tbuckley/cabot-search huggingface dataset:
A 30 gene panel as prognostic for survival outcomes in clinically resectable gastric cancer.
Authors: Matthew Porembka, Jae-Ho Cheong, Sam Wang, Sunho Park, Alana Christie, Michael A. Choti, Hong Zhu, Hyun Ki Kim, Woo Jin Hyung, Sung Hoon Noh, Tae Hyun Hwang
Journal: Journal of Clinical Oncology (2016)

4039 Background: Current pre-treatment risk stratification modalities for gastric cancer (GC) are inadequate. Methods: Somatic mutation data from 19 cancer types sequenced by The Cancer Genome Atlas with published gene-gene interaction networks was integrated using NTriPath in order to identify altered pathways unique to GC. Gene expression profile of 565 treatment-naive GC patients who underwent resection with curative intent at Yonsei University (Seoul, South Korea) from 1999-2006 were used generate molecular subtypes based on consensus clustering. A predictive risk score (RS) was developed based on high and low risk molecular subtypes. The prognostic utility of the RS was validated using the profiling data from the 300 GC patient Asian Gastric Cancer Cohort. Patients with the lowest and highest quintile risk score were defined as low and high risk, respectively. The remaining patients were grouped as an intermediate risk group. Results: Four molecular subtypes were identified. Five-year survival for the low, intermediate, and high risk groups were 72% (95% confidence interval [CI], 0.58 to 0.81), 53% (0.46 to 0.60), and 30% (0.19 to 0.42), respectively (P < 0.001). On multivariate analysis, the RS was significantly associated with survival independent of AJCC staging (HR 1.13 [1.00 to 1.27] per unit increase in RS). Conclusions: The 30 gene risk score is prognostic for GC patients and can be use at the pre-treatment setting to help guide management. Multivariate Analysis P-value HR (95% CI) Stage I Reference -- II 0.16 2.01 (0.76, 5.34) III 0.04 2.70 (1.03, 7.11) IV < 0.001 7.17 (2.74, 18.75) Lauren type (Diffuse VS Intestinal) 0.82 0.95 (0.63, 1.44) Perineural invasion 0.02 1.57 (1.07, 2.30) Lymphovascular invasion 0.03 1.69 (1.04, 2.74) RS (per 1 unit increase) 0.046 1.13 (1.00, 1.27)
Changes in skeletal muscle cross sectional area (CSA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZ).
Authors: Sundhar Ramalingam, David J. Sermer, Rajan Gupta, Patrick Healy, Yuan Wu, Daniel J. George, Andrew J. Armstrong, Michael Roger Harrison
Journal: Journal of Clinical Oncology (2016)

e16601 Background: Phase III studies that led to ENZ approval in the treatment of mCRPC included side effects like fatigue, musculoskeletal pain, and falls, which could result from skeletal muscle loss. Such muscle loss (sarcopenia), in a variety of cancer populations, is correlated with mortality. While conventional androgen deprivation therapy in prostate cancer is known to cause sarcopenia, there is a paucity of data with next generation androgen receptor directed therapies like ENZ. Methods: Through query of pharmacy records, we conducted a retrospective analysis of patientstreated with ENZ prior to the use of docetaxel for mCRPC from April 28, 2011 - June 15, 2015 at Duke University. We included patients with a computed tomography (CT) scan available for analysis of skeletal muscle cross sectional area (CSA) both at baseline (+/- 6 wks) and after 6 months (+/- 6 wks) of treatment with ENZ. Muscle CSA was measured using the Slice-O-Matic (TomoVision, Montreal CA) at the level of the third lumbar vertebrae (L3) by a trained reviewer, and each measurement was verified and edited at the discretion of a second trained reviewer. The primary objective was to determine the change in muscle CSA at L3 from baseline to 6 mos of ENZ treatment (tx). Results: At the time of ENZ initiation (baseline),characteristics of 39 patients identified included a median age 74, ECOG performance status 0, BMI 30.4 kg/m2, time on ADT of 43.5 mos prior, Gleason score 8, and PSA 13.7 ng/mL. Across all time points, concordance between reviewers was high, r > 0.99. Mean CSA differed significantly from baseline (153.9 cm2, standard deviation = 30.17) to 6 months ENZ tx (145.4 cm2, standard deviation = 29.9; paired t-test p < 0.0001). In a sub-group (n = 13) with 3 measurements available (CT scan 6 mos pre-ENZ tx, baseline, and 6 mos post-ENZ tx), there was a significant change in CSA from baseline to 6 mos post-ENZ tx (paired t-test p = 0.0356), but no change from pre-ENZ tx to baseline (p = 0.1065). Conclusions: Patients treated with ENZ had significant muscle loss after six months of treatment. Prospective studies of exercise interventions to mitigate ENZ skeletal muscle toxicity are underway (NCT02256111).
Phase II study of second line pazopanib in patients with metastatic renal cell carcinoma (mRCC) previously treated with a tyrosine kinase inhibitor (TKI).
Authors: Emilio Esteban, Xavier Garcia del Muro, Juan Manuel Sepúlveda, Pablo Maroto, Enrique Gallardo Diaz, Aranzazu Gonzalez del Alba, Olatz Etxaniz, Marta Guix, Jose-Luis Gonzalez-Larriba, Jose Angel Arranz Arija, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2016)

e16129 Background: Pazopanib is regarded as one of the standard first-line treatment options for patients with advanced renal cell carcinoma (aRCC). Pazopanib is also approved as second-line treatment of patients who have been treated with cytokines. There is limited data available regarding the activity and safety of pazopanib in in second line mRCC patients previously treated with a tyrosine kinase inhibitor (TKI). Methods: This was a phase II, open-label, multicentre study that included patients who had progressed during or three months after first-line treatment with a TKI or who discontinued TKI treatment due to adverse effects. Patients received pazopanib (800 mg/day) until disease progression or unacceptable toxicity. The main objective of the study was the objective response rate (ORR). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Results: The study included 27 pts: median age 63.0 years (range 55-83), 50% men. ORR was 15.4% (95% confidence interval [CI]: 1.5-29.3). Stable disease was obtained in 65.4% of pts. Median PFS was 6.7 months (95% CI: 4.0-11.0). With a median follow-up of 19.1 months, the median OS was 19.2 months (95% CI: 12.8-33.4). The incidence of grade 3-4 treatment-related adverse events (AEs) was 19.2%. The most frequent grade 3-4 AE was neutropenia reported in 2 patients (7.7%). Only one patient developed Grade 3 reversible hepatotoxicity. No toxic deaths were reported. Conclusions: Continuously targeting the VEGF axis in second line using pazopanib shows activity and good tolerability in patients with mRCC. Efficacy results are similar to those achieved with other antiangiogenic agents in second-line. Clinical trial information: NCT01577784.
Assessment of established patient reported outcomes (PROs) instruments measuring toxicities and quality of life (QOL) for patients (pts) with head and neck cancer (HNC) treated on ECOG 1308 and 2399 studies.
Authors: Anthony Cmelak, Yael Flamand, Shuli Li, Shanthi Marur, Barbara A. Murphy, David Cella, Arlene A. Forastiere, Barbara Burtness
Journal: Journal of Clinical Oncology (2017)

6074 Background: HPV HNC pts are younger and have a higher cure rate than smoking-related pts, and therefore carry treatment toxicities longer. Dose deintensification and conformal RT may result in decreased toxicity. We report the impact of these techniques on patient outcomes in E2399 and E1308 as measured through PROs. Methods: Longitudinal data on acute and late toxicities were recorded prospectively at baseline, post-treatment, and at 6, 12, 24 and 30 months in HPV+ pts on E1308 and HIV+/- pts on E2399 using the following measures: E1308: FACT-HN, KATZ Index of Independence (ADL), Brief Fatigue Index (BFI), Instrumental Activities of Daily Living (IADL), and the Vanderbilt Head and Neck Symptom Survey Version 2 (VHNSS V2); on E2399: FACT-HN. We correlated acute and late toxicities with de-escalation of RT dose (69.3Gy to 54Gy) on E1308, and with IMRT (E1308) vs. conformal RT (E2399). Results: 38 pts on E1308 completed 12 mo VHNSS V2; 32 received low dose IMRT and 6 standard dose, and 56 E2399 pts completed 12 mo FACT-HN. Items from the VHNSS V2 showed that difficulty eating solids (40% vs. 89%, p = 0.011) and improved nutrition (10% vs 44%, p = 0.025) were statistically improved at 12 months by lowering IMRT dose from 69.3Gy to 54Gy. The FACT-HN showed an improvement in eating solids at 12 mo when comparing low dose IMRT vs. 3DRT (65% vs. 33% had no or minimal solid food problems, p = 0.057). No other statistically significant reductions in toxicity were noted on any of the other PRO instruments. Conclusions: Both FACT-HN and VHNSS V2 demonstrated an improvement in eating solids by reducing IMRT dose. FACT-HN demonstrated that IMRT is associated with an improvement in eating solids when compared to 3DRT. Analyses are exploratory and need to be validated using randomized data.Future studies should stress accurate and complete PRO data. The KATZ, BFI, and IADL were not sensitive to detecting differences in toxicities from IMRT dose reduction on E1308. The VHNSS V2 and FACT-HN instruments corroborated specific toxicities both by RT technique as well as IMRT dose, and will therefore be utilized in future ECOG-ACRIN HNC studies. Clinical trial information: NCT01084083.
A phase I study of metformin in combination with cisplatin and radiation in locally advanced head and neck squamous cell carcinoma.
Authors: Trisha Michel Wise-Draper, Vinita Takiar, Michelle Lynn Mierzwa, Bradley Joseph Huth, Kevin P. Redmond, William Barrett, Julianne Qualtieri, Changchun Xie, John Charles Morris, J. Silvio Gutkind, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2016)

TPS6109 Background: Diabetic patients with head and neck squamous cell carcinoma (HNSCC) receiving the oral hypoglycemic, metformin, demonstrated improved survival compared to those not on metformin when treated with curative intent cisplatin and radiation (CRT) in retrospective analyses. Pre-clinically, metformin has been shown to inhibit mTOR, a signaling pathway that regulates cell growth and survival, commonly activated in HNSCC. Pretreatment with metformin resulted in a decrease in oral cavity tumors in mice. Here we are prospectively investigating escalating doses of metformin in combination with CRT in locally advanced HNSCC in non-diabetic patients, and the mechanism by which metformin may exert its effect. Methods: Patients with locally advanced HNSCC receive oral metformin administered in escalating doses (1000mg BID, 850mg TID or 1000mg TID) for 7-14 days prior to initiation of cisplatin (100 mg/m2 administered on days 1, 22 and 43) along with concurrent radiation therapy (70 Gy). Initially, metformin was escalated to assigned cohort dose over 7 days prior to CRT. However, quick escalation was poorly tolerated and therefore, the protocol was modified to allow a slower dose escalation over 14 days. Metformin is continued throughout treatment. Blood samples are collected before and after metformin as well as during chemotherapy. Flow cytometry to detect percent circulating immune activated cells (CD8+ and PD-1+) and clinical laboratory tests including serum glucose, vitamin B12 and C-peptide levels are being performed. Clinical trial information: NCT02325401.Dose-escalation schedule. Dose Level Dose Metformin Daily (in divided doses) Cisplatin Days 1, 22, 43 Level -1 1500mg 100mg/m2 Level 1 2000mg 100mg/m2 Level 2 2550mg 100mg/m2 Level 3 3000mg 100mg/m2 Expansion MTD 100mg/m2
East Carolina University clinical experience study: Utilization of liquid biopsy to determine time to diagnosis and treatment in non-small cell lung cancer (NSCLC).
Authors: Sweta Jonnalagadda, Aparna Madhukeshwar Hegde, Mark Bowling, Paul R. Walker
Journal: Journal of Clinical Oncology (2018)

e18519 Background: There are several technical and biological challenges in utilizing tumor tissue for clinical molecular analyses. Liquid biopsy represents a non-invasive tool which provides us a circulating bio-marker for optimizing and monitoring regimens. We set out to review the impact of multi-disciplinary patient management coupled with the use of the liquid biopsy testing strategy on patient experiences in the thoracic oncology clinic. Methods: This was a Retrospective cohort study comparing processes of standard molecular testing strategies prior to March 2016 with liquid biopsy from March 2016 to May 2017. Liquid biopsy testing utilized Biodesix Lung Reflex (BLR) assay at time of diagnosis. Patient demographics, time from diagnosis to treatment, time from diagnosis to molecular test results, time from diagnostic biopsy to treatment start and treatment selection was collected. Results: The tissue group included 97 patients diagnosed prior to liquid biopsy and BLR group included 90 patients. The results are as follows: Conclusions: This study demonstrates that with team approach and rapid blood-based testing at our institution, patients consistently start treatment within a median of 8 days from diagnosis. This is particularly important in Eastern North Carolina with socioeconomic and racial health care disparities. There was also a marked increase in availability of molecular results at the time of diagnosis which has led to use of targeted actionable therapies to improve long-term clinical outcomes. Patients tested with BLR at diagnosis N = 90 Patients diagnosed prior to BLR uptake N = 97 Time from diagnosis to treatment start Median:8 days (IQR:1-19) Median 10 days (IQR: 0-21) % of patients with Molecular test results prior to start of front line treatment 72% 4% Time from diagnosis to molecular test results Median: 3.5 days (IQR: 2-5) Median: 26 days (IQR: 18.5-42) Time from diagnostic biopsy to treatment start Median:11 days (IQR: 4-21) Median: 12 days (IQR: 2-23) Time from diagnostic biopsy to diagnosis Median: 1 day (IQR:1-2) Median: 2 days (IQR: 1-3)
Interrogating machine learning classifiers and dimensionality reduction techniques for radiomic prediction of glioma tumor grade.
Authors: Kareem Wahid, Aikaterini Kotrotsou, Srishti Abrol, Ahmed Hassan, Nabil Elshafeey, Rivka R. Colen
Journal: Journal of Clinical Oncology (2018)

2031 Background: Radiomics derives quantitative features from medical images to reveal novel information about imaging phenotypes. Although significant research has been conducted on the application of machine learning algorithms to radiomic features for clinical prediction, much remains unknown about which models are best. Further, for models to be reproducible in the clinical setting, machine learning models should be explored using open-source tools and data. Herein, we assess the performance of various machine-learning classifier methods and dimensionality reduction techniques in predicting brain tumor grade with open-source tools and data. Methods: We utilized the publicly available 2017 BraTS Challenge magnetic resonance imaging dataset for lower-grade gliomas (n = 44) and glioblastomas (n = 191). Radiomic features were extracted using PyRadiomics, an open-source radiomics toolbox. A bootstrap approach was used to assess model predictive performance. Results: Logistic regression (area under curve [AUC] = 0.91) and factor analysis (AUC = 0.90) demonstrated the highest average performance among dimensionality reduction techniques and classifier methods, respectively. The highest overall performance was achieved by a support vector machine classifier coupled with factor analysis (AUC = 0.94). Variance analysis revealed that classifier method is the major contributor to performance variation (42%), followed by number of dimensions (15%) and dimensionality reduction technique (4%). Conclusions: This study demonstrated that the appropriate choice of classifier methods and dimensionality reduction techniques plays a significant role in machine learning model performance for prediction of glioma grade.
A multicenter, open-label, phase II study of PGG beta-glucan and pembrolizumab in patients (pts) with advanced melanoma (MEL) following progression on treatment with checkpoint inhibitors (CPI) or triple negative breast cancer (TNBC) failing front-line chemotherapy for metastatic disease.
Authors: Jose Luis Iglesias, Radha Prathikanti, Bo Ma, Paulette Mattson, Deb Kedrowski, Jamie Lowe, Nandita Bose, Katie E. Ertelt, Nadine Ottoson, Mark T. Uhlik, Jeremy Graff, Richard Dale Huhn, Michael Jon Chisamore
Journal: Journal of Clinical Oncology (2017)

TPS3105 Background: Imprime PGG (Imprime) is a Pathogen- Associated Molecular Pattern that enhances innate immune cell killing, counteracts immune suppression and triggers activation and maturation of antigen presenting cells. Imprime’s ability to trigger a coordinated innate and adaptive immune response is critical for enhancing the efficacy of CPIs in several pre-clinical tumor models. We are now exploring the combination of PGG beta-glucan and Pembrolizumab, a humanized mAb against programmed death receptor-1 (PD-1) in the clinic. In previous trials, Pembro yielded a 33% ORR and 23 mo mOS in 655 pts with advanced MEL and an 18.5% ORR and 11.2 mo mOS in 27 evaluable pts with metastatic/recurrent TNBC (Ribas et al., 2016; Nanda et al., 2016). Pre-treatment levels of anti-beta glucan antibodies (ABA) are correlated with pt response to Imprime. Methods: This Phase 2 study is enrolling ABA positive pts with advanced MEL following progression on treatment with a CPI or metastatic TNBC failing front-line chemotherapy. The study is a Simon optimal 2-stage design with sample size of 12 pts of each tumor type in Stage 1. If response and AE criteria (≤ 4 [or ≤ 33%] pts with grade 3/4 in Cycle 1) for each tumor type are met, an additional 17 pts with MEL and 30 pts with TNBC will be enrolled in Stage 2. Primary endpoints of the study are ORR (based on RECIST 1.1) and safety. Secondary endpoints include TTR, CRR, DoR, PFS, and OS. PK data will be profiled. Exploratory endpoints include ORR and PFS based on irRECIST, analysis of an ABA biomarker, immune cell activation markers, and changes in the tumor immune microenvironment. Screening and enrollment are underway in the US. Biothera Pharmaceuticals, Inc. is sponsoring the trial (ClinicalTrials.gov NCT02981303) under a collaborative agreement with Merck. Clinical trial information: NCT02981303.
Therapeutic and cytotoxic responses after radiofrequency ablation combined to <i>in situ</i> immunomodulation and PD1 blockade in colorectal cancer.
Authors: Katia Lemdani, Nathalie Mignet, Johanne Seguin, Vincent Boudy, Jean Francois Emile, Claude Capron, Robert Malafosse
Journal: Journal of Clinical Oncology (2018)

e15562 Background: After radiofrequency ablation (RFA), cancer cells death releasing tumor antigens and expression of danger signals activate a specific T-cell response however inadequate to avoid recurrence. We purpose to combine RFA with priming of a strong immune antitumor response as curative treatment of colorectal cancer (CRC). Methods: After RFA of colorectal liver metastases in patients, the tumour infiltration by lymphocyte (TILs) was characterized on later resected distant lesions. In mice, RFA was used to treat a CT26-luc tumor as primary lesion. Macroscopic or microscopic distant tumors were established as secondary lesions. Injection, in the treated area, of a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeted recruitment and maturation of dendritic cells. In mice with far large lesions, this strategy was combined with PD1 checkpoint inhibition. The efficiency was assessed on survival, morphologic and bioluminescent evolution of distant lesions, characterization of TILs and specific TNFα and IFN-y expression in spleen and lymph nodes Results: Proportion and characteristics of TILs were comparable in 17 patients who had preoperative RFA and in 53 paired patients who had a single hepatectomy for colorectal metastases. After RFA in mice the in situ injection of immunogel resulted in prolonged survival. Regression of distant lesions was related to the induction of a strong immune response and a great increase in TILs. This approach induced a complete cure of microscopic secondary lesions without another treatment. Immune escape of large secondary lesions was reversed by association of the RFA-immunogel with systemic PD1 checkpoint inhibition separately ineffective. Conclusions: The lack of an efficient distant immune response in RFA treated patients confirmed relevance of a new strategy. Combined to RFA the in situ priming of a strong immune response targeting microscopic disease is an effective abscopal adjuvant treatment. For distant large lesions the synergy between in situ immunomodulation and PD1 blockade, ineffective in microsatellite stable CRC or after single RFA, allows reconsidering the use of checkpoint inhibitors in CRC.
Relationship between liver metastases and PD-1 blockade in melanoma.
Authors: James Chi-Chiang Lee, Katy K. Tsai, Alain Patrick Algazi, Michael Rosenblum, Jeffrey Bluestone, Adil Daud
Journal: Journal of Clinical Oncology (2017)

3072 Background: WhilePD-1 blockade is effective in melanoma, durable responses remain elusive. We have previously reported that liver metastasis is associated with reduced response rates and that the fraction of CTLA4 hi/PD-1 hi CD8+ cells (“activated-exhausted” or T-ex cells) within the TIL is predictive of response to PD-1 blockade. Here, we explore the biology behind liver metastasis in human melanoma and in animal models. Methods: Patients with metastatic melanoma with or without liver metastasis were biopsied pre- PD-1 treatment and immune infiltrates were analyzed by FACS. The CD8 fraction was gated on CTLA4 and PD-1. C57BL/6 mice were implanted with a “primary” subcutaneous tumor and a “metastatic” tumor in the liver or the lungs (control), and given systemic PD-1 blockade therapy. Results: Patients with melanoma and liver metastasis (n = 25) had 15.2% T-ex cells while those without liver metastasis (n = 76) had 26.5 % T-ex cells, p = 0.0092. A T-ex fraction &lt; 20% was significantly associated with lack of PD-1 response, p &lt; 0.005. In C57BL/6 mice implanted with a B16 tumor (subQ &amp; liver) treated with PD-1 antibody, 0/35 mice achieved subQ tumor rejection while in the SubQ only mice 9/30 mice (30%) rejected their tumors. The mean tumor size of mice with Sub Q+liver metastasis was 139.2 mm2 vs subQ only mice 23.4 mm2 at d 14, p = 0.002. Mice with liver metastasis showed a T-ex fraction 31.9% vs 67.3%without liver met, p = 0.0003. In contrast, in mice made lung metastatic, the subQ tumor rejection rate was 7/20 (35%), with T-ex infiltrate at 57.9%. The implantation of liver metastases from an unrelated MC38 tumor does not protect the subQ tumor from immune rejection. Conclusions: The presence of liver metastases is associated with reduced response to PD-1 blockade and reduced T-ex infiltrate in patients with stage IV melanoma. Mechanistic studies using a mouse model of syngeneic organ site specific metastasis confirms that the liver metastasis results in reduced antigen specific T cell at distant sites, resulting in reduced response. Site of metastasis may determine immune responsiveness in both mouse models and in humans with melanoma.