom analysis pipeline. Demographic and treatment data was prospectively collected. Fisher’s exact tests were performed to look for MEGA and associations between clinical characteristics and genetic alterations. Results: 137 pts were studied: 78% EHC and 22% IHC; 50% male, from metastatic sample (70%) and primary (30%). Median mutations per sample: 3, median sample coverage was 680X. Most commonly altered genes in IHC were IDH1 (30%), ARID1A (23%) BAP1 (20%), p53 (20%) and FGFR2 gene fusions (14%), Tendency towards MEGA was seen between multiple genes in IHC including TP53:IDH1 (p = 0.01), IDH1:KRAS (p = .03), TP53:BAP1 (p = 0.03), IDH1:FGFR2 (p = 0.04). Genetic alterations more common to EHC versus IHC included KRAS, SMAD4, STK11 and p53 (p < 0.05). FGFR2 fusions and BAP1 alterations were not identified in EHC. 120 pts received 1st line chemotherapy for advanced disease (77% gemcitabine/platinum), median TTP was 9.1 months and did not differ for pts with IDH1 mutations or FGFR2 gene fusions. Conclusions: Distinct patterns of genetic alterations and MEGA both within IHC and between IHC and EHC were identified. Response to 1st line chemotherapy did not differ between different molecular subgroups; these prospective data provide a contemporary benchmark for better understanding and development of targeted therapies in molecularly profiled IHC and EHC.