tbuckley/cabot-search huggingface dataset:
Effect of hyperlipidemia in patients with a history of colon cancer.
Authors: Zahid Tarar, Muhammad Usman Zafar, Ghulam Ghous, Umer Farooq, Arjan Ahluwalia
Journal: Journal of Clinical Oncology (2021)

e15603 Background: The most common cancer of the digestive system is colorectal cancer. 5-year survival rate of early-stage colon cancer is &gt; 90% whereas it is only 10% for patients with distant metastases. Recent studies have shown that lipids influence a tumor’s metastatic capabilities. High fat diet has also been linked with colon cancer. In this study, we try to understand the effect of hyperlipidemia in patients with a history of colon cancer. Methods: This is a retrospective study examining data from the National Inpatient Sample (NIS) Database of the year 2018. We identified patients with any history of Colon cancer using their specific ICD-10 codes. Additionally, we queried for ICD10 codes for hyperlipidemia. Primary outcome was inpatient mortality. Secondary outcome was hospital length of stay and total charge. Utilizing STATA MP 16.1 we performed multivariate logistic regression analysis. Various comorbidities including previous history of coronary artery disease, peripheral artery disease, stroke, smoking, diabetes, hypertension and chemotherapy were incorporated into the analysis. Additionally, hospital demographics were included in the analysis as well including race, hospital bed size teaching status, location, region, insurance and patient income. Data was considered statistically significant if p-value was &lt; 0.05. Results: The total number of patients included in this study were 34,792. They were all adults age &gt; 18 years. Approximately 49% were females. Mean age was 67 years and average hospital length of stay was 6.5 days. After running multivariable analysis for inpatient mortality, we noted that patients with hyperlipidemia had lower odds of mortality (Odds Ratio (OR) 0.64, 95% Confidence Intervals (CI) 0.56 – 0.73). Higher odds of mortality were seen in patients with coronary artery disease (OR 1.23, 95% CI 1.05 – 1.44). Among racial distributions, Blacks had higher odds of mortality when compared with White (OR 1.3, 95% CI 1.1 – 1.5). Hispanics had lower odds of inpatient mortality compared to Whites (OR 0.8, 95% CI 0.6 – 0.9). The odds of mortality were higher with increasing age (OR 1.025, 95% CI 1.02 – 1.031) and lower among females (0.82, 95% CI 0.73 – 0.91). Among secondary outcomes, hyperlipidemia did not affect the hospital length of stay or cost. Several factors increased the hospital length of stay which included any history of coronary artery disease, peripheral artery disease, or diabetes. In addition, patients admitted over the weekend had a higher length of stay. Conclusions: In this study, we find that hyperlipidemia is associated with lower mortality in patients with colon cancer. This could be possible because patients with hyperlipidemia are on statin therapy. This indirectly could point to a potential benefit of statins in colon cancer. Hyperlipidemia does not affect hospital length of stay or cost.
The role of chemotherapy plus immune checkpoint inhibitors in oncogenic driven non-small cell lung cancer: A University of California Lung Cancer Consortium retrospective study.
Authors: Karen Kelly, Shuai Chen, Joanna B Eldredge, David Joseph Benjamin, Matthew C Mulroy, Nadeem Tabbara, John Sharp, Jonathan Wade Goldman, Matthew A. Gubens, Jeremy P. Harris, Megan Eileen Daly, Sandip Pravin Patel, Jason Chan, Amy Lauren Cummings, Viola Weijia Zhu
Journal: Journal of Clinical Oncology (2021)

9059 Background: Immune checkpoint inhibitors (ICIs) have demonstrated limited efficacy in patients (pts) with actionable oncogenic drivers. As a result, pts with the prototypic oncogenic drivers (EGFR and ALK) have purposefully been excluded from many NSCLC ICI trials although ICI is commonly used in combination with chemotherapy for these pts. Data from one randomized trial that included pts with known EGFR and ALK alterations did not show a survival benefit with an ICI plus a platinum doublet. We sought to gain further insight into the role of chemotherapy plus ICI in pts with oncogenic driven tumors. Methods: We conducted a retrospective analysis of pts with oncogenic drivers (EGFR, ALK, ROS1, BRAF, MET, RET, HER2 and KRAS) who were treated with chemotherapy (C) or chemotherapy plus ICI (C+ICI) between 2018 and 2019 at the five University of California (UC) NCI Designated Cancer Centers (UC Irvine, UC Davis, UC Los Angeles, UC San Diego and UC San Francisco). Descriptive statistics were used. Kaplan-Meier plots and confidence intervals summarize PFS and OS in the overall cohort and oncogenic subgroups. Results: 125 pts were identified. Median age 64.1 years; M/F (45%/55%); White/Asian (59%/33%); Current/Former/Never Smokers (4%/39%/57%); PS 0/1/2(22%/68%/10%); prior number of tyrosine kinase inhibitors 0/1/2/ &gt; 3 (46%/23%/19%/11%); Oncogenic driver: EGFR mutations (60%), KRAS mutations (23%), ALK fusions (8%), MET mutations (2.4%), RET fusions (1.6%), ROS1 fusions (1.6%), HER2 mutations (1.6%), and BRAF mutations (0.8%). The table below displays the efficacy outcomes. Conclusions: There was no survival benefit for pts with oncogenic drivers treated with chemotherapy plus an immune checkpoint inhibitor in the overall cohort or any of the subsets. Pts with KRAS mutations treated with C+ICI had a numerically longer median PFS than their counterparts treated with C. Updated data and additional analyses including PD-L1, TMB, co-mutations and toxicity will be presented.[Table: see text]
Comparison of population characteristics, treatment modes, and clinical outcomes of patients with advanced non-small cell lung cancer in clinical trials and in the real world received PD-1/PD-L1 inhibitor.
Authors: Zhiyong Ma, Huijuan Wang, Chunhua Wei, Zhang guo Wei, Xiangtao Yan, Mina Zhang, Xiaojuan Zhang, Yuanyuan Niu, Jinpo Yang
Journal: Journal of Clinical Oncology (2021)

e18733 Background: Although PD-1/PD-L1 inhibitors have become the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), data from clinical trials are difficult to be verified in the real world. This study aims to compare the differences in population characteristics, treatment modes and clinical outcomes of advanced NSCLC patients received PD-1/PD-L1 inhibitors between the real-world (RWS) and the clinical study (RCT). Methods: This study enrolled 305 advanced NSCLC patients who received at least one PD-1/PD-L1 inhibitor treatment selected in the Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital Information System and the Zero Krypton database during January 2016 to September 2019. The patients were divided into RWS group and RCT group. The PD-1/PD-L1 inhibitors included pembrolizumab, sintilizumab, nivolizumab, tislelizumab, carrelizumab, teriprizumab, durvalizumab and Atezolizumab. We performed paired analysis in clinical characteristics and treatment modes. Results: There were 155 cases in the RCT group and 150 cases in the RWS group. The RCT group consisted of higher proportion in male (79.4%) and squamous-carcinoma type (41.3%) than the RWS group, while more patients of brain metastasis (28%) and combination therapy (50.7%) in the RWS group. The ORRs were 42.4% and 20.6% respectively in the RCT and RWS groups receiving first-line treatment with PD-1/PD-L1 inhibitors, and the difference was statistically different. Moreover, the ORRs were 42.4% and 20.6% respectively in the RCT and RWS groups receiving PD-1/PD-L1 inhibitor as second-line treatment, without statistical difference. The progression-free survival (PFS) was 15.5 vs. 13.5 months in the RCT and RWS groups ( P= 0.91), and the median overall survival (OS) was 25.4 vs. 33.8 months respectively ( P= 0.24), with no statistical difference. After propensity match of baseline characteristics of the two groups of patients, it contained 108 patients in the RCT and RWS groups. The PFS was 13.3 vs. 13.3 months in the RCT and RWS groups ( P= 0.47), and the median OS was 21.1 vs. 23.2 months ( P= 0.58), with no statistical difference. Conclusions: Although more female, brain metastases and adenocarcinoma patients receiving PD-1/PD-L1 inhibitors in the real world, the clinical benefits were consistent with those in clinical trials. The results of propensity matching on the baseline characteristics of patients supported this conclusion.
Renal Response in Relapsed Refractory Multiple Myeloma Patients with Severe Renal Impairment at treatment Initiation: Intermediate Data of a Large, Observational, Prospective Study
Authors: Antoni Garcia, Queralt Salas, Enrique Morales, González Esther, Maria Soledad Duran, Fernando Escalante, Mercedes Gironella, Tomás Jose Gonzalez, Rafael Duro, Manuel Pérez, Paz Ribas, Elena Cabezudo, Rafael Lluch, Ignacio Español, Valentin Cabañas, Ricardo Francisco Garcia, Jose Antonio Márquez, Marta Duran, Javier Soriano, Javier de la Rubia
Journal: Blood (2017)
EPCT-25. SMO PROTEIN DEPLETION IN SHH MEDULLOBLASTOMAS USING MICROBUBBLE-ENHANCED ULTRASOUND AND SIRNA LOADED CATIONIC NANOPARTICLES
Authors: Yutong Guo, Hohyun Lee, Zhou Fang, Anastasia Velalopoulou, Jinhwan Kim, Midhun Ben Thomas, Jingbo Liu, Ryan G Abramowitz, YongTae Kim, Ahmet F Coskun, Daniel Pomeranz Krummel, Soma Sengupta, Tobey J MacDonald, Costas Arvanitis
Journal: Neuro-Oncology (2021)

Abstract RNA-based therapies offer unique advantages for treating pediatric brain tumors. However, the systemic delivery remains a major problem due to degradation of unmodified RNA in biological fluids, poor brain accumulation, and poor cancer cell uptake or escape from the endosomal lipid bilayer barrier. While nanoparticle encapsulation can prolong circulation time and facilitate cellular uptake, their accumulation in brain tumor remains particularly poor due to their low permeability across the blood-brain barrier and limited intratumoral penetration. Focused ultrasound, when combined with circulating microbubbles (MB-FUS) provides a physical method to transiently modulate the brain tumor microenvironment (TME) and improve nanoparticle delivery. Here, we have examined the delivery of siRNA targeting the Smoothened (SMO) pathway, packaged in 50 nm cationic lipid-polymer hybrid nanoparticles (cLPH:siRNA-SMO), combined with MB-FUS in murine SmoA2 sonic hedgehog (SHH) medulloblastoma. At 30 hours after treatment, we observed the depletion of the SMO protein target, responsible for driving SHH medulloblastoma formation and growth, in mice that had received treatment with MB-FUS and cLPH:siRNA-SMO, but not with cLPH:siRNA-SMO alone. We also confirmed that SMO protein depletion was spatially achieved in the tumor regions with detected cLPH:siRNA-SMO using FISH assay, and that there was 15 fold induction of tumor cell apoptosis compared to tumors in mice that had received cLPH:siRNA-SMO alone. The limited induction of apoptosis was observed with either cLPH:siRNA (non-targeting) or MB-FUS and cLPH:siRNA (non-targeting), suggest that the observed apoptosis induction in the SmoA2 model was the direct result of SMO depletion rather than nonspecific effects of MB-FUS or cLPH:siRNA. Our findings provide a paradigm shift in drug delivery in brain tumors, where physical methods and nanotechnology are tuned together to develop rational strategies for the effective delivery of nucleic acids in brain tumors.
Immune subtypes in LUAD identify novel tumor microenvironment profiles with prognostic and therapeutic implications.
Authors: Shuoyan Liu, Feng Wang, Xuan Gao, Peiyuan Wang, Yujie Chen, Peng Chen, Hao He, Xiaofeng Chen, Derong Zhang
Journal: Journal of Clinical Oncology (2021)

e20512 Background: The incidence of lung adenocarcinoma (LUAD) is increasing year by year worldwide. Thorsson et al. identified six immune subtypes (ISs) (C1 - C6) in 33 diverse cancer types, including LUAD. The tumor microenvironment and lung cancer cells of 6 ISs have complex and different interplay, and the consequence of the interplay determines the growth of tumor cells and the prognosis of patients. Methods: Clinical and molecular information of TCGA LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) (N = 457). Kaplan-Meier survival analysis and Cox proportional-hazard analyses were performed in 4 independent GEO LUAD data sets (GSE31210, GSE37745, GSE50081, and GSE68465) and, where five immune subtypes C1-C4, C6 were stratified according to Thorsson et al.’s immune classification method. Results: Only 5 ISs were identified in the TCGA NSCLC cohort; the proportion of the C3 inflammatory IS (39.2%) was the most common IS observed in the TCGA LUAD cohort, whereas C1 was particularly dominant in LUSC (57.1%). The proportion of C3 was also the most common IS observed in GEO LUAD cohorts (GSE37745, GSE50081, GSE68465), except for one stage I-II lung adenocarcinomas cohort (GSE31210). The prognostic relevance of the C3 IS was associated with significantly longer overall survival and progression-free interval time of LUAD in the TCGA cohort. In contrast, the association was not significant in the TCGA LUSC cohort. C3 was also associated with significantly longer overall survival (p &lt; 0.001) and disease-free interval time (p &lt; 0.001) in the 4 GEO LUAD cohorts by multivariate analyses. To further evaluate prediction accuracies of C3, we compared the C3 model with the other 3 reported immune-related signatures. For all comparisons in these 4 GEO cohorts, C3 outperformed the other 3 signatures with superior overall survival and DFS predictive performances according to the time-dependent Concordance index. C3 presented higher levels of CD8 T, follicular helper T, M1 macrophage, CD4 memory resting, myeloid dendritic, neutrophils, and endothelial cells by using CIBERSORT and MCP counter. Low levels of M2 macrophages and cancer-associated fibroblast cells were also found in the C3 subtype. GSEA pathway analysis showed that the C3 subtype had a heightened activation in the antigen process and presenting pathway, interferon-gamma response pathway, T cell receptor signaling pathway, and neural killer cell-mediated cytotoxicity pathway than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, MMR repair DNA repair, and p53 signaling pathways than the C3 subtype. Conclusions: The robust prognostic relevance of the C3 IS allows a more precise categorization of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in LUAD patients.
Retrospective analysis of ovarian cancer patients treated with PARP inhibitors.
Authors: Connie Liang, Ashley Leung, Chung-Shien Lee, Jennifer Hernandez, Kit Cheng, Dimitre C. Stefanov, Veena S. John
Journal: Journal of Clinical Oncology (2021)

e17555 Background: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1 or BRCA2 mutations. Poly ADP ribose polymerase (PARP) inhibitors are effective in the treatment of patients who are in complete or partial remission. PARP inhibitors are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Methods: We conducted a single institution, IRB approved, retrospective study on patients who were treated with PARP inhibitors from December 2016 to October 2020. Patients were stratified according to which PARP inhibitor they received. Our primary objective was to assess the incidence of hematological and non-hematological adverse events associated with the use of PARP inhibitor therapy used in patients with ovarian cancer. Data from absolute neutrophil count, hemoglobin and platelet count during the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: A total of 126 patients received a PARP inhibitor during the study time frame. 34 were excluded and 92 patients were included for analysis. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) white, and 84 (91.3%) had an ECOG PS of 0/1. Thirty-one (33.7%) of patients received niraparib and 61 (66.3%) of patients received olaparib. Patients in the niraparib group experienced more hematologic AEs, with 11 (35.5%) (95% CI 19.2-54.6), 20 (64.5%) (95% CI 45.4-80.8), and 18 (58.1%) (95% CI 39.1-75.5) experiencing neutropenia, anemia, thrombocytopenia, respectively. Eight (13.1%) (95% CI 5.8-24.2), 24 (39.3%) (95% CI 27.1-52.7), 16 (26.2%) (95% CI 15.8-39.1) patients in the olaparib group experienced neutropenia, anemia, thrombocytopenia, respectively. Conclusions: This single institution retrospective study outlines the hematological toxicities observed between two PARP inhibitors. Although there are four PARP inhibitors approved by FDA, our data compared only two of the four (as they were the most commonly prescribed PARP inhibitors in our institution). Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Our data showed anemia as the most common hematologic toxicity which was consistent with what has been widely documented in the literature.
IMMU-14. COMPUTATIONAL DECONVOLUTION OF TUMOR-INFILTRATING IMMUNE COMPONENTS IN PEDIATRIC NERVOUS SYSTEM TUMORS
Authors: Pengbo Beck, Arash Nabbi, Martin Sill, Sumedha Sudhaman, Marcel Kool, Adam C Resnick, David T W Jones, Stefan M Pfister, Trevor J Pugh, Natalie Jäger
Journal: Neuro-Oncology (2021)

Abstract Introduction In the last decade, checkpoint inhibitor-based immunotherapy has been a groundbreaking development in the treatment of cancer. However, only a subset of patients treated with immune checkpoint inhibitors show long-lasting clinical benefit. Studies showed the tumor immune microenvironment (TME) as a particularly important factor influencing treatment response, critical for the design of other or combinatorial immunotherapy treatment strategies. Extensive research has been performed in the adult cancer field to unravel its immunogenomic aspects. However, in pediatric cancer this insight into tumor-infiltrating immune components is still lacking. This study aims to provide insight into the landscape of the immune microenvironment in pediatric primary nervous system tumors. Methods Bulk RNA-seq data of 936 pediatric primary solid tumors acquired from multiple international initiatives including Therapeutically Applicable Research To Generate Effective Treatments (TARGET), the International Cancer Genome Consortium (ICGC) and the Children’s Brain Tumor Tissue Consortium (CBTTC) were included in this study. We applied computational tumor immune microenvironment deconvolution, repurposed RNA-seq data to recover infiltrating T- and B-cell clonotypes and studied checkpoint gene expression across pediatric neural tumors. Results Among pediatric neural tumors, embryonal tumors with multilayered rosettes (ETMR) and medulloblastomas (MB) were least immune infiltrated. Neuroblastomas (NBL) had the highest T-cell infiltration among pediatric cancers, while atypical teratoid/rhabdoid tumors (ATRT) had the highest levels of CD8 T cell infiltration among pediatric CNS tumors. While tumor mutational burden (TMB) was associated with immune cell infiltration in adult lung cancers and melanomas, we found no significant associations in pediatric cancers. The majority of NBL samples expressed LAG3, but ~10% of samples had elevated levels of TIM3 gene expression, suggesting a distinct mode of immunosuppression in this subset.
Accumulation of genome-wide somatic loss of heterozygosity (LOH) as a prominent feature of advanced malignant soft tissue tumors and association with the BRCAness status, suppression of immune responses, and lower survival rates.
Authors: Katsuhito Takahashi, Yasutomo Miyaji, Ryotaro Ohkuma, Hajime Higuchi, Yoshihiro Komohara, Shinsuke Aida, Jun Yashima, Hiromasa Yamamoto, Ken Suzawa, Yuko Takahashi, Shinichi Toyooka, Hiroya Ashimine, Yu Oyama, Hiroyuki Narahara, Junko Yotsumoto, Hiroo Ishida, Takuya Tsunoda, Yasutsuna Sasaki, Yasuo Ono, Satoshi Teraoka
Journal: Journal of Clinical Oncology (2021)

11533 Background: Malignant soft tissue tumor is a rare cancer with few therapeutic options. Recent genomic analysis revealed widespread CNA and the cumulative burden of cancer-related pathogenic germline mutations/variants, their clinical and therapeutic significance were unknown. Methods: We recruited 155 patients with advanced malignant soft tissue tumors (135 female and 20 male, mean age 51 at analysis, 100 LMS, 19 LPS, 4 ESS, 3 UPS, 3 AS, 3 MPT, 3 GIST and others) with confirmed metastasis/recurrence and information on familial cancer burden. Whole exome sequencing was performed in both blood and tumor samples as described in 2018ASCO. The copy number of BRCA2 gene was determined by the MLPA method. Tumor immune microenvironment was assessed by immunohistochemistry. The MSI status was analysed by PCR. Results: We analyzed the LOH status in 595 COSMIC genes and found that genome-wide accumulation of somatic LOH of polygenic germline mutations/variants. Patients with more than 33% LOH genes (n=102) in the total of somatic and LOH mutations showed significantly lower OS rates compared with those (n=53) with less LOH genes (5-year survival rates; 49 vs 75%, p=0.010), which constitute 78% of LMS (n=78/100) and 26% of LPS (n=5/19). Total of 41 patients (26%, n=41/155) including 33 LMS (33%, n=33/100) showed LOH in the BRCA2 locus with hemizygous VUS. Those patients with BRCA2 LOH (n=41) showed significantly lower OS rates compared with those without BRCA2 LOH (n=114) (5-year survival rates; 43 vs. 64%, p=0.019). Neither TMB nor the MSI status was associated with LOH. In contrast, accumulation of somatic LOH (mean LOH values of 71.7 vs. 15.7%) was clearly and negatively associated with CD8+T-cell immune infiltrates (T-cells; 44±23 vs 555±180/mm 2 , n=7, p=0.016), CD20+B-cell accumulation in tertiary lymphoid structures (TLS) (TLS; 0.57±0.43 vs. 20.1±6.1/tumor, n=7, p=0.008) and low levels of neutrophil-to-lymphocyte ratio (NLR) (NLR; 3.63±0.45 vs. 1.71±0.17, n=7, p=0.002), hallmarks of the immunological response to tumors. Conclusions: This study suggests that in advanced malignant soft tissue tumors, accumulation of genome-wide LOH of germline mutations/variants is associated with the BRCAness status and suppression of the immune responses to tumors, and thus influences therapeutic response and survival of the patients.