tbuckley/cabot-search huggingface dataset:
Clinical and molecular features of patients with cholangiocarcinoma harboring FGFR genetic alterations.
Authors: Alice Boileve, Islam Baiev, Caroline Dinicola, Nora K Horick, Melodie Tazdait, Andrew X. Zhu, Antoine Hollebecque, Lipika Goyal
Journal: Journal of Clinical Oncology (2019)

4084 Background: Genetic alterations (GAs) in the fibroblast growth factor receptor (FGFR) pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR GAs are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR GA on tumor molecular profiling as part of routine care. Data on demographics, risk factors, pathology, systemic therapy, radiographical response, progression free survival (PFS), and overall survival (OS) were collected. Results: Among 65 pts, the median age at diagnosis was 55 years old (range = 27-92), and 38 (58%) pts were female, 63 (97%) had intrahepatic CCA, and 5 (11%) had chronic HBV. At presentation, 37% of pts had resectable disease. Of 47 pts with a known CA 19-9 at the time of initial diagnosis, 21 (45%) had a value &lt; 35U/mL. FGFR2 fusions were the most common FGFR GA (78%), followed by FGFR2 mutations (14%), FGFR3 mutations (4%), FGFR3 fusion (2%) and FGFR1 amplification (2%). The most common fusion partners were BICC1 (20%), POC1B (6%), SORBS1 (6%), DBP (4%), and TACC2 (4%). The most common co-alterations were in ARID1A, CDKN2A/B, TP53, BAP1, IDH1, HER2, BRCA2, and PTEN. The median lines of palliative systemic therapies received was 3 (range = 0-8), and 9/65 (14%) pts had &gt; 1 FGFR inhibitor (FGFRi). For the 30 (46%) pts with FGFR2 fusions who received gemcitabine/platinum as first line palliative systemic therapy, the median PFS was 4.7 months (95% CI: 2.1-6.0). In the overall population, the median OS from time of initial diagnosis was 35.8 months (95% CI:29.7-52.7). Among 46 pts who received an FGFRi on a clinical trial and had ≥ 1 follow-up scan, the overall response rate (ORR) by RECIST v1.1 in pts with FGFR2 fusions, was 35.8% (14/39) on their first FGFRi; ORR was 16.7% (1/6) for pts with FGFR2 mutations. Conclusions: Pts with CCA harboring FGFR GAs were found to have a high rate of normal CA 19-9 and short median PFS on first line gemcitabine/platinum compared to historical controls but additional comparative studies are necessary to evaluate these findings.
Factors associated with recurrence and death in patients with aggressive hobnail morphology papillary thyroid carcinoma.
Authors: Jonathan Matthew Sharrett, Hong Li, Akeesha Shah, Christian Nasr, Joseph Scharpf, Shlomo A. Koyfman, Nikhil Joshi, Jessica Lyn Geiger
Journal: Journal of Clinical Oncology (2019)

e17590 Background: Papillary thyroid carcinoma (PTC) with hobnail morphology (HM) is an aggressive variant associated with poorer outcomes compared to classical PTC, with a little over 100 cases reported in the literature. We aim to identify prognostic factors potentially associated with recurrence and death in the largest single institutional experience of PTC with HM. Methods: From an IRB approved registry, we identified all PTC HM cases with patient, diagnostic and treatment data and outcomes. Hobnail variant (HV) PTC had ≥30% HM; pure hobnail features (PHF) had &lt; 30% HM without tall cell morphology (TCM) &amp; multi variant features (MVF) had both HM &amp; TCM. Demographic and clinical features at time of HM diagnosis that were potentially associated with 3-yr event free (death or recurrence) survival (EFS) were evaluated using Kaplan-Meir method (KM). Results: Forty-five (median age 55 yo, range 19-86 yo; 66.7% female) HM pts (35 HM at initial PTC, 10 at recurrence) were evaluable. Majority were ECOG 0 (84.1%). HM: 44.4% MVF, 37.8% PHF, &amp; 17.8% HV; 68.9% pT3/T4; 64.4% node positive; &amp; 15.6% metastatic. Positive surgical margins (+SM) with HM in 31.8%. RAI at HM given to 73%. Overall EFS was 83.5% at 1-yr &amp; 69.6% at 2-yr. Of 13 events at 3 yrs, 4 were deaths (3 from PTC) &amp; 9 recurrences. All events were in those &gt; 55 yo (p &lt; 0.001) with pT3/T4 disease (p = 0.01). Non-0 ECOG (KM 2-yr EFS: 28.6% vs 77.7%, p = 0.002), cT3/T4 (49.5% vs 85.5%p = 0.004), and +SM (32.1% vs 92.1%, p = 0.001) were also associated with EFS compared to their counterpart. HM grouping, RAI, initial HM vs HM at recurrence, sex, and tumor size were not statistically significant. Conclusions: To our knowledge, this is the largest reported cohort of PTC with HM. We identified several factors potentially associated with recurrence and death. There was no difference in outcomes between HV versus PHF versus MVF, which raises question to validity of 30% cutoff in defining “variant” versus “features of variant”. Age &gt; 55 yo, T3/T4 disease, and +SM exhibited significantly inferior EFS. Further evaluation in a multi-institutional cohort will help in validating these findings and help identify patients who warrant more aggressive initial treatment.
IOLite: Multipart, phase 1b, dose-finding study of the PD-1 inhibitor dostarlimab in combination with the PARP inhibitor niraparib ± bevacizumab (bev), or with platinum-based chemotherapy ± bev for advanced cancer.
Authors: Nashat Y. Gabrail, Alberto Bessudo, Erika Paige Hamilton, Jasgit C. Sachdev, Manish R. Patel, Jordi Rodon Ahnert, Lena Evilevitch, Meghan Duncan, Wei Guo, Sharon Lu, Bruce Jeffrey Dezube, Timothy A Yap
Journal: Journal of Clinical Oncology (2019)

2560 Background: Novel combinations of drugs may overcome resistance in patients (pts) with solid tumors who had progressed on standard therapy. Methods: IOLite (NCT03307785) is a multicenter, open label, multipart study to determine dosing and evaluate safety and efficacy of dostarlimab in combination with approved therapies in pts with advanced solid tumors. Pts were enrolled in each part based on tumor histology, prior treatment (tx) history, and physician preference. Primary endpoint is dose-limiting toxicities (DLTs) deemed as tx-related per investigator, and safety and tolerability of the combination. Tumor responses were assessed per RECIST v1.1. Results: Parts A-D (see Table) are fully enrolled. One complete response was reported in part B (endometrial); confirmed partial responses in part A (ovarian, small cell lung [SCLC], gastrointestinal stromal [GIST]); part B (breast [2], bladder, SCLC); part C (prostate, fallopian tube), and part D (endometrial, non-SCLC). Stable disease was reported in part A (colorectal, prostate [2], breast, GIST, gastric); part B (SCLC, squamous cell, head and neck, prostate); part C (pancreatic, ovarian, GIST, breast [2], liver, endometrial); part D (ovarian, head &amp; neck, cholangiocarcinoma). At data cutoff, 24 pts remain on treatment. PK’s of dostarlimab and niraparib (nir) were not altered by any of the combination agents tested. Conclusions: Dostarlimab is well tolerated in combination with nir ± bev, or carbo-pac ± bev. Preliminary efficacy data show responses in various histologies. No new safety signals were identified. Clinical trial information: NCT03307785. [Table: see text]
Interim report on CIV recombinant human endostatin in combination with docetaxel/cisplatin (DP)) in comparison to DP in the first-line treatment of phase IIIb/IV squamous-cell NSCLC (JSLCG-001): A multicenter, open-label, randomized phase III controlled study (NCT: 02513342).
Authors: Jian'An Huang, Yong Song, Minhua Shi, Jian Feng, Xuedong Lv
Journal: Journal of Clinical Oncology (2019)

e20541 Background: Endostar registration Phase III and post-marketing Phase IV clinical study had confirmed Endostar in combination with Platinum double drugs can improve the NSCLC patients’ outcomes of ORR, PFS and OS. However, It influenced on the patients’ compliance for Endostar day 1-14 intravenous infusion (I.V). Endostar day 1-7 continuous intravenous infusion (CIV) can have the compliance improved obviously. So, we carried out this phase III trial to confirm the efficacy and safety of CIV Endostar in combination with DP regimen for first line treatment of phase IIIB/IV squamous-cell NSCLC. Methods: The planed 188 patients with phase IIIB/IV squamous-cell NSCLC without the history of chemotherapy would be randomly assigned to receive Endostar and DP (Endostar, 15mg/m 2 /d, civ, d1-7; Docetaxel, 60mg/m 2 /d, iv, d4; Cisplatin, 75mg/m 2 /d, iv, d4), or DP (Docetaxel, 60mg/m 2 /d, iv, d1; Cisplatin, 75mg/m 2 /d, iv, d1). The cycle was every 3 weeks and 4-6 cycles would be needed in total in each groupl. After 4-6 cycles, CIV Endostar in Endostar+DP group would maintain till PD. The primary end point was PFS. Results: The interim data from 94 cases was included in the analysis. The median PFS in Endostar+DP group was 6.8 months ( 95% CI, 4.0-9.6) versus 3.1 months ( 95% CI, 2.9-3.4) in DP group ( P = 0.024 ). The response rate was 33% in Endostar+DP versus 31% in DP group ( P = 0.838 ). The AEs in each group was comparable. No unexpected AEs in Endostar+DP was found. Conclusions: This preliminary result showed Endostar in combination with DP improved PFS significantly (P = 0.024). Among patients with advanced, previously untreated squamous-cell NSCLC, the longer PFS was related to CIV Endostar on the duration of maintenance. Clinical trial information: NCT02513342.
Preventive surgery after multiplex genetic panel testing (MGPT).
Authors: Gregory Idos, Allison W. Kurian, Charité Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Koff, Nicolette M. Chun, Courtney Rowe-Teeter, Peter Levonian, Christine Hong, Meredith Mills, Cindy Ma, Johnathan M. Lancaster, Krystal Brown, John Kidd, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2019)

1525 Background: Guidelines recommend consideration of prophylactic surgery for patients with a germline pathogenic variant in some cancer predisposition genes. We assessed surgery utilization in a prospective, multi-institutional cohort study of MGPT. Methods: 2000 patients had MGPT and completed questionnaires at 3, 6, and 12 months. Patients reported surgical utilization and indication (treatment or prevention). Surgery utilization was assessed according to cancer history and MGPT test results: Positive, pathogenic variant; VUS, variant of uncertain significance; Negative, benign variants. Results: Overall, 12.9% (198/1537) of patients reported surgery after MGPT (median follow-up 13 months). Only 31.3% (62/198) of patients specified that their surgery was preventive. Preventive surgery utilization was significantly higher among patients who tested positive (n=30, 14.9%) compared to those testing negative (n=20, 2.3%, p&lt;0.001) or VUS (n=12, 2.2%, p&lt;0.001). Preventive surgery was very low among patients testing negative or VUS who had no personal history of cancer in the relevant organ (Table). For example, mastectomy was not reported among any patients testing negative or VUS who had no personal history of breast cancer (Table). Conclusions: More than one year after MGPT, prophylactic surgery use was low among patients with VUS or negative results, especially among those with no personal history of cancer at the relevant site. Surgery utilization. [Table: see text]
Case 29-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Moshe Lahav, Scott M. Whitcup
Journal: New England Journal of Medicine (1989)

Presentation of CaseA 79-year-old man was admitted to the hospital because of fever, abdominal pain, and an inflamed right eye.The patient felt well until six days earlier, when he ate a huge turkey sandwich. Several hours later he began to experience abdominal pain and dizziness, both of which worsened as the evening progressed, even after he went to bed. Chilliness developed, and he was taken to another hospital, where physical examination showed that the temperature was 40.4°C; the blood pressure was 200/100 mm Hg. No explanation for the patient's fever was found; the bowel sounds were increased, and . . .
Phase 2 trial of first-line pembrolizumab with platinum doublet chemotherapy and radiotherapy in patients (pts) with unresectable, locally advanced stage III non–small-cell lung cancer (NSCLC): KEYNOTE-799.
Authors: Salma K. Jabbour, Keunchil Park, Dosinda Cohn, Hong Liu, Steven M. Keller, Dariusz M. Kowalski
Journal: Journal of Clinical Oncology (2019)

TPS8575 Background: Standard therapy for pts with unresectable stage III NSCLC is concurrent platinum doublet chemotherapy with radiotherapy (CCRT); however, this therapy does not reduce the risk of distant relapse, and the 5-y survival rate is low. The anti–PD-1 checkpoint inhibitor pembrolizumab has durable clinical activity as first-line therapy for advanced/metastatic NSCLC: as monotherapy for PD-L1–positive tumors and in combination with chemotherapy irrespective of PD-L1 status. KEYNOTE-799 evaluates the safety/efficacy of first-line pembrolizumab plus CCRT for unresectable, locally advanced stage III NSCLC. Methods: This nonrandomized, open-label phase 2 study enrolls pts ≥18 y with previously untreated, unresectable, pathologically confirmed stage IIIA–C NSCLC with measurable disease per RECIST 1.1. Pts receive 17 cycles of pembrolizumab 200 mg Q3W plus standard thoracic radiotherapy in cycles 2 and 3 (60 Gy in 30 daily 2 Gy fractions). In cycles 1–3, treatment also includes investigator’s choice of either paclitaxel 200 mg/m 2 and carboplatin area under the curve (AUC) 6 Q3W for 1 cycle, followed by paclitaxel 45 mg/m 2 and carboplatin AUC 2 weekly for 6 weeks, or cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 Q3W (nonsquamous only). Tumor imaging occurs at baseline and Q9W until week 54, verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. Primary endpoints are the rate of grade ≥3 pneumonitis and ORR (RECIST 1.1 by blinded independent central review [BICR]); confidence intervals for both will be estimated by the Clopper-Pearson method. Secondary endpoints are PFS (RECIST 1.1 modified to follow ≤10 target lesions; ≤5 per organ by BICR), OS, and safety. PFS and OS will be analyzed by Kaplan-Meier method. Approximately 216 pts (108 per cohort) will be enrolled in 59 sites in 10 countries beginning on Nov 5, 2018. As of Feb 12, 2019, 30 pts have enrolled. Continuous interim analyses using binomial sequential testing will be performed after ≥36 pts have ≥15 weeks of follow up in each cohort, to allow earlier treatment discontinuation, if required. Clinical trial information: NCT03631784.
Clinical characteristics, treatment (Tx) patterns, and overall survival (OS) in advanced (Adv) NSCLC patients (Pts) with and without brain metastases (BM).
Authors: Emily Nash Nash Smyth, Ramon Velasquez Tiu, Melinda D Willard, Julie Beyrer, Yajun Emily Zhu, Lee Bowman, Kristin M Sheffield, Yimei Han, Priscilla Brastianos
Journal: Journal of Clinical Oncology (2019)

2035 Background: BM in NSCLC pts are associated with significant morbidity and mortality. This analysis describes the frequency and timing of BM development, pt characteristics, systemic txs, and OS in NSCLC pts with and without BM. Methods: This retrospective observational study identified pts from the Flatiron-Foundation Medicine NSCLC Clinico-Genomic Database diagnosed from 1 Jan 2011 to 31 Oct 2017 with adv NSCLC and a tumor sample analyzed via FoundationOne. Tx pattern data were summarized by period (1 Jan 2011-1 Mar 2015; 2 Mar 2015-31 Dec 2017), therapy class (eg, anti-VEGF and EGFR, platinum-based), and BM occurrence. Descriptive statistics were used to summarize data; Chi-square and t-tests assessed statistically significant differences. OS was measured by site of met (BM only vs no-BM only vs BM and no-BM) via K-M methods from adv diagnosis until death or last activity date (censored). Results: Of 3257 pts, 1018/3257 (31.3%) had BM during follow-up; 726/1018 (71.3%) presented with BM within 30 days of adv diagnosis. The median age at adv diagnosis was 66.2 yrs. Relative to pts without BM, BM pts were younger, more likely to be female, of Asian descent, have stage IV disease, ≥2 met sites (including BM) at initial presentation, ≥3 met sites (including BM) during follow-up, and non-squamous histology (all p &lt; 0.01). Approximately 78% (n = 2534) were treated with ≥1 systemic tx; platinum-based chemo-combinations were the most common 1 st line tx, regardless of BM status. Increased use of PD-1/L1 tx was seen in 1 st , 2 nd , and 3 rd line during the latter vs earlier period. No statistically significant difference in OS was observed in pts with BM only (17.1 mos; 95% CI 12.5-29.9), no-BM only (21 mos; 95% CI 19.4-22.8), or BM and no-BM (20.4 mos; 95% CI 18.9-23.3) (log rank p = 0.3027). Conclusions: In met NSCLC pts with a tumor sample that was molecularly profiled, OS was comparable, regardless of site(s) of disease; additional multivariate analyses including molecular profiles are needed. BM screening at initial diagnosis is important given the frequency in NSCLC. Future studies should assess whether the shift in systemic tx patterns impact the development and clinical outcomes.
Phase II trial of nab-paclitaxel (ABI) and ipilimumab (ipi) in patients with treatment naïve metastatic melanoma.
Authors: Kaysia Ludford, Daniel H. Johnson, Tarin Hennegan, Stephen K. Gruschkus, Cara L. Haymaker, Chantale Bernatchez, Natalie Jackson, Patrick Hwu, Adi Diab
Journal: Journal of Clinical Oncology (2019)

9554 Background: Conventional chemotherapies possess intrinsic immune-regulatory properties. Some taxanes for instance, stimulate antigen presentation and impair regulatory T-cells while leaving effector T cells intact. Combining chemotherapies with immune checkpoint inhibitor at carefully designed dosing regimens may increase tumor cell susceptibility to immune-mediated death and thus enhance therapeutic efficacy. We describe the safety and updated efficacy of ABI and ipi in patients with metastatic melanoma. Methods: In this open-label, single center, phase II trial, ABI was administered to treatment naïve metastatic patients at 150mg/m 2 on days 1,8 and 15 every 4 weeks and ipi at 3mg/kg on day 1 every 3 weeks limited to 4 cycles until disease progression or unacceptable toxicity. Endpoints included ORR, OS and safety. Results: 18 of 21 enrollees between 6/2013 and 6/2015 with Stage IV melanoma (M1c: 56%, M1b: 33%, M1a: 11%) were included in the analysis. The median age was 57 years old (33-69) and 67% were men. 44% harbored BRAF mutations. Median duration of treatment was 9 weeks (5 to 17). Median follow-up time for OS analysis was 22.5 months (2 to 52 months). 12 and 24 month OS were 77.8% and 60.6% respectively with median not yet reached. The ORR by by irRECIST was 27.8%. Grade 3 adverse events were reported in 50% of patients, the most common being neutropenia. 17% of patients had grade 3 immune-related adverse events, the most common being hypophysitis and colitis. Immune analysis showed absolute lymphocyte count was significantly elevated post treatment compared with pre-treatment (p = 0.024). In addition, deep immune analysis of peripheral blood samples and tumor tissue including nanostring, gene expression and TCR sequencing will be assessed and reported. Conclusions: The combination of ipi and ABI in this small study demonstrates acceptable safety, tolerability and clinical activity. ABI may contribute to tumor cytoreduction and enhance antitumor clinical response of ipi without impactful immunosuppression. This data together with further immune analysis may provide rationale to design prospective chemo-immunotherapy regimens and treatments for metastatic melanoma and other solid tumors. Clinical trial information: NCT01827111.
Reovirus strain R-92 in in vitro generation of tumor-specific T-lymphocytes.
Authors: Anastasia O. Sitkovskaya, Elena Yu. Zlatnik, Sergey A. Kolpakov, Elena P. Kolpakova, Irina V. Mezhevova, Elena S. Bondarenko, Inna A. Novikova, Andrey Dashkov, Dmitry O. Kaymakchi, Gapiz M. Chupanov, Nairi B. Oganyan, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e14216 Background: The purpose of the study was to assess the potential of the reovirus strain R-92 for in vitro generation of tumor-specific T-lymphocytes. Methods: The human reovirus strain R-92 used as a master seed strain was previously isolated from a patient with infectious hepatitis and adapted to the growth on the pig embryo kidney cell culture (PEKC); it lost its pathogenicity after multiple passages and was characterized by electron microscopic, serological methods and PCR. HeLa lysate was prepared by the incubation with the R-92 reovirus in medium 199+L-glutamine during 5 days (37 о C, 5% СО 2 ), cytopathogenic effect was observed. Immature dendritic cells (DCs) were derived from blood monocytes cultivated for 7 days in presence of IL-4 and GM-CSF. For the DC loading during 48 hours we used: 1. HeLa lysate obtained by repeated freezing and thawing of cells (control); 2. HeLa lysate obtained by co-culturing with reovirus; 3. reovirus cultured in a standard PEKC. To assess the DC ability to activate lymphocytes, they were co-cultured for 5 days in a 3:1 ratio, 1.5x10 5 of target cells (HeLa) were added (1:1) for 48 hours; number of dead HeLa cells was count. At each stage of the generation of DCs and activated lymphocytes, they were phenotyped by flow cytometry. Results: DC samples 2 and 3 showed increased percentage of activated cells compared to the loaded with the control tumor lysate, CD86 and HLA-DR coexpression was 62 and 69% vs. 25%, respectively; CD83 expression was maximal after DC loading with reovirus (72.9%). After co-culturing of DC with autologous lymphocytes, the highest number of activated CD4+CD38+ and CD8+CD38+, was observed in sample 2, T-regs (CD4+CD25+CD127 low ) - in the control. The death of target cells cultured with activated lymphocytes obtained by DC samples 2 and 3, was 100%, control sample showed minimal cytotoxicity against HeLa. The number of T-lymphocytes in samples 2 and 3 cultured with HeLa exceeded the control values by 3-10 times. Conclusions: Reovirus R-92 used for the immature DC loading increases their presenting activity. DCs loaded with reovirus HeLa lysate, when co-cultured with lymphocytes, activate CD4+ and CD8+ and suppress T-regs, apparently leading to the total death of target tumor cells.