tbuckley/cabot-search huggingface dataset:
Cardiac events in survivors of childhood cancer treated in more recent eras: A report from the Childhood Cancer Survivor Study.
Authors: Daniel A. Mulrooney, Geehong Hyun, Kirsten K. Ness, Matthew J. Ehrhardt, Yutaka Yasui, Daniel Duprez, Rebecca M. Howell, Wendy Leisenring, Louis S. Constine, Kevin C. Oeffinger, Todd M. Gibson, Emily S. Tonorezos, Leslie L. Robison, Melissa M. Hudson, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2019)

10058 Background: Contemporary cancer protocols have incorporated modifications to minimize cardiotoxic exposures and preserve long-term health. We investigated the impact of these changes on late cardiac outcomes in a large cohort of adult survivors of childhood cancer. Methods: Congestive heart failure (CHF), myocardial infarction (MI), valvular disease, pericardial disease, and arrhythmias were graded by the National Cancer Institute’s Common Terminology Criteria for Adverse Events among 23,462 five-year cancer survivors [6,193 (26%) treated in the 1970s, 9,363 (40%) in the 1980s, and 7,906 (34%) in the 1990s] and 5,057 siblings. Cumulative incidence and 95% confidence intervals (95% CI) were estimated by treatment decade. Adjusted multivariable subdistribution hazard models were used to estimate hazard ratios (HR) and 95% CI for cardiac outcomes by decade. Mediation analysis examined risks with and without cardiotoxic exposures. Results: For survivors [median age 6 years (range: 0-21) at diagnosis, 28 years (8.2-58) at follow-up], cardiac radiation (RT) exposure declined from 77% of those treated in the 1970s to 55% and 40% in the 1980s and 1990s. Anthracycline exposure increased from 28% to 50% to 64%. The 20-year cumulative incidence of CHF (0.69% for those treated in 1970s, 0.74% in the 1980s, 0.54% in the 1990s) and MI (0.38%, 0.24%, 0.19%) declined in more recent treatment eras (p &lt; 0.01). This change was not seen for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%) or arrhythmias (0.08%, 0.09%, 0.13%). Compared to survivors diagnosed in the 1970s, the risk of CHF, MI, and valvular disease decreased in the 1980s and 1990s, but only significantly for MI (HR 0.64 95% CI 0.47-0.89 and 0.52 95% CI 0.32-0.83). The overall MI risk was attenuated by adjustment for cardiac RT exposure (HR 0.94 95% CI 0.80-1.11), mostly among Hodgkin lymphoma (HL) survivors (HR 0.82 95% CI 0.69-0.98 [unadjusted for RT]; 1.03 95% CI 0.83-1.28 [adjusted for RT]). Conclusions: Reductions in exposure to cardiotoxic cancer therapies have resulted in declines in adverse cardiac outcomes, particularly for the RT-associated risk of myocardial infarction among HL survivors.
Outcomes of treatment of carcinoma gall bladder undergoing curative intent surgery.
Authors: Arun Chaturvedi, Vijay Kumar, Sameer Gupta, Naseem Akhtar, Shiv Rajan Saini, Puneet Prakash
Journal: Journal of Clinical Oncology (2019)

e15621 Background: Gall bladder carcinoma (GBC) is the most common malignancy of the biliary tract. North India reports one of the highest incidences of GBC in the world. Majority of patients present with advanced disease where surgery is not possible. We report the results of patients undergoing curative intent surgery at a tertiary care University hospital in North India. Methods: Data of 270 patients undergoing curative intent surgery for GBC at the Department of Surgical Oncology, King George’s Medical University, Lucknow (India) between January 2014 and December 2018 was retrospectively studied. We have analysed the collected data using descriptive and survival statistics. Results: During the period of study 270 patients were operated for GBC. Mean age of patients was 50.2 years and majority (75.2%) were females. On surgical exploration 82 (30.4%) had unresectable disease and only a biopsy or palliative procedure was done. Simple cholecystectomy was done where frozen section showed benign calculus cholecystitis in 26 (9.6%) patients. Radical cholecystectomy was performed in 162 (60%) patients. Final histopathology revealed Xanthogranulomatous cholecystitis in 28 (17.3%) of these 162 patients. Adjacent organ resection was done in 29 of the 134 (24.1%) patients undergoing radical cholecystectomy for pathologically proven GBC. Colon and CBD were the most common adjacent organs resected. Completion radical cholecystectomy was done in 22 patients with incidental GBC. Adjuvant chemotherapy as per our institutional protocol was given to 68 (50.7%) patients having Stage 3 or more disease. After a mean follow-up of 19 months the median disease free interval (DFI) is 38 months and the median overall survival (OS) has not been reached. Patients undergoing adjacent organ resection had an inferior median OS of 20 months compared to those without it where the median has not been reached (Log Rank P = 0.006). Conclusions: Nearly a third of GBC patients planned for curative intent surgery are found to have unresectable disease on exploration. This proportion needs to be brought down. Radical cholecystectomy in properly selected GBC patients without adjacent organ involvement gives satisfactory survival outcomes.
Patient-reported quality of life (QoL) of advanced melanoma patients in a Phase 3 study of nivolumab (NIVO) with or without ipilimumab (IPI) versus IPI: CheckMate 067 4-year data.
Authors: Dirk Schadendorf, James M.G. Larkin, Jedd D. Wolchok, Vanna Chiarion-Sileni, Fiona Taylor, Rachael Lawrance, Alejandro Moreno-Koehler, Jennifer Lord-Bessen, Jasmine I. Rizzo, Andriy Moshyk, SRIVIDYA KOTAPATI, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2019)

9551 Background: Early CheckMate 067 data showed maintenance of QoL in patients with advanced melanoma treated with NIVO with or without IPI based on 1-year data; however, the long-term QoL of these patients has not been evaluated previously. The patient-reported outcomes (PRO) analyses presented here for CheckMate 067 is the first time QoL results have been evaluated in this melanoma population over a 4-year period. Methods: In CheckMate 067, 945 patients were randomized 1:1:1 to receive NIVO (3mg/kg Q2W) + placebo (PBO), NIVO+IPI (1mg/kg+3mg/kg Q3W X 4) followed by NIVO (3mg/kg Q2W), or IPI (3mg/kg Q3W X 4) + PBO. PRO data were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, VAS) at baseline, weeks 1 and 5 of each 6-week tx cycle, and off-tx follow-up (FU) visits. Mean changes in PRO scores from baseline (randomization) were evaluated descriptively for the PRO analysis population, with conclusions drawn from time points with ≥30 patients completing assessments per tx arm. Least square mean changes from baseline were assessed using a longitudinal mixed model analysis adjusting for repeated measures, including all on-tx data for patients. Results: Completion rates at baseline ranged from 89-92% across tx arms. Of 813 patients included in the PRO analysis population (278 NIVO, 274 NIVO+IPI, 261 IPI), &gt; 200 receiving tx remained for the first year, &gt; 100 receiving tx remained after 2 years, and &gt; 50 receiving tx remained after 3 years. QoL, including assessment of functioning and symptom burden, was maintained for the duration of tx and in FU, with no sustained clinically meaningful deterioration in any tx arm. Global health status (EORTC QLQ-C30) and general QoL (EQ-5D-3L VAS) were also maintained during prolonged tx. Overall, results from the mixed model analysis support the long-term maintenance of QoL over the course of tx. Conclusions: Patient-reported QoL and symptoms in patients with advanced melanoma were maintained from baseline during extended tx with NIVO with or without IPI. Clinical trial information: NCT01844505.
Renal function after treatment for childhood cancer: A report from the St. Jude Lifetime Cohort Study.
Authors: Daniel M. Green, Mingjuan Wang, Matthew J. Krasin, Deokumar Srivastava, Carrie R. Howell, Dennis W. Jay, Kirsten K. Ness, William Greene, Jennifer Q. Lanctot, Kyla C. Shelton, Andrew M. Davidoff, Matthew J. Ehrhardt, Daniel A. Mulrooney, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2019)

10048 Background: We assessed renal function in a large, clinically assessed cohort of childhood cancer survivors. Methods: Creatinine and qualitative urine protein was measured in 2753 survivors (&gt;10 years (years) post-diagnosis, age ≥18 years). Renal function was graded per the Kidney Disease International Global Outcomes 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD). Multivariable logistic regression was used to estimate associations between demographics, treatment exposures, and CKD (grades 1-5 and 3-5). Radiation treatment was expressed as percentage of total kidney volume treated with 5 (V5), 10 (V10), 15 (V15) and 20 (V20) Gray. Results: Among 2753 survivors, 48.7% were female and 82.5% non-Hispanic white. Median age at diagnosis - 7.3 years (interquartile range [IQR]=3.3-13.2), median age at evaluation - 31.4 years (IQR=25.8-37.8), and median time from diagnosis to evaluation - 23.2 years (IQR=17.6-29.7). Prevalence of grades 1-5 and 3-5 CKD was 7.4% and 2.1%, respectively (grade 1=113, grade 2=30, grade 3=44, grade 4=5, and grade 5=8). Individual and cumulative aminoglycoside doses and treatment with high-dose methotrexate were not associated with CKD (data not shown). Cumulative number of doses of ambisome/abelcet and of amphotericin B were significant risk factors for grades 1-5 and grades 3-5 CKD in models for V15 and V20 (data not shown). The multivariable results for V10 are shown in the Table. Conclusions: In addition to nephrotoxic antineoplastic and supportive care therapy, race, ethnicity, and body composition contribute to risk of CKD in long-term survivors. These novel results inform late effects reduction strategies for future treatment protocols and identify survivors at highest risk for CKD. [Table: see text]
Clinical significance of Ki-67 index expression in advanced non-small cell lung cancer.
Authors: Di ming Wang, Qingming Shi
Journal: Journal of Clinical Oncology (2019)

e20576 Background: It is unclear how the Ki-67 index expression affects the objective response to chemotherapy in non-small cell lung cancer(NSCLC). The study analyzed the relationship among the Ki-67 index, the objective response rate and progression-free survival(PFS) of chemotherapy in ad-NSCLC. Methods: 112 patients of advanced NSCLC in our hospital from 2014 to 2017 were studied. Both EGFR and ALK were wild type in adenocarcinoma patients, and no gene test was performed in squamous carcinoma. The relationship among Ki-67 index ,tumor stage, response of chemotherapy and progression-free survival was analyzed by univariate and multivariate analysis.Ki-67 index was used to predict the objective response of chemotherapy by receiver operating characteristic curve(ROC curve). Results: The objective response rate of chemotherapy was 61.6%(69/112);squamous carcinoma was 69.1%(38/55);adenocarcinoma was 54.4%(31/57). Ki-67 index(P = 0.000) and tumor stage(P = 0.025) were the factors influencing the objective efficacy of chemotherapy.Ki-67 index was linearly correlated with tumor stage (r = 0.341,P = 0.001).In the univariate and multivariate analyses, the Ki-67 index was significantly associated with the objective response to chemotherapy (B = -0.069,P = 0.000).Ki-67 index expression can accurately predict the objective response rate of ad-NSCLC chemotherapy by ROC curve(P &lt; 0.0001,AUC = 0.7467,95%CI = 0.6578-0.8356):squamous carcinoma group (P = 0.0003,AUC = 0.8065,95%CI = 0.6922- 0.9208), adenocarcinoma group (P = 0.0193, AUC = 0.681,95%CI = 0.536-0.8262).In the test cohort, the sensitivity of the Ki-67 index to the objective response rate of chemotherapy was 93.02%.In the squamous carcinoma group the sensitivity was 94.12%.In the adenocarcinoma group the sensitivity was 65.54%.The best Cut-off was 55% for the adenocarcinoma group with good chemotherapeutic efficacy and the adenocarcinoma group with poor efficacy. The best Cut-off value was 65% in squamous carcinoma group with good curative effect and squamous carcinoma group with poor curative effect.The overexpression of Ki-67 index was a negative prognostic factor for PFS in ad-NSCLC (P &lt; 0.0001):squamous carcinoma (P = 0.0055), adenocarcinoma (P &lt; 0.0001). In multivariate Cox analysis, Ki-67 index (P = 0.000) and stage (P = 0.001) were negative factors of PFS. Conclusions: Ki-67 index is a clinically significant biomarker in ad-NSCLC, which can predict the objective efficacy of chemotherapy. The high expression of Ki-67 might be an indicator of the shortened PFS time.
Safety and clinical outcomes of GT0918 (Proxalutamide), a potent androgen receptor (AR) blocker, in patients with mCRPC progressing on standard (SoC) and experimental therapies: Phase I/II trial.
Authors: Nicholas J. Vogelzang, Richard Levin, David Chu, Nashat Y. Gabrail, Luke T. Nordquist, Mark N. Stein, Harish P. Dave, Phoebe Zhang, Karl Zhou
Journal: Journal of Clinical Oncology (2019)

e16527 Background: GT0918 is a new chemical entity of AR blocker. A phase I dose escalation study was planned for 6 dose cohorts in pts with mCRPC who have progressed on SoC and experimental therapies. No DLT or major toxicity was found in planned doses, therefore a cohort of 600 mg daily was added in December 2018. Methods: Patients (pts) with histologically confirmed mCRPC who progressed on enzalutamide +/- abiraterone and docetaxel were eligible. GT0918 was administered once daily orally for 28 consecutive days for DLT assessment. Pts could continue on GT0918 until they experienced intolerable toxicity, disease progression or withdrew consent. All pts consented for exploratory biomarker studies of CTC and cf-DNA/RNA. Results: 40 pts were treated with GT0918 in 7 cohorts. Pts had metastatic disease to bone only (44%), and lymph node +/-visceral +/- bone (56%), who progressed on multiple lines of therapies including but not limited to abiraterone, enzalutamide, docetaxel, cabazitaxel. GT0918 related adverse events (AEs) were grade 1 or 2 as per CTCAE v4.03. including fatigue, anemia, nausea, loss of appetite, hot flushing, depression, etc. The most common TEAE is fatigue and all pts at 500 mg dose reported having fatigue and one pt required dose reduction. Toxicity at the 600mg is still being analyzed but at least 2 pts had tremor. Treatment duration showed more pts in the treatment of 400 mg and 500 mg with SD in this heavily pretreated group (see Table). Exploratory biomarkers of CTCs also suggested higher dose of GT0918 resulted in better clinical outcomes. Conclusions: GT0918 administrated orally once daily was well tolerated. Better clinical outcomes were shown in dose cohorts of 400 mg and 500 mg without major toxicities. Thus these 2 doses were selected for dose expansion. Table. Clinical outcomes of GT0918 in heavily pretreated mCRPC pts Clinical trial information: NCT02826772. [Table: see text]
Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study.
Authors: Jonathan W. Riess, Susan G. Groshen, Karen L. Reckamp, Heather A. Wakelee, Geoffrey R. Oxnard, Sukhmani Kaur Padda, Marianna Koczywas, Zofia Piotrowska, Lynette M. Sholl, Cloud P. Paweletz, Christie J. Lau, Jill Kolesar, Philip C. Mack, Jeffrey Moscow, Pasi A. Janne, Primo Lara, Edward M. Newman, David R. Gandara
Journal: Journal of Clinical Oncology (2019)

9057 Background: Osi (3 rd gen EGFR TKI) has robust activity in 1 st line EGFR mutant NSCLC and TKI resistant T790M pos NSCLC but progressive disease (PD) occurs and outcomes with Osi alone are poor in T790M neg , C797X pos and EGFR exon 20 insertion (ins20) disease. This study examined the EGFR monoclonal antibody Neci with Osi in select settings of EGFR TKI resistance. Methods: Using a 3+3 design, Neci was examined in advanced EGFR mutant NSCLC at dose levels (DL) of 600 mg (DL1) &amp; 800 mg (DL2) D1, D8 IV q21 days + Osi 80 mg qd. Four expansion cohorts (ExC; 18 each) included: A) T790M neg PD on 1 st /2 nd gen TKI as last therapy, B) T790M neg PD on 3 rd gen TKI, C) T790M pos PD on 3 rd gen TKI, D) EGFR ex20ins PD on chemotherapy. Central T790M testing by ddPCR in ExC A-C. Additional studies performed include: NGS panel of &gt; 400 genes, EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR as exploratory analyses. Adverse events (AEs) graded (Gr) by CTCAEv5 with ORR and PFS by RECIST 1.1. Results: Dose escalation and ExC B completed accrual. In total 55 pts were evaluable (Table). 1 pt had DLT at DL2, Gr 3 sinus bradycardia. Drug related Gr 3 AEs were seen in 27% (15) of pts, mainly rash (7;13%). ctDNA showed decreased mutant allele frequency with therapy in all pts studied with detected EGFR at baseline, with complete plasma clearance in a pt with detectable C797S. Conclusions: The RP2D (Osi 80 mg qd and Neci 800 mg D1, D8 IV on q21d cycle) is feasible and tolerable. In ExC A,T790M neg pts with 1 st /2 nd gen EGFR TKI as last treatment, using curtailed sampling, the pre-specified efficacy signal was reached for Osi + Neci comparing favorably to Osi alone in analogous pts from the AURA trial. Clinical activity was also seen in EGFR-dependent resistance (T790M pos C797S pos ) after PD on 3 rd gen TKI and in EGFR ins 20. Clinical trial information: NCT02496663. [Table: see text]
Case 15-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely
Journal: New England Journal of Medicine (1987)

Presentation of Case A 65-year-old woman was admitted to the hospital because of an enlarging goiter and stridor. The patient was well until 10 months earlier, when she began to experience increasi...
Prospective observational study for treatment resistance-related gene screening using plasma circulating tumor DNA in the third generation EGFR TKI osimertinib therapy elucidator.
Authors: Akihiro Tamiya, Shun-Ichi Isa, Yoshihiko Taniguchi, Masahiko Ando, Shinji Atagi, Yasuhiro Koh
Journal: Journal of Clinical Oncology (2019)

TPS3171 Background: Osimertinib (Osi) is a third-generation epidermal growth factor receptor (EGFR) – -tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations (mu). O showed superior efficacy compared with first generation EGFR-TKIs in patients (pts) with previously untreated advanced NSCLC harboring sensitizing EGFR mu in the prior phase III trial. Therefore, Osi is one of the most important standard therapies in EGFR mu positive pts. However, there are few reports about mechanisms of Osi resistance as the first line (1L) EGFR-TKI. Understanding of 1L Osi resistance mechanisms is essential to conduct future therapeutic strategy for EGFR mu NSCLC pts. We planned the analysis of the resistant mechanism by the ultra-sensitive next-generation sequence (NGS) using the circulating tumor (ct) DNA to clarify a resistant mechanism of 1L Osi. Methods: We prospectively collect ctDNA samples from EGFR mu positive NSCLC who will be treated with Osi as 1L. Planned enrollment is 180 cases, we estimate an analysis case at exacerbation to be 120 cases in a registration period and the observation period of for each two years. ctDNA samples are collected at treatment initiation, 3 and 12 months after Osi treatment, and disease progression. We will analyze the mechanisms of 1L Osi by the ultra-sensitive NGS using ctDNA. The key inclusion criteria are histologically or cytologically proven NSCLC, EGFR mu positive, pts treated with Osi as 1L, and written informed consent. The key exclusion criteria are patients who were deemed unsuitable for participation by an attending physician due to other conditions. The primary outcome is to clarify the incidence and ratio of Osi resistance by the ultra-sensitive NGS method using ctDNA at treatment initiation and progression disease. And key secondary endpoint is to examine how the detection quantity of the Osi resistance association mu in ctDNA at treatment initiation influences progressive disease. Clinical trial information: jRCTs031180051.
Possible viral oncolysis by members of the Reoviridae and Paramyxoviridae families (an in vitro study).
Authors: Anastasia O. Sitkovskaya, Elena Yu. Zlatnik, Sergey A. Kolpakov, Elena P. Kolpakova, Inna A. Novikova, Aleksandr B. Sagakyants, Andrey Dashkov, Dmitry O. Kaymakchi, Gapiz M. Chupanov, Patimat M. Gamzatova
Journal: Journal of Clinical Oncology (2019)

e14212 Background: Our purpose was to study possible oncolytic activity of Newcastle disease virus and reovirus in different tumor cell cultures in vitro. Methods: The study was performed on LaSota strain Newcastle disease virus (NDV) vaccine (OOO NPP AVIVAK, 5000 doses) and human reovirus strains R-92 (3 serotype) deposited in the State collection of viruses of the Research Institute of Virology named after. D.I.Ivanovsky. HeLa (cervical cancer), A549 (lung adenocarcinoma), BT20 (breast cancer), PC3 (prostate cancer), HT29 (colon cancer) cell lines were used; pig embryo kidney cell culture (PEVKC) was used as a positive control. Results: After Newcastle disease virus was placed in the medium with tumor cell lines, a 5-day visual microscopic control of the cell morphology did not show signs of the cytopathic action, while a complete lysis of cell biomass was observed in the positive control (PEKC) by the third day. After the incubation with reovirus, the oncolytic activity was registered already in 24 hours: partial or complete destruction of the monolayer, decreased cell adhesion (only solitary cellular conglomerates remained at the bottom of vials), changes in the typical cell appearance. The complete cytopathogenic effect was observed after 2 days. Conclusions: The results demonstrated a marked lytic effect of reovirus in vitro, as well as varying sensitivity of the studied tumor lines to it, which may depend on their molecular genetic characteristics, for example on the RAS mutation status. Despite ambiguous results, we consider it expedient to continue the studies of these and other viruses in tumor models both in vitro and in vivo.
Abstract 11394: The Image-Based Surgical Strategy and Outcomes of Transaortic Extended Myectomy for Patients With Midventricular Obstruction
Authors: Yajie Tang, Yunhu Song, Fujian Duan
Journal: Circulation (2018)

Introduction: Data on the strategy of transaortic myectomy for midventricular obstruction (MVO) were limited. Hypothesis: We assessed the reliability and efficacy of preoperative echocardiographic ...