tbuckley/cabot-search huggingface dataset:
Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets
Authors: Michaela T. Reichmann, Liku B. Tezera, Andres F. Vallejo, Milica Vukmirovic, Rui Xiao, James Reynolds, Sanjay Jogai, Susan Wilson, Ben Marshall, Mark G. Jones, Alasdair Leslie, Jeanine M. D’Armiento, Naftali Kaminski, Marta E. Polak, Paul Elkington
Journal: Journal of Clinical Investigation (2021)

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.
Methylation of <i>MMP2</i> and <i>MMP9</i> in patients with localized and generalized forms of Ewing's sarcoma.
Authors: Natalia A. Petrusenko, Dmitry Yu. Gvaldin, Darya Yu. Yurchenko, Sergey A. Kuznetsov, Dmitriy V. Burtsev, Oleg I. Kit
Journal: Journal of Clinical Oncology (2021)

e23503 Background: MMPs play a critical role in tumor growth and progression, metastatic development, angiogenesis, and tumor invasion. Epigenetic regulation of MMP2 and MMP9 levels is often disrupted in cancer and is considered as potential biomarkers. In this study, we tried to assess the methylation of the MMP2 and MMP9 genes in patients with localized and generalized forms of Ewing's sarcoma (ES). Methods: As a material used DNA from FFPE of primary tumor of 20 patients with localized forms ES and 20 patients with generalized forms ES. After bisulfite conversion of total DNA and PCR, the level of CpG methylation was assessed by sequencing on a Genetic Analyzer Applied Biosystems 3500. Results: The analysis showed the presence of hypomethylation of the MMP2 in the group with generalized forms (100%) 1.25 times more often than in the group with localized forms (80%), and hypermethylation was observed only in the group with localized forms–20% of cases (χ2 = 4.234, p = 0.040). On the other hand, hypermethylation was 1.9 times more common in the group with localized forms of ES (90%) (χ2 = 8.313, p = 0.004). Differences in the methylation status of the MMP2 and MMP9 indicate that the presence of hypomethylation at two loci increases the risk of developing generalized ES by 22 times (OR = 22.2, p &lt; 0.05; CI95% 2.460-20.769). Conclusions: Specific methylation of the matrix metalloproteinases genes MMP2 and MMP9 identified in the groups of localized and generalized Ewing's sarcoma. At the same time, the group with generalized forms of ES was characterized by gene hypomethylation.
Immune status in merkel cell carcinoma: Relationships with clinical factors and independent prognostic value.
Authors: Mehran Yusuf, Jeremy T. Gaskins, Abbas Rattani, Grant McKenzie, Steven Mandish, Weston Wall, Alyssa Farley, Paul Tennant, Jeffrey Bumpous, Neal E. Dunlap
Journal: Journal of Clinical Oncology (2021)

e21509 Background: Immunosuppression (IS) is not currently considered in staging for Merkel cell carcinoma (MCC). We performed an analysis of the National Cancer Database (NCDB) to investigate immune status as an independent predictor of overall survival (OS) for patients with MCC and describe the relationship between immune status and other prognostic factors. Methods: The NCDB was queried for patients diagnosed with MCC from 2010 to 2016 with known immune status. Multivariable Cox proportional hazards models were used to define factors associated with OS. Adjuvant radiation and chemotherapy were treated as time-dependent predictors to limit immortal time bias. Secondary models were constructed to assess the association between IS etiology and OS. Multivariable logistic regression models were used to characterize relationships between immune status and other factors. Multiple imputation was used to minimize missing data bias. Results: The overall cohort included 3,882 patients (3,470 patients with known immunocompetence and 412 patients with known immunosuppression). Etiologies for profound IS included chronic lymphocytic leukemia (CLL, n = 118), Other including HIV/AIDS (n = 116), solid-organ transplant (n = 106), and Non-Hodgkin Lymphoma (NHL, n = 72). 2,864 patients (73.8%) underwent surgical nodal examination. The median follow-up time was 33 months (Interquartile Range: 18 to 55 months). The 3-year OS was lower for patients with IS (44.6%, CI 39.8-49.9%) compared to immunocompetent (IC) patients (68.7%, CI 67.1-70.4%, p &lt; .0001). IS was associated with increased adjusted mortality hazard (HR 2.36, 95% CI 2.03-2.75). Etiology of IS was associated with OS ( p = .0015) with lowest 3-year OS (32.7%, CI 24.6%-43.5%) for patients with solid-organ transplantation. IS was associated with increased odds of greater nodal burden (OR 1.70, CI 1.37-2.11) and lymphovascular invasion (OR 1.58, CI 1.23-2.03). Conclusions: Immune status was independently prognostic for OS for patients with localized MCC. Etiology of IS may be associated with differential survival outcomes. Multiple adverse prognostic factors were associated with increased likelihood of IS. Immune status and potentially etiology of IS may be useful prognostic factors to consider for future MCC staging systems.
Elective-high frequency oscillatory ventilation in preterm infants with respiratory distress syndrome: an individual patients data meta-analysis
Authors: Giovanni Vento, Valentina Vendettuoli, Filip Cools, Lisa Askie, Martin Offringa, Jeanette Asselin, Sandra Calvert, Sherry Courtney, Carlo Dani, David Durand, Dale Gerstmann, David Henderson Smart, Neil Marlow, Janet Peacock, Jane Pillow, Roger Soll, Ulrich Thome, Patrick Truffert, Michael Schreiber, Patrick Van Reempts
Journal: The Lancet (2010)
Outcomes of patients who progressed while receiving avelumab + axitinib (A + Ax) and received subsequent treatment (Tx) in JAVELIN Renal 101.
Authors: Laurence Albiges, Martin H Voss, Brian I. Rini, Gwenaelle Gravis, Marc-Oliver Grimm, Paul D. Nathan, Georg A. Bjarnason, Yoshihiko Tomita, Konstantin Penkov, Bradley McGregor, Bo Huang, Despina Thomaidou, Mariangela Mariani, Alessandra Di Pietro, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

4514 Background: There are limited data on the outcomes of patients receiving second-line (2L) therapy following immunotherapies plus tyrosine-kinase inhibitors in the first-line (1L). We describe the outcomes of patients with advanced renal cell carcinoma (aRCC) who had received 1L A + Ax in the phase 3 JAVELIN Renal 101 trial and went on to receive subsequent Tx. Methods: At the cutoff date for the third interim analysis (April 28, 2020), patients who received 1L A + Ax (n = 442) and received any subsequent lines of Tx were assessed. We report the overall survival (OS), progression-free survival on next-line systemic therapy (PFS2) per type of Tx, and duration of 2L Tx. Results: Anticancer drug therapies were received by 204/442 patients following A + Ax Tx. Of patients who received a follow-up anticancer drug Tx, 163/204 received a single agent (SA), and 41/204 received a combination Tx (CT) regimen. The most common 2L SA was cabozantinib (60/163), and the most frequent 2L CT was everolimus + lenvatinib (12/41). OS, PFS2, and duration of treatment (DOT) for the various subgroups are summarized in the table below. Analyses on additional subgroups will also be presented. Conclusions: In patients with aRCC who received 2L CT following 1L treatment with A + Ax, long-term OS and PFS2 were observed. Clinical trial information: NCT02684006. [Table: see text]
Efficacy of vincristine, irinotecan, and temozolomide (VIT) combination in adult patients with metastatic Ewing sarcoma.
Authors: Izzet Dogan, Ayca Iribas, Meltem Ekenel, Mert Basaran
Journal: Journal of Clinical Oncology (2021)

e23510 Background: The purpose of the study was to evaluate the efficacy of vincristine, irinotecan, and temozolomide (VIT) combination in heavily pretreated adult patients with metastatic Ewing sarcoma. Methods: We evaluated data of the patients with metastatic Ewing sarcoma retrospectively. We recorded clinical, pathological, radiological, and treatment features of the patients and used SPSS 25. version for statistical analysis. Kaplan-Meier and Cox regression analysis were used for survival analysis. Results: Sixteen patients were included in the study. The median age was 25 (range, 20-42) years. Eleven (68.8%) of the patients were male. The origin of the tumor was bone (75%) and soft tissue (25%). The most common primary tumor localization was pelvic (41.7%), extremity (33.3%), and other sites (25%), respectively. Six (37.5%) patients were de-novo metastatic at diagnosis. The most common metastatic site was the lung (75%). Before the vincristine, irinotecan, and temozolomide (VIT) combination, patients had received at least two different chemotherapy regimens (87.5%) and palliative radiotherapy (37.5%). Median progression-free survival was 3.4 (95% CI, 1.8-4.9) months. The partial response was observed in five (31.3%) patients, and all other patients (68.7%) had progressive disease. Grade 1-2 adverse events were observed in thirteen (81.3%) patients and grade 3-4 in five (31.3%) patients. The most common adverse events were hematological (87.5%). Median overall survival was 5.6 (95% CI, 3.6-7.5) months. Conclusions: In this study, we showed real-life efficacy of vincristine, irinotecan, and temozolomide (VIT) combination in adult patients with metastatic osteosarcoma. Toxicities were concern about in these heavily pretreated patients. Treatment options of metastatic Ewing sarcoma are limited. VIT regimen may be considered in patients who have a good performance.
Analysis of homologous recombination DNA repair gene mutation status in patients with metastatic small cell lung cancer treated with cediranib and olaparib on NCI 9881 study.
Authors: Joseph W. Kim, Marc R. Radke, Navid Hafez, Hatem Hussein Soliman, Siqing Fu, Shumei Kato, Primo "Lucky" N. Lara, Ulka N. Vaishampayan, Albiruni Ryan Abdul Razak, Dana Backlund Cardin, Pamela N. Munster, Joseph Paul Eder, Yu Shyr, S. Percy Ivy, Patricia LoRusso, Elizabeth M. Swisher
Journal: Journal of Clinical Oncology (2021)

8563 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of homologous recombination DNA repair (HRR) genes and increases sensitivity of tumors to a poly-(ADP-ribose) polymerase (PARP) inhibitor in vitro and in vivo models of breast and ovarian cancer. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumor with a deleterious mutation in HRR genes. We hypothesized that cediranib induces HRR deficient phenotype by suppressing expression of HRR genes and cediranib and olaparib combination (C+O) results in an objectives response in patients with HRR proficient (HRP) advanced solid tumors. Herein, we report the biomarker data from analyses of targeted sequencing of 84 DNA repair (DR) genes with BROCA-HR assay in patients with metastatic small cell lung cancer (mSCLC). Methods: This multi-institutional phase 2 trial enrolled patients with mSCLC previously treated with a platinum-based chemotherapy. Patients received cediranib 30mg orally (po) daily plus olaparib 200mg po twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. A tumor biopsy was obtained from the patients with safely accessible metastatic tumor. HRR deficiency (HRD) was defined as presence of a deleterious mutation in any of the 10 key HRR-related genes per BROCA-HR assay including: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, or RAD51D. Otherwise, the tumors were defined as HRR proficiency (HRP). Results: A total of 25 patients with SCLC received the study treatment. Fourteen patients had available tumor biopsy samples and/or germline available for BROCA-HR. One patient (7%) was determined to have a HRD tumor by a presence of PALB2 mutation. This patient had stable disease as a best overall response but came off study due to unequivocal clinical progression. Thirteen patients (93%) had a HRP tumor. Six of these (46%) patients had PR. Median PFS in patients with HPR tumors was 122 days. The most common gene alterations detected by BROCA-HR assay was TP53 (93%) and RB1 (79%). Other DR gene alterations noted from our study samples were MRE11, CKD12 PALB2, ERCC4, FANCB, and BAP1. Conclusions: HRD was infrequent in our mSCLC samples. C+O resulted in objective responses in 46% of mSCLC patients with HRP tumors. Mutations in TP53 and RB1 were the most common gene alterations. Further investigation in warranted to confirm this observation. Clinical trial information: NCT02498613.
Multicentre retrospective assessment of toxicity and response to immunotherapy in elderly patients with metastatic melanoma.
Authors: Shivanshan Pathmanathan, Hari S Babu, Robert Mason, Saw Htut, Zulfiquer Ali Otty, Megan Lyle, Marcin Radoslaw Dzienis
Journal: Journal of Clinical Oncology (2021)

9565 Background: The incidence of melanoma increases with age, however, elderly patients remain under-represented in landmark immunotherapy trials for metastatic melanoma. This study aims to investigate the impact of age on efficacy and toxicity of immunotherapy, and complications of immunosuppression to treat toxicity. Methods: A multicentre retrospective study involving centres in Australia [Gold Coast University Hospital, Cairns Base Hospital, Townsville University Hospital] was performed to compare the efficacy and toxicity of immunotherapy in metastatic melanoma in patients ≥70 years versus patients &lt; 70 years treated between 2015 and 2019. Data collected included: baseline demographics, PFS, OS, Grade 3 or higher (Gr3+) adverse events as per CTCAEv5, adverse events leading to discontinuation, duration of steroids used to treat toxicity and complications secondary to steroids. Comparison of survival outcomes between the groups was calculated using Kaplan Meier, Log rank test and multivariate Cox regression analysis. Fisher exact test was used to determine differences in toxicity between the two groups. Results: A total of 229 patients were included with 106 patients ≥70years and 123 patients &lt; 70 years. Baseline demographics were similar. Dual immunotherapy (ipilimumab + nivolumab) was less commonly used in patients ≥70years [13 v 38% p &lt; 0.001]. Although the median PFS was numerically higher amongst ≥70years [10.8 v 6.9months p = 0.99], the landmark PFS was not [3yr PFS: 31 v 39%; 4yr PFS: 22 v 39%]. The median OS was similar in patients ≥70 years v &lt; 70years [27.5 v 28.7 months p = 0.91], with similar landmark survival [3yr OS: 46 v 49%; 4yr OS: 42 v 49%]. Age was not associated with a difference in overall survival on multivariate analysis. There was no increase in Gr3+ adverse events in patients ≥70 years [22 v 21% p = 1.00] or discontinuation rates [26 v 20% p = 0.35]. There was one death in a patient &lt; 70years secondary to colitis. There was a significantly higher rate Gr3+ adverse events in ≥70years patients receiving dual immunotherapy [71 v 35% p = 0.029] and a similar rate of Gr3+ adverse events with PDL1 inhibitors [13 v 11% p = 0.7]. Median duration of steroids was similar in both group [15 v 17wks], as was the median duration of high dose steroids defined as greater than 10mg of prednisone [5 v 6wks]. Complications of steroids was numerically higher in the elderly population [42 v 25% p = 0.15]. The most common adverse event to immunosuppression was infection. Conclusions: Patients ≥70years received similar benefit from immunotherapy in comparison to their younger counterparts. Toxicity related to PDL1 inhibitors was similar in both groups and was higher in patients ≥70years receiving dual immunotherapy. Patients ≥70 years had a clinically significant higher rate of complications secondary to steroids.
Comparison of Clinical Features and Outcomes Between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in the United States
Authors: Yi‐Te Lee, Jasmine J. Wang, Michael Luu, Mazen Noureddin, Nicholas N. Nissen, Tushar C. Patel, Lewis R. Roberts, Amit G. Singal, Gregory J. Gores, Ju Dong Yang
Journal: Hepatology (2021)

Background and Aims Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large‐scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. Approach and Results The Surveillance, Epidemiology, and End Results Program 18 Database (2000‐2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (&lt;50 or ≥65), female sex, non‐Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P &lt; 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99‐1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80‐0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72‐0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73‐0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83‐0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93‐0.98). Conclusions We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.
Derivation and Validation of a 10-Year Risk Score for Symptomatic Abdominal Aortic Aneurysm: Cohort Study of Nearly 500 000 Individuals
Authors: Paul Welsh, Claire E. Welsh, Pardeep S. Jhund, Mark Woodward, Rosemary Brown, Jim Lewsey, Carlos A. Celis-Morales, Frederick K. Ho, Daniel F. MacKay, Jason M.R. Gill, Stuart R. Gray, S. Vittal Katikireddi, Jill P. Pell, John Forbes, Naveed Sattar
Journal: Circulation (2021)

Abdominal aortic aneurysm (AAA) can occur in patients who are ineligible for routine ultrasound screening. A simple AAA risk score was derived and compared with current guidelines used for ultrasound screening of AAA.United Kingdom Biobank participants without previous AAA were split into a derivation cohort (n=401 820, 54.6% women, mean age 56.4 years, 95.5% White race) and validation cohort (n=83 816). Incident AAA was defined as first hospital inpatient diagnosis of AAA, death from AAA, or an AAA-related surgical procedure. A multivariable Cox model was developed in the derivation cohort into an AAA risk score that did not require blood biomarkers. To illustrate the sensitivity and specificity of the risk score for AAA, a theoretical threshold to refer patients for ultrasound at 0.25% 10-year risk was modeled. Discrimination of the risk score was compared with a model of US Preventive Services Task Force (USPSTF) AAA screening guidelines.In the derivation cohort, there were 1570 (0.40%) cases of AAA over a median 11.3 years of follow-up. Components of the AAA risk score were age (stratified by smoking status), weight (stratified by smoking status), antihypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and diabetes. In the validation cohort, over 10 years of follow-up, the C-index for the model of the USPSTF guidelines was 0.705 (95% CI, 0.678-0.733). The C-index of the risk score as a continuous variable was 0.856 (95% CI, 0.837-0.878). In the validation cohort, the USPSTF model yielded sensitivity 63.9% and specificity 71.3%. At the 0.25% 10-year risk threshold, the risk score yielded sensitivity 82.1% and specificity 70.7% while also improving the net reclassification index compared with the USPSTF model +0.176 (95% CI, 0.120-0.232). A combined model, whereby risk scoring was combined with the USPSTF model, also improved prediction compared with USPSTF alone (net reclassification index +0.101 [95% CI, 0.055-0.147]).In an asymptomatic general population, a risk score based on patient age, height, weight, and medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. Further development and validation of risk scores to detect asymptomatic AAA are needed.