tbuckley/cabot-search huggingface dataset:
Prognostic significance of the hepatoma arterial embolization prognostic (HAP) score in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization: A single centre experience.
Authors: Preetha Aravind, Kiruthikah Thillai, Debashis Sarker, Nigel Heaton, John Karani, Abid Suddle, Pauline Kane, Dylan Lewis, Praveen Peddu, Gillian Al-Kadhimi, Paul J. Ross
Journal: Journal of Clinical Oncology (2016)

e15617 Background: Hepatocellular carcinoma (HCC) is sixth most common cancer worldwide. Prognosis following trans arterial (chemo) embolization (TAE/TACE) for HCC remains unclear. The hepatoma arterial-embolization prognostic (HAP) score has been proposed as a prognostic tool for TACE. Methods: In this retrospective study, 431 patients with HCC who received TACE at a Liver Centre in the United Kingdom between 2005 and 2012 were included. Individual HAP score was calculated based on multivariate Cox regression analysis of pre-determined prognostic factors. The primary objective was to correlate HAP score with overall survival (OS). We also assessed age group above 75 years and portal vein involvement as independent variables. Results: Median age of the study population was 69 years. Viral aetiology of HCC accounted for 44% (113 for hepatitis C, 83 for hepatitis B). Maximum tumour size, serum albumin, total bilirubin and alpha-fetoprotein were selected as predictors of mortality following TACE. Patients were divided into four groups A, B, C and D based on their scores. The median OS for groups A, B, C and D were 39.8 (95% CI 25.6- 53.6), 24.6 (95% CI 17.1 to 31.4), 18.8 (95% CI 15.1- 22.5) and 9.3 months (95% CI 7.6-11.0) respectively. The HAP score validated well with our dataset. PFS was 30.3, 19.5,15, 6.2 months for HAP score A, B, C, D respectively with p < 0.005. Median OS with PV involvement was 7.7 months (n 64) (5.4 vs 10.02) compared to absence of PV involvement, 23.7 months (19.8 Vs 27.4, p < 0.005). 53 were above 75 years with median OS of 10.3 months (5.6 vs 14.9) while below 75yrs (n 377) (19.1 vs 25.6, p < 0.005) median OS was 22.4 months. Our data of age above 75 years and PV involvement did not correlate with their HAP score. Conclusions: There was a trend to longer survival with lower HAP scores. The HAP score predicts outcomes in patients with HCC undergoing TACE/TAE. Independent variables like age and PV involvement require further validation as predictors.
Implementation of a democratized approach to multi-omic molecular profiling via the LungMATCH program.
Authors: Jennifer C. King, R Joseph Bender, Andrew Ciupek, Tara Perloff, Kimberly Mason, Subha Madhavan, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2018)

e21033 Background: For metastatic non-small cell lung cancer (NSCLC) guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Previous studies indicate that many patients with NSCLC are not receiving testing, even for actionable changes in EGFR, ALK, and ROS, BRAF, and PD-L1. There are widespread gaps in the community setting and Lung Cancer Alliance data shows that less than 50% of callers to the patient HelpLine have had molecular testing on their lung cancer. Methods: The LungMATCH molecular testing program is operationalized via a turn-key precision medicine (PM) operation system. This approach provides a standardized workflow from tissue acquisition through multi-omic molecular profiling, treatment history integration, and AI-based computational analysis to produce a treatment decision support tool of therapeutic options matched to the patient. Longitudinal outcome is collected on every patient along with treatment decisions and patient experience. Results: The majority of the patient referrals (72%) came from non-academic centers across a wide geographic region that covered nearly 75% of the United States (36/50 states). Barriers to signing informed consent and completing biopsy have been identified including: patients in poor health, cost concerns, unsupportive physicians, and patient loyalty to the physician (discomfort with advocating for testing). For patients who have received reports, 72% (12/17) had actionable genomic alterations that indicated either a standard of care agent or a clinical trial. An additional 82% (9/11) had actionable proteomic findings and 31% (5/16) had high tumor mutational burden. Conclusions: There is broad patient interest in accessing PM information but still many barriers to widespread adoption. The LungMATCH program provides a turn-key solution to help provide a facile means to “democratize” access to PM information unbound by geography or community/academic setting. Importantly, the majority of patients who received a completed profiling report had actionable molecular alterations, which underscores the potential impact of testing. Treatment decisions and patient outcomes continue to be followed.
Comparing treatment strategies for stage I small cell lung cancer: A National Cancer Database study.
Authors: Peter Alexander Paximadis, Jennifer Lynn Beebe-Dimmer, Julie George, Ann G. Schwartz, Antoinette J. Wozniak, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2017)

8566 Background: Concurrent chemoradiotherapy is the standard of care for limited stage small cell lung cancer (SCLC). The ideal treatment strategy for stage I SCLC, however, is less clear. The purpose of this study is to compare outcomes for patients receiving definitive surgery, stereotactic body radiation therapy (SBRT), or external beam radiation therapy (EBRT) for stage I SCLC using the National Cancer DataBase (NCDB). Methods: Patients with a first primary diagnosis of stage I (T1-2 N0 M0) SCLC treated between 2004 and 2013 were identified in the NCDB. Patients were defined as having a first course of treatment of either definitive surgery, EBRT (45-74 Gy in 15-40 fractions) or SBRT (40-60 Gy in ≤5 fractions). Other recorded information included age, gender, race, T stage, Charlson-Deyo score, and use of chemotherapy. Overall survival (OS) was determined using the Kaplan-Meier method and Cox proportional hazards regression methods were used to estimate risk of overall mortality. Results: A total of 5944 patients with stage I SCLC were identified; of those, 2681 fit the study criteria. The median age of patients in the cohort was 68 years and median follow up was 26.6 months. Definitive surgery was performed in 944 (35%), EBRT in 1597 (60%), SBRT in 140 (5%), and chemotherapy was delivered in 2067 (77%). The 2- and 3-yr OS for the whole cohort was 62% and 50%; 72% and 62% for surgery, 56% and 44% for EBRT, and 56% and 40% for SBRT. Patient age, female gender, Charlson-Deyo score &lt; 2, tumor size ≤3 cm, receipt of surgery and receipt of chemotherapy were all associated with improved OS. Comparing treatment strategies in a multivariate model, surgical resection demonstrated improved OS over EBRT (HR 2.0, p &lt; 0.001) and SBRT (HR 1.66, p &lt; 0.001). When excluding patients who underwent surgery, SBRT demonstrated improved OS compared with EBRT (HR 1.28, p = 0.04). In addition, receipt of chemotherapy resulted in improved OS (HR 0.66, p &lt; 0.001). Conclusions: In this hospital-based registry study, definitive surgical resection and use of chemotherapy resulted in improved survival outcomes for patients with stage I SCLC. For patients who are not candidates for surgery, SBRT may offer a survival benefit compared with standard EBRT.
SMART in the Management of Patients With Persistent Asthma—Reply
Authors: Diana M. Sobieraj, William L. Baker
Journal: JAMA (2018)

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Immune checkpoint marker expression and clinicopathological factors in primary TNBC.
Authors: Mascha Pervan, Karen Bräutigam, Christoph Thorns, Achim Rody, Cornelia Liedtke
Journal: Journal of Clinical Oncology (2018)

e13119 Background: Immunotherapy emerges to a promising concept for patients with Triple-Negative Breast Cancer (TNBC). Immune Checkpoint Inhibitors (ICI) are expressed by tumor tissue to evade the immune system, Programmed Death-1/Programmed Death-Ligand1 (PD-1/PD-L1) and Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) are known pathways to inactivate T-Lymphocytes. Potential therapies targeting ICI are part of ongoing Phase-III-Trials and have produced a few cases with effective immune reactivation, however a safe predictive biomarker is still unknown. Methods: Immunohistochemical expression of PD-L1 and CTLA-4 was evaluated through Tissue Micro Arrays of 74 primary TNBC. 3 cores per tumor resulted in a mean value per case, pre-defined cut-offs determined categorical variables for PD-L1 (percent of positive tumor cells; 'positive' ≥ 10 %) and CTLA-4 expression (intensity (0-3) times proportion of positive cells (0.0–1.0); 'positive' ≥ median 1.3). Tumor-infiltrating Lymphocyte (TIL) Status (positive vs. negative), Lymphocyte expression of CTLA-4 (as above, median = 0.6) and PD-1 (positive lymphocytes per 500; 'positive' ≥1/500) were also assessed. Heterogeneity of marker expression was explored using standard deviation of the 3 cores. Correlation analysis was carried out using clinical follow-up data of up to 83 months. Results: A significant inverse correlation between PD-1 expression and overall survival (OS) was observed (p = 0,045). Heterogeneity of tumor CTLA-4 expression correlated significantly with OS (p = 0,023) and progression free survival (PFS; p = 0,015). Kaplan-Meier survival analysis showed an advantage for low CTLA-4 expressing tumors compared to high expressing ones with a mean survival of 70 vs. 62 months (95% CI 61–79 vs. 52–71), however it is not significant in the log-rank-test (p = 0,150). Conclusions: Our data suggests a predictive value of PD-1 and CTLA-4 expression although further evaluation is required. Worse clinical outcome has so far been attributed to heterogeneity of tumor tissue and marker expression, whereas this data proposes improved OS and PFS with heterogeneous CTLA-4 expression, possibly indicating increased immune system interaction and potential tumor recognition.
ATIM-33. NOA-16: A FIRST-IN-MAN MULTICENTER PHASE I CLINICAL TRIAL OF THE GERMAN NEUROONCOLOGY WORKING GROUP EVALUATING A MUTATION-SPECIFIC PEPTIDE VACCINE TARGETING IDH1R132H IN PATIENTS WITH NEWLY DIAGNOSED MALIGNANT ASTROCYTOMAS
Authors: Michael Platten, Daniela Schilling, Lukas Bunse, Antje Wick, Theresa Bunse, Dennis Riehl, Edward Green, Khwab Sanghvi, Irini Karapanagiotou-Schenkel, Inga Harting, Felix Sahm, Joachim Steinbach, Astrid Weyerbrock, Jörg Hense, Martin Misch, Dietmar Krex, Stefan Stevanovic, Ghazaleh Tabatabai, Andreas von Deimling, Michael Schmitt, Wolfgang Wick
Journal: Neuro-Oncology (2018)

In preclinical studies we have defined IDH1R132H as a clonal neoantigen presented on MHC class II. A peptide vaccine encompassing IDH1R132H induces tumor-specific T helper cell responses effective in controlling syngeneic IDH1R132H-mutant tumors in humanized mouse models. NOA-16 (NCT02454634) is a first-in-man, multicenter, phase I trial testing the safety and immunogenicity of an IDH1R132H peptide in incomplete Freunds adjuvant in patients with newly diagnosed, IDH1R132H mutant WHO °III and °IV astrocytomas. Between September 2015 and October 2016, 32 patients were enrolled in seven German sites. 23 patients (71.9%) received radiochemotherapy with temozolomide, six patients (18.8%) received radiotherapy alone and three patients (9.4%) received temozolomide alone. 249 vaccines were administered, 29 (90.6%) of the patients of the safety set (N=32) and 27 (90.0%) patients of the immunogenicity set (N=30) received all eight vaccines. No regime-limiting toxicity was observed. The majority of the patients (N=29, 90.6%) experienced treatment related adverse events (trAE), 1 (3.1%) of them had treatment related SAE. None of the reported AEs were severe. 28/30 (93.3%) patients, who were evaluable for immunogenicity, displayed mutation-specific T cellular (24/30 (80%)) or humoral (26/30 patients (87%)) immune responses not detectable before vaccination. Until end of study no deaths were observed. 4/32 (12.5 %) patients had PD according to RANO criteria, all other patients (N=28, 87.5%) had SD. 12/32 (37.5%) patients displayed pseudoprogressions after the initiation of the vaccine. Single-cell T cell receptor (TCR) sequencing allowed for the identification of IDH1R132H-specific TCRs. In conclusion, NOA-16 met its primary endpoints by demonstrating safety and immunogenicity of a mutation-specific IDH1R132H peptide vaccine given with standard of care in patients with newly diagnosed IDH1R132H mutant malignant astrocytoma.
Addressing unmet medical needs in maintenance treatment for newly diagnosed multiple myeloma (NDMM).
Authors: Wee Joo Chng, Meral Beksac, Roman Hajek, Katja Weisel, Maria-Victoria Mateos, Andrew Spencer, Shinsuke Iida, Danielle de Farias, Richard Labotka, Tomas Skacel, Antonio Palumbo, Sagar Lonial, Shaji Kumar, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2018)

e20049 Background: In NDMM, following response to primary therapy, maintenance may delay progression and prolong OS; however, maintenance is not an established treatment option worldwide; lenalidomide (R) is the only approved agent, and only post-ASCT. Methods: We reviewed published/ongoing phase 3 trials of current/emerging maintenance treatments to identify unmet needs and how these may be addressed. Results: Maintenance with R, bortezomib (V), or thalidomide (T) has been well-studied and offers differential benefit, leaving unmet needs in some populations. R post-ASCT prolongs PFS/OS but increases the risk of SPMs and shows a less pronounced benefit in some subgroups, e.g high-risk (HR) cytogenetics, high ISS stage. R has improved PFS but not OS in the non-ASCT setting. T prolongs PFS/OS but not in HR cytogenetics, and with notable toxicity. V has activity post-ASCT, including in HR cytogenetics, and in the non-ASCT setting, but has not been studied in a placebo-controlled setting. Long-term use of these agents may be limited by short- and long-term toxicity and the treatment burden of repeated IV/SC administration. There is a need for a therapy that can be dosed for an extended time without cumulative/late-onset toxicity or emergence of resistant clones and that can offer benefit in all patients, including HR subgroups. Ongoing studies of ixazomib (I), carfilzomib (K), and daratumumab (D) (Table) may address some of these needs. Long-term I/K/D-based treatment results in deepening responses and improved outcomes, including in HR subgroups; oral ixazomib potentially offers convenient, feasible long-term proteasome inhibitor therapy with a manageable toxicity profile. Conclusions: Current maintenance therapies improve patient outcomes, with some limitations. Emerging therapies may offer a feasible approach due to manageable long-term toxicity profiles and convenience, especially oral agents. Ongoing phase 3 maintenance trials Agent Study Design NCT number I TOURMALINE-MM3 I vs placebo, post-ASCT NCT02181413 TOURMALINE-MM4 I vs placebo, non-ASCT NCT02312258 GEM2014MAIN I-R vs R, post-ASCT NCT02406144 K Uni of Chicago KRd vs R, post-ASCT NCT02659293 D Cassiopeia D vs observation, post-ASCT NCT02541383
Differential diagnosis of pulmonary enteric adenocarcinoma (PEAC) with the assistance of next generation sequencing.
Authors: Jie Zhang, Keke Yu, Han Han-Zhang, Chan Xiang, Yuchen Han, Shaokun Chuai, Haohua Teng, Junyi Ye, Xiaojing Li, Jinchen Shao, Lei Zhu
Journal: Journal of Clinical Oncology (2018)

e20537 Background: The morphological features and immunohistochemical profiles of PEAC overlap with those of colonic adenocarcinomas; therefore, definitive diagnosis of PEAC has to be confirmed by a negative colonoscopy. Due to the rareness of PEAC, its molecular signature has not been comprehensively examined. In this study, we investigated the molecular signatures associated with PEAC and its histological counterparts, colorectal cancer (CRC) and metastatic colorectal carcinoma (MCC). We also developed a model to effectively distinguish PEAC from MCC/CRC. Methods: Four genetic variant groups clustered from 12 genes were utilized as input variables for model construction. In each round, the best model was selected by 10-fold cross-validation. In the end, 10 models were averaged to generate the parameters for the final model. Results: Capture-based targeted sequencing was performed on tumor tissue samples from 13 PEAC, 15 MCCs and 5 CRC patients using a panel consisting of 295 cancer-related genes. All PEAC patients harbored driver mutation of non-small cell lung cancer (NSCLC), expect for one, who had no mutation detected from this panel. No classic CRC mutation was detected in PEAC. In contrast, classic colon cancer mutations, such as APC and KRAS mutations, were the predominant mutations detected in CRC and MCC, accounting for 78% and 91% of all mutations detected, respectively. Furthermore, we constructed a two-level decision tree model based on 4 genetic variant groups clustered from 12 genes (NSCLC driver mutations, RAS family, APC and MMR genes) to accurately distinguish PEAC from its histological counterparts, achieving an accuracy of 97%. This model accurately classified every patient except for one, who had no mutation detected from this panel. Conclusions: Our data revealed that the molecular profile of PEAC, distinctive to CRC and MCC, resembles that of NSCLC; in contrast, the mutation spectrum of patients with MCC resembles that of CRC. We developed a two-level decision model, which can effectively distinguish PEAC from MCC/CRC, paving its way as routine diagnostic method in clinical settings.
Utility of multi-gene panel testing with next generation sequencing in women with endometrial cancer.
Authors: Jing-Yi Chern, Nigel Madden, Jessica Lee, Deanna Gerber, Anna Cantor, Shabnam Asgari, Jessica Martineau, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2017)

5588 Background: Lynch syndrome (LS) accounts for 2-6% of all endometrial cancers (EC), and women with a germline mutation in the mismatch repair (MMR) genes ( MLH1, MSH2, MSH6, and PMS2) have an average lifetime risk of EC of 40%. As with breast and ovarian cancer syndromes, there are likely other genes implicated in the development of EC outside of the MMR genes. Multi-gene panel testing (MGPT) with next generation sequencing (NGS) allows for simultaneous analysis of numerous genes.We sought to evaluate the characteristics and incidence of gene mutations in women with newly diagnosed EC. Methods: We conducted a review of EC patients diagnosed from 6/2013 to 12/2016 who had MGPT at our institution. Demographics, family history, genetic testing results, and tumor characteristics were collected and analyzed using χ 2 tests. Results: Of the 129 patients who had MGPT, 13 (10%) had a mutation and only 5 (38%) were in patients &lt; 50 years old. The median age of EC diagnosis is 55 (31-100) years and median BMI = 27.5 (21-59). Majority were stage 1, 76 (59%) and grade 1, 50 (39%). Patients with additional primary cancers, breast or colon were not more likely to have a mutation. However, patients with a family history of gynecologic cancer were more likely to have a mutation identified, 10 (77%) mutation vs no mutation 34 (29%), p = 0.003. Among all patients tested, 8 (6%) had a mutation in LS genes, and 6 (5%) had mutations in other genes ( BRCA1, BRCA2, RAD51C, MUTYH, CHEK2); 1 (0.8%) had both MSH2 and CHEK2 mutation. Three patients had prior testing for breast cancer; 2 were found to have a BRCA1/ 2 mutation and the other was on Tamoxifen and BRCA negative. IHC was performed on 7 of 13 patients, and 5 (71%) had a loss of MMR protein expression. Variants of uncertain significance were noted in 35/129 (27%) of patients tested. Conclusions: Majority of EC patients with a mutation detected with NGS were &gt; age 50. We identified additional new mutations in non-LS genes including, CHEK2, RAD51C, and MUYTH with MGPT. These accounted for 29% of the mutations and would have not been not detected using classic LS gene testing. These genes are implicated in breast, ovary or colon cancer. MGPT testing is feasible and useful in identifying additional actionable gene mutations.
Landscape of genetic alterations in oropharyngeal squamous cell carcinoma (OPSCC) based on RNA-seq and WES analysis of FFPE samples and correlation with data from TCGA.
Authors: Sandra Seby, Michael R. Rossi, Kelly R. Magliocca, Mihir Patel, Christopher C Griffith, Conor Ernst Steuer, Xu Wang, Mark El-Deiry, Dong Moon Shin, Jeanne Kowalski, Zhuo Georgia Chen, Nabil F. Saba
Journal: Journal of Clinical Oncology (2017)

e17527 Background: Whole human exome sequencing (WES) has identified well characterized somatic mutations (such as TP53, CDKN2A, PIK3CA and HRAS) in patients with squamous cell carcinoma of the head and neck (SCCHN). We sought to optimize a combined RNA-seq and WES approach for identifying actionable mutations and gene expression signatures in p16 + versus - OPSCC. Methods: Relying on formalin fixed and paraffin embedded (FFPE) samples we applied a minimal mutation and copy number content (151 genes) on DNA and an extensive RNA panel on a total of 27 OPSCC (22 p16 +, and 5 p16 -). SAMSeq was used to identify the differentially expressed genes. Unsupervised hierarchical clustering of the TCGA OPSCC samples with available p16 status (n = 31) was performed for external validation of the results. Statistical significance was further tested by Fisher’s exact test. Results: We identified a gene signature differentially expressed in p16+ and p16- OPSCC. External validation showed a significant association between gene expression and p16 status (P = 0.00033). We did not however find an association with mutation burden and smoking history. A number of pathways associated with this gene signature such as NCAM1 may have relevant biologic implications in OPSCC. Conclusions: Our results underscore the reliability of integrating data from FFPE samples in distinguishing gene signatures characteristic of p16 + versus p16- OPSCC; these signatures need to be further explored for their biologic relevance in OPSCC (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).