tbuckley/cabot-search huggingface dataset:
Association of proton pump inhibitors with survival in Veterans with non-small cell lung cancer receiving immunotherapy.
Authors: William A. Stokes, Madhusmita Behera, Renjian Jiang, David Gutman, Felipe Giuste, Abigail Burns, Nikhil Sebastian, Selvi Ramalingam, Vidula Sukhatme, Michael C. Lowe, Suresh S. Ramalingam, Vikas Sukhatme, Drew Moghanaki
Journal: Journal of Clinical Oncology (2021)

e18729 Background: Proton pump inhibitors (PPI) can disrupt the gut microbiome and thereby modulate response to immunotherapy in cancer patients. In a recently published post-hoc analysis of 757 non-small cell lung cancer (NSCLC) patients receiving atezolizumab pooled from two prospective trials, overall survival (OS) and progression-free survival were significantly lower among the 234 patients receiving PPI. We investigated the impact of PPI in a larger cohort of NSCLC patients treated with ICI within the Veterans Health Administration. Methods: We conducted a nested cohort study of Veterans who were diagnosed with NSCLC between 2010 &amp; 2018 and treated with ICI (immune checkpoint inhibitors). Exposure was defined as receipt of a PPI prescription within 90 days of an ICI infusion. Chi-square tests were used to compare characteristics of exposed versus unexposed Veterans. OS was measured from start of ICI. Cox proportional hazard multivariate (MV) regression was used to calculate hazard ratios (HR) corresponding to variables associated with OS. Results: We identified 3,634 Veterans receiving ICI with non-exclusive exposures to nivolumab (59.3%), pembrolizumab (35.1%), durvalumab (6.9%), and atezolizumab (3.3%). Their median age was 69, and a plurality had male gender (97.0%), white race (73.0%), comorbidity count ≥1 (60.4%), adenocarcinoma (47.8%), and stage IV disease at diagnosis (40.9%). In this nested cohort, 2,159 (59.4%) were exposed to PPI, predominantly omeprazole (1,264 or 85.6% of PPI group). Patients receiving PPI were more likely to be ≤71 years of age, to be white, to reside in rural areas, to have a higher comorbidity burden, to have adenocarcinoma histology, and to receive chemotherapy (all p≤0.04). On MV analysis, PPI use was not significantly associated with detriment in OS (HR 0.96 [0.89-1.04], p= 0.35). In the matched cohort analysis, median survival did not significantly differ between the 1,389 patients taking PPI and the 1,389 without PPI (median 10 versus 10 months, HR 0.98 [0.90-1.06], p= 0.59). Conclusions: In the largest analysis to date of concurrent PPI use in patients with NSCLC receiving ICI, there were no survival differences associated with concomitant PPI use. These results suggest that PPIs do not compromise ICI efficacy.
Analysis of demographics and outcomes of surgical resection in the CNS of patients with melanoma.
Authors: Achuta Kumar Guddati, Takefumi Komiya, Picon Hector, Allan N. Krutchik, Gagan Kumar
Journal: Journal of Clinical Oncology (2021)

e21534 Background: Patients with melanoma frequently develop central nervous system metastases. Oligometastatic disease is often treated either by surgical resection or by stereotactic radiotherapy. This study investigates the trends and clinical outcomes of patients with melanoma who have undergone surgical procedures on the central nervous system during their hospitalization. Methods: A retrospective cohort study was performed based on admissions of adult patients who underwent craniectomy/surgical resection for metastatic melanoma from 2002 -2014 using the Nationwide Inpatient Sample database. The primary outcome measure was all-cause in-hospital mortality. Secondary outcomes included length of hospital stay(LOS) and discharge disposition (home/home with health care and skilled nursing facilities/long term acute care (SNF/LTAC)). Factors associated with in-hospital mortality were examined by multivariable logistic regression. We adjusted for patient and hospital characteristics, payer, and comorbid conditions. We also examined trends of mortality for the study years. P was kept at 0.05. Results: There were an estimated 5972 discharges of patients with melanoma undergoing craniectomy/surgical resection during the study period. Patients undergoing surgical interventions were typically males (69%) and whites (79%). 98% of procedures were performed at teaching hospitals. Unadjusted all-cause in-hospital mortality was 3.1%. There was no significant difference in mortality over 13 years. Age, gender, and race were not associated with increased in-hospital mortality. Median LOS was 5 days (IQR 3-9 days). LOS was longer in elderly and those with higher Charlson co-morbid index. Of the survivors, 76% were discharged to home or with home healthcare while 24% were discharged to SNF/LTAC. Patients with age &gt; 65 (OR 2.9; 95%CI 2.2-3.9, p &lt; 0.001) and those with higher Charlson co-morbid index (OR 1.2; 95%CI 1.1-1.3) had higher odds for being discharged to SNF/LTAC. Conclusions: Patients who undergo craniectomy/surgical resection for melanoma have a low in-hospital mortality rate. One quarter of patients are discharged to SNF/LTAC.
Association of plasma adiponectin with tumor infiltrating lymphocytes and survival in patients with stage III colon cancer (NCCTG N0147; Alliance).
Authors: Frank A. Sinicrope, Qian Shi, Thomas C. Smyrk, Richard M. Goldberg, Steven J. Cohen, Sharlene Gill, Morton S. Kahlenberg, Suresh Nair, Anthony Frank Shields, Balkrishna N. Jahagirdar, Sawyer B. Jacobson, Nathan R. Foster, Michael N. Pollak, Steven R Alberts
Journal: Journal of Clinical Oncology (2021)

3591 Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in participants in a phase 3 trial of adjuvant chemotherapy. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon carcinoma who received adjuvant FOLFOX +/- cetuximab. TIL densities were determined at light microscopy in routine histopathological sections. The associations between adiponectin and 25(OH)D, TILs, other factors were evaluated by Fisher’s Exact, Chi-squared, t-test, and Kruskal-Wallis tests where appropriate. The association between adiponectin or 25(OH)D with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were evaluated by multivariable Cox regression, adjusting for body mass index (BMI), race, T, N stage, performance status, tumor location, TILs, BRAF/KRAS, and mismatch repair status. Results: A statistically significant and inverse association between adiponectin level and BMI was observed with lower levels found with obesity (BMI &gt; 30 kg/m 2 ) [p &lt; 0.001]. The level of adiponectin was significantly lower in men vs women (p &lt; 0.001), in blacks vs whites or Asians (p &lt; 0.032), and in patients with fewer regional lymph node metastases (N1 vs N2 stage, p = 0.011). A significantly lower level of adiponectin was found in patients whose tumors had high vs low TIL densities (p = 0.040), but was unrelated to 25(OH)D. Insufficiency of 25(OH)D ( &lt; 30 ng/ml) was detected in 291 (49%) of patients and was not associated with TILs. By multivariable analysis, adiponectin was not associated significantly with patient DFS (HR adj = 0.98, 95% CI 0.74-1.29, p adj = 0.88) nor with OS nor time-to-recurrence (TTR). TIL densities were significantly prognostic, but 25(OH)D was not (DFS: HR adj = 1.12, 95% CI 0.85-1.47, p adj = 0.44). No significant interaction was observed for adiponectin with TILs for the association with DFS. Conclusions: Lower adiponectin levels were associated with significantly increased TIL densities in colon cancers, indicating an enhanced anti-tumor immune response. In contrast to TILs, adiponectin was not independently associated with patient outcome. Nearly one-half of stage III patients were vitamin D insufficient, although 25(OH)D was not prognostic.
The sarcoma microbiome as a diagnostic and therapeutic target.
Authors: Gabriel Tinoco, Marium Husain, Rebecca Hoyd, Malvenderjit Jagjit Singh, YunZhou Liu, Xiaokui Mo, James Lin Chen, David A. Liebner, Daniel Spakowicz
Journal: Journal of Clinical Oncology (2021)

11541 Background: Sarcoma is a heterogeneous group of malignant tumors that consist of distinct histological and molecular subtypes, each with unique features. Despite immunotherapy’s promise in many cancers, immunotherapeutic approaches for sarcoma have had variable response rates. Evaluating the tumor microbiome is a promising new approach that aims to improve our understanding of the immunogenicity of sarcoma subtypes, leading to improved treatment options and better clinical outcomes. Methods: We utilized The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) database to obtain RNA sequencing (RNAseq) data to identify microbes in sarcoma samples (all subtypes available). Due to the large number of sarcoma subtypes, we focused on three groups: dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS) and “other,” representing all other sarcoma subtypes. We utilized ExoTIC, “Exogenous sequences in Tumors and Immune cells,” a tool recently developed by Dr. Daniel Spakowicz and Dr. Xaiokui Mo. ExoTIC takes raw RNAseq reads and carefully aligns to both human and non-human reference genomes to identify low-abundance microbes. Models of association were analyzed based on each of the three groups as well as all the samples: “All” group. We performed Cox proportional hazards regression to identify the microbes associated with overall survival (OS). Results: We evaluated 97 LMS, 56 DDLPS and 100 “other” RNAseq samples (Table). ExoTIC identified 1304 microbes, of which 431 were statistically associated with OS in the “All” group. Of these, 50 microbes were statistically associated only with DDLPS, 54 only with LMS (e.g., Candida dubliniensis, Mycobacterium avium, Streptococcus sp. Z15), and 46 with “other.” The presence of no organism was associated with improved survival. Median hazard ratios were largest in DDLPS (2.3), followed by “other” (2.1) and LMS (1.9). Only 18 microbes were found in the DDLPS, LMS and “All” groups, including Bacillus sp., Streptococcus lutetiensis, Clostridium tetani, and Pseudomonas sp. LTJR-52. Each was negatively correlated with survival with a median hazard ratio of 2.5. Conclusions: We found a specific relationship between microbial presence and histological sarcoma subtype (DDLPS, LMS), which also statistically correlated with OS. Assessing individual characteristics of a sarcoma histological subtype with its particular microenvironment (e.g., microbes) can lead to personalized treatment insights and improvements in outcomes. Our future research will consist of validating and correlation of the microbial profile of sarcoma subtypes with clinical outcomes retrospectively and prospectively. [Table: see text]
MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING
Authors: Yong Zhang, Qifan Yang, Xiangyu Zeng, Manxiang Wang, Shuang Dong, Bin Yang, Xinyi Tu, Ting Wei, Wenzhuan Xie, Chao Zhang, Qiang Guo, Jake A. Kloeber, Yueyu Cao, Guijie Guo, Qin Zhou, Fei Zhao, Jinzhou Huang, Li Liu, Kai Zhang, Mingwei Wang, Ping Yin, Kuntian Luo, Min Deng, Wootae Kim, Jing Hou, Yu Shi, Qian Zhu, Lifeng Chen, Sheng Hu, Junqiu Yue, Guoliang Pi, Zhenkun Lou
Journal: Cancer Discovery (2021)

Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3'-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. SIGNIFICANCE: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR-tyrosine kinase inhibitor resistant-related MET amplification.This article is highlighted in the In This Issue feature, p. 2659.
Abstract 14290: Long-Term Statin Persistence is Poor Among High-Risk Patients With Baseline ASCVD or Revascularization: A Real-World Administrative Claims Analysis
Authors: Peter P Toth, Craig Granowitz, Michael Hull, Sephy Philip
Journal: Circulation (2018)

Introduction: A decade ago, statin persistence was <50% at 1 year, and recent short-term analyses have revealed very little progress in improving statin persistence, even in patients with a prior C...
Survival trends of men and women with metastatic clear cell renal cell carcinoma.
Authors: Claud Grigg, Sally Trufan, Peter E Clark, Stephen Boyd Riggs, Jason Zhu, Justin T. Matulay, Derek Raghavan, Earle F Burgess
Journal: Journal of Clinical Oncology (2021)

4566 Background: Clear cell renal cell carcinoma (ccRCC) is nearly twice as common in men as in women, and women with non-metastatic RCC have a better prognosis than men. The etiology for these disparities is not known, though sex-specific differences in risk factor prevalence and tumor biology have been reported. The differential impact of systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), on prognosis in women and men with metastatic ccRCC is not defined. Methods: Clinicopathologic features and survival of patients with clinical stage IV ccRCC were obtained from the National Cancer Database (NCDB). Patients were grouped by date of metastatic diagnosis into three eras that correspond to major advances in systemic therapy: 2004-2005 (pre-TKI), 2006-2014 (TKI), and 2015-2016 (ICI). Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: 15,025 male and 7,100 female patients with metastatic ccRCC were identified. Demographic features were similar between cohorts though females were slightly older (median 64.8 vs 62.7 mo, p &lt; 0.0001), more likely to be black (6.5% vs 6.0%, p = 0.0119) or receiving Medicare benefits (46.4% vs 39.9%, p &lt; 0.0001). In the combined cohort, median overall survival (OS) was higher in patients diagnosed in the ICI vs TKI (23.0 vs 16.5 mo) and pre-TKI eras (14.4 mo, log-rank p &lt; 0.0001). Compared with men of the same age groups, OS was inferior for women age 50-64 yr (median 18.4 vs 21.1mo, p = 0.0084) and &gt; 64 yr (15.3 vs 12.6mo, p = 0.0001), but not &lt; 50 yr (20.3 vs 21.7mo, p = 0.6290). In the ICI era, median OS improved by a lesser absolute but similar relative amount for women compared to men (+5.6mo [+39%] and +7.2mo [+41%]), respectively). After controlling for age, race, Charlson-Deyo score, initial treatment modality, and insurance and socioeconomic status, women remained at increased risk of death in both the ICI era (HR 1.12 [95% CI 1.04-1.22], p = 0.004) and the TKI era (HR 1.08 [1.04-1.12], p &lt; 0.001). Conclusions: Women with metastatic ccRCC have a worse prognosis than men which is not explained by demographic differences. This disparity is observed in both the TKI and ICI eras. This finding contrasts with previous studies suggesting women with localized RCC have a favorable prognosis compared with men. Further investigation into the sex-specific biology of metastatic ccRCC is warranted.
Abstract GMM-055: BMI1 AND RING1A ARE INVOLVED IN H2A UBIQUITINATION AT SITES OF PLATINUM-INDUCED DAMAGE
Authors: Shruthi Sriramkumar, Heather M. O'Hagan
Journal: Clinical Cancer Research (2019)

Abstract Ovarian cancer is the 5th leading cause of death among women with the five year survival rate for ovarian cancer patients being only 46%. The standard of care for treatment of ovarian cancer patients is debulking surgery followed by platinum-taxane based chemotherapy. However, the major obstacle in the treatment of these patients with platinum based agents is development of chemoresistance. The platinum agents, cisplatin and carboplatin damage DNA by forming adducts with adjacent guanines, a high density of which are found in the promoter CpG islands of genes. Aberrant promoter DNA hypermethylation of genes and their subsequent transcriptional repression has been associated with development of cisplatin resistance. However, the mechanism of initiation of this aberrant DNA methylation and subsequent transcriptional repression is not known. Our overall hypothesis is that platinum induced DNA damage or repair of the damage leads to recruitment of repressive proteins to sites of damage. These repressive proteins transiently repress transcription in vicinity of damage to promote repair. However, similar to our findings with enzyme induced double strand breaks, repressive proteins may be retained at some key loci causing persistent transcriptional repression and gene silencing contributing to the development of platinum resistance. Our preliminary data demonstrates that BMI1, a member of polycomb repressive complex 1, localizes to sites of damage after cisplatin treatment. We also observe mono-ubiquitination of H2AX after cisplatin treatment and we hypothesize that this ubiquitination is occurring on K119. Mono-ubiquitination of H2A/H2AX at K119 has been associated with transcriptional repression and gene silencing during development and differentiation and also during repair of ionizing radiation and enzyme induced double strand breaks. Our data suggests that knockdown of RING1A reduces the cisplatin induced H2AX ubiquitination. We are currently determining which repair pathways and/or proteins result in recruitment of BMI1, RING1A to sites of damage. Importantly, after acute cisplatin treatment we also observe a reduction in expression of candidate genes which are known to be methylated in cisplatin resistant cells. We plan to determine if RING1A mediated ubiquitination is responsible for reduction in expression of target genes after acute cisplatin treatment and their methylation in cisplatin resistant cells. Understanding the mechanism of platinum induced gene silencing will enable us to design therapies to avert the development of drug resistant ovarian cancers. Citation Format: Shruthi Sriramkumar, Heather M. O'Hagan. BMI1 AND RING1A ARE INVOLVED IN H2A UBIQUITINATION AT SITES OF PLATINUM-INDUCED DAMAGE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-055.
OMIC-04. IDENTIFICATION AND CHARACTERIZATION OF CIRCULATING RNAS (CODING AND NONCODING) AND METABOLITES IN CEREBROSPINAL FLUID IN MEDULLOBLASTOMA PATIENTS
Authors: Bongyong Lee, Stacie Stapleton, Rudramani Pokhrel, Chetan Bettegowda, George Jallo, Ranjan Perera
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, and monitoring patients for treatment response and recurrence can be challenging with available current technologies in neuro-imaging and performing a biopsy to confirm response or recurrence carries risks, whereas cerebrospinal fluid (CSF) can be obtained with a little invasiveness. MB has altered cellular metabolism due to changes in gene expression, therefore, we hypothesized that any changes in MB cells lead to changes in cell-free transcripts and metabolites in CSF. To test this, we applied RNA-sequencing and mass spectrometry to analyze transcripts and metabolites including lipid in CSF from patients with different sub-groups of MB tumors (i.e., WNT, SHH, G3/4, G4, and unknown) and compared them to non-cancerous CSF. Tumor and sub-group specific transcriptomic and metabolic signatures were shown by unsupervised hierarchical clustering facilitating tumor type differentiation. By comparison with previously published tumor tissue RNA-seq data, we were able to identify a group of upregulated molecular signatures in both tumor tissue and CSF. We also identified a group of lipids that differentiate each MB sub-group from normal CSF, and Pathway analysis confirmed alterations in multiple metabolic pathways. Finally, we attempted to integrate RNA-seq data with lipidomics data, and results depict that the combinatorial analysis of CSF RNAs and metabolites can be useful in diagnosing and monitoring patients with MB tumors. (This research was conducted using samples made available by The Children’s Brain Tumor Network.)