tbuckley/cabot-search huggingface dataset:
<i>CXCL10</i> potentiates immune checkpoint blockade therapy in homologous recombination-deficient tumors
Authors: Zhiwen Shi, Jianfeng Shen, Junjun Qiu, Qingguo Zhao, Keqin Hua, Hongyan Wang
Journal: Theranostics (2021)

Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability, and has been proven to be a biomarker for target therapy. However, until now, no research has explored the changes in the transcriptomics landscape of HRD tumors. Methods: The HRD score was established from SNP array data of breast cancer patients from the cancer genome atlas (TCGA) database. The transcriptome data of patients with different HRD scores were analyzed to identify biomarkers associated with HRD. The candidate biomarkers were validated in the gene expression omnibus (GEO) database and immunotherapy cohorts. Results: Based on data from the gene expression profile and clinical characteristics from 1310 breast cancer patients, including TCGA database and GEO database, we found that downstream targets of the cGAS-STING pathway, such as CXCL10, were upregulated in HRD tumors and could be used as a predictor of survival outcome in triple-negative breast cancer (TNBC) patients. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that the expression of CXCL10 was positively correlated with neoantigen load and infiltrating immune cells. Finally, in vivo experimental data and clinical trial data confirmed that the expression of CXCL10 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Conclusions: Together, our study not only revealed that CXCL10 is associated with HRD but also introduced a potential new perspective for identifying prognostic biomarkers of immunotherapy.
Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients
Authors: Hector Rincon-Arevalo, Mira Choi, Ana-Luisa Stefanski, Fabian Halleck, Ulrike Weber, Franziska Szelinski, Bernd Jahrsdörfer, Hubert Schrezenmeier, Carolin Ludwig, Arne Sattler, Katja Kotsch, Alexander Potekhin, Yidan Chen, Gerd R. Burmester, Kai-Uwe Eckardt, Gabriela Maria Guerra, Pawel Durek, Frederik Heinrich, Marta Ferreira-Gomes, Andreas Radbruch, Klemens Budde, Andreia C. Lino, Mir-Farzin Mashreghi, Eva Schrezenmeier, Thomas Dörner
Journal: Science Immunology (2021)

Patients with kidney failure are at increased risk of SARS-CoV-2 infection, making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DPs) or kidney transplant recipients (KTRs) compared with healthy controls (HCs). We studied humoral and B cell responses of 35 HCs, 44 DPs, and 40 KTRs. Markedly impaired anti-BNT162b2 responses were identified among KTRs and DPs compared with HCs. In DPs, the response was delayed (3 to 4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5 and 68.2%, respectively. In contrast, KTRs did not develop IgG responses except for one patient who had a previous unrecognized infection and developed anti-S1 IgG. Most antigen-specific B cells (RBD + ) were identified in the plasmablast or post-switch memory B cell compartments in HCs, whereas RBD + B cells were enriched among pre-switch and naïve B cells from DPs and KTRs. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.
Positive association between <i>Helicobacter pylori</i> infection and pancreatic cancer: A case-control study.
Authors: Steve Otieno, Amit L Jain, Omar Mohammed, Jay R Patel, John Collyer, Peter Deleeuw, Arshad Husain, Alva Bowen Weir
Journal: Journal of Clinical Oncology (2021)

e16243 Background: Pancreatic adenocarcinoma is a malignancy with a very poor prognosis. The 5-year overall survival is about 9%. Helicobacter pylori ( H. pylori) is a known risk factor for gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Whether H.pylori is a risk factor for pancreatic adenocarcinoma is still unclear. Previous observational retrospective studies trying to see if there is an association between H.pylori and pancreatic adenocarcinoma have used serology as a marker for H.pylori infection, but these have yielded mixed results. We seek to probe the association of H.pylori infection and pancreatic adenocarcinoma in a case-control study using histology for H.pylori bacteria from esophagogastroduodenoscopy (EGD) biopsies. Methods: A database for patients diagnosed with pancreatic adenocarcinoma at the Veterans Affairs Medical Center in Memphis, TN, from 1988 to 2018 was analyzed to obtain suitable cases. Pathology was reviewed to confirm the diagnosis and then the charts were reviewed to determine if the patient had undergone an EGD and if biopsies done obtained were tested for H.pylori. H.pylori positivity was determined using Steiner staining of the biopsy samples. 402 charts were reviewed and 51 cases meeting the above criteria were obtained. Controls were obtained by reviewing charts for all EGDs that were tested for H.pylori. Care was taken to make sure patients did not have any history of pancreatobiliary malignancy. 130 matched controls fit the screening criteria. Univariate and multivariate logistic regression analysis was done to analyze the risk factors. Results: Significantly more subjects in the case group (53%) were found to have H.Pylori infection compared to the control group (18%). Risk factors associated with pancreatic cancer in the literature, including age, race, smoking history, obesity, alcohol consumption, chronic pancreatitis, and diabetes, were analyzed using multivariate logistic regression. The results revealed that pancreatic cancer was significantly associated with a positive family history of pancreatic cancer (OR = 11.2, 95%CI 2.8-44.4, p = 0.001) and H.Pylori infection (OR = 5.5), 95%CI 2.4-12.7,p &lt; 0.001). Conclusions: A positive association was found between H.pylori infection and pancreatic adenocarcinoma.
A comprehensive literature review and meta-analysis on prevalence of BRCAm, HRRm and HRD+ across tumor types.
Authors: Changxia Shao, Jun Wan, Huilin Tang, Andrew Marley, Chelsey Miller, Madeline Brown, Yiqing Song, Jiali Han, Gboyega Adeboyeje
Journal: Journal of Clinical Oncology (2021)

10589 Background: Poly (ADP-ribose) polymerase inhibitor (PARPi) may have broad application in the treatment of cancer patients with mutations in BRCA (BRCAm) or other homologous recombination repair genes (HRRm) or with homologous recombination deficiency positive (HRD+). A literature review and meta-analysis were conducted to evaluate the prevalence of BRCAm, HRRm, and HRD+ across tumor types. Methods: Comprehensive searches for eligible studies in Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane reviews were performed in May 2020 to capture studies published in English, within 10 years for manuscripts and 3 years for abstracts across geographic regions. A weighted summary estimate was calculated for BRCAm. A summary estimate with corresponding 95% CI was calculated using random-effects models for HRD+ and HRRm. Results: A total of 342 eligible studies with at least 100 samples were included in the review of BRCA1/2m prevalence, containing a total of over 469,000 samples across 24 tumor types. The most frequent indications examined in the included studies were breast (study number n = 144), ovarian (53), prostate (17) and pancreatic (11) cancers. The prevalence of germline BRCA1m (gBRCA1m) and gBRCA2m was 5% and 4% for breast, 12% and 5% for ovarian, 1% and 3% for prostate, and 1% and 4% for pancreatic cancer, respectively. The prevalence of somatic BRCA1m (sBRCA1m) and somatic BRCA2m (sBRCA2m) was 3% and 3% for breast, 7% and 5% for ovarian, 3% and 5% for prostate, and 1% and 3% for pancreatic cancer, respectively. Few studies evaluated endometrial, lung and colon cancers, the prevalence of gBRCA1m or gBRCA2m was generally less than 1%, and the prevalence of sBRCA1m and sBRCA2 ranged 1 to 3%. Seven publications were identified where HRD+ was defined by either BRCAm or genomic instability score (GIS) ≥ 42 across breast, ovarian and pancreatic cancers. The overall HRD+ prevalence was 56% (95%CI: 48, 64), with similar prevalence observed across the 3 tumor types and was 50% (34, 66) for the 3 studies only counting GIS≥ 42. 194 studies across 26 tumor types were identified that examined HRRm as mutations in one or more HRR genes other than BRCA1/2m. The definitions of HRRm varied substantially across the studies, and ATM (2.8%), CHEK2 (1.6%), and PALB2 (1.6%) accounted for most of the observed mutations among HRR genes. Conclusions: Prevalence of BRCAm, HRRm and HRD+ varied by cancer type. This comprehensive meta-analysis enriches the knowledge in this field and demonstrates the need to standardize the measurement of HRRm and HRD.Understanding the prevalence of these biomarkers could have important clinical implications.
Impact of COVID-19 pandemic in hospitalizations due to brain tumors from the epicenter of Latin America.
Authors: Isabella Batista Martins Portugal, Luis Eduardo Werneck De Carvalho, Jean Henri Schoueri, Leandro Fórnias Machado Rezende, Fernando Luiz Affonso Fonseca, Gerson Ferrari, Luiz Carlos de Abreu, Fernando Adami
Journal: Journal of Clinical Oncology (2021)

e18785 Background: The novel coronavirus disease 2019 (COVID-19) pandemic has disrupted health care systems worldwide. In Brazil, the disease had its first case in the city of São Paulo, thus being the starting point and epicenter of this disease in Latin America. Neurological features are currently well recognized in COVID-19 indicating the neurotropic nature of the virus and include anosmia, myalgia, myositis, encephalitis, meningitis, cerebrovascular disease, Guillain–Barré syndrome, and post-infectious myelitis. CNS tumors though relatively rare (&gt; 2% of all cancers) are a relevant source of cancer-related morbi-mortality worldwide. Although studies have reported higher COVID-19 severity in cancer patients, the consequences of the pandemic on health care for CNS tumors remain inconclusive and will probably be felt for decades. This study aimed to determine the impact of pandemic on the hospital admissions (HA) due to CNS tumors in the city of São Paulo, Brazil. Methods: This is a cross-sectional study of the HAs due to CNS tumors in the city of São Paulo comparing the outbreak period (January-June 2020) and a pre-pandemic corresponding period of the years 2017-2019. Data were obtained from the Brazilian Unified Health System - Hospital Information System database according to the chapter II of the International Classification of Diseases - 10th revision (ICD-10). Linear regression was used to analyze the relationship between the incidence of HAs and time (months). Results: A significant reduction in HAs due to CNS tumors was observed during the outbreak period (January-June 2020). Benign neoplasm of brain and other parts of CNS (-2, CI -2 to -1) and malignant neoplasm of brain (-5, CI -7 to -3) showed to be remarkably affected (see table). To our knowledge, this is the first scientific report of significant reduction of HAs due to CNS tumors during COVID-19 era. Conclusions: Our findings seem to be associated to delayed oncological diagnose and care to CNS tumor patients during the lockdown and health system collapse. A rebound help-seeking effect as well as more severe complications may present in the post‐pandemic. Further studies are needed to evaluate the impact of the ongoing pandemic in CNS neoplasms in order to strategically corroborate public health actions for short- and long-term implications of COVID-19 pandemic. [Table: see text]
Multivalent state transitions regulate the intratumoral composition of small cell lung carcinoma.
Authors: Priyanka Gopal, Aaron Petty, Rohan Bareja, Titas Bera, Kevin Rogacki, Jyoti D. Patel, Craig Peacock, Mohamed E. Abazeed
Journal: Journal of Clinical Oncology (2021)

e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. Methods: We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify transcriptional state heterogeneity. Using the expression of the Ascl1, NeuroD1, and Yap1 as markers of well-conserved SCLC states, we developed a state-of-the-art fluorescent platform that can directly measure single-cell state transitions in a multi-layered ecosystem using tandemly integrated reporters. We modeled population dynamics using a discrete time Markov chain and directly measure single-cell state transitions. Results: We show significant cell-state heterogeneity in several SCLC primary tumors, patient-derived xenografts (PDX), and ex vivo cultures. These states comprise distinct subpopulations marked by the master regulatory transcription factors (TFs) Ascl1, NeuroD1, and Yap1. Ex vivo, the 3 TFs are associated with suspension aggregates of small neuroendocrine cells, pre-suspension (loosely adherent) aggregates, and large mesenchymal cells with visible cytoplasm and spindle-like membrane extensions, respectively. We have observed equilibria in cell-state proportions in SCLC tumors both in vivo (PDX) and ex vivo. In addition, we have shown that the “elasticity” of SCLC responses, measured as the extent of clinical response during chemotherapy followed by the time to relapse from the end of therapy, is dependent on tumor TF levels. These observations suggest that mechanistic modeling of intra-tumoral state dynamics is of high clinical relevance. Conclusions: Our integrative approach is poised to formulate and validate a unified model of cellular states and program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs, their plasticity, and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming will create a new scientific canvas for the study of this highly lethal disease.
Accelerated epigenetic age among HIV-infected Nigerian women with invasive cervical cancer.
Authors: Jonah Musa, Kyeezu Kim, Yinan Zheng, Lois B. Travis, Demirkan Gursel, Olugbenga A. Silas, Fatimah Biade Abdulkareem, Godwin Imade, Alani Akanmu, Jian-Jun Wei, Masha Kocherginsky, Kwnag-Youn Kim, Firas Hazem Wehbe, Chad Achenbach, Rose Anorlu, Melissa A. Simon, Atiene Sagay, Folasade Ogunsola, Robert Murphy, Lifang Hou
Journal: Journal of Clinical Oncology (2021)

e17504 Background: Invasive cervical cancer (ICC) is one of the HIV-associated cancers with a high burden in Nigeria. ICC occurs at relatively younger age in HIV infected women, with HIV known to promote aging and related diseases, including cancer. DNA methylation changes with increasing age, various health-related exposures, and age-related health outcomes, suggesting a role of DNA methylation in biological aging and disease. We sought to understand the effect of HIV infection on epigenetic age acceleration (EpiAgeAccel) in Nigerian women with ICC. Methods: Epigenetic age (EpiAge) was estimated by Horvath’s calculator using genome-wide methylation data in 116 cervical tissue samples from three groups of women: a) HIV positive with ICC (n=39); b) HIV positive and cancer-free (n=53); and c) HIV negative with ICC (n=24). EpiAgeAccel was computed as the regression residuals of EpiAge against chronological age (ChronAge), representing the independent deviation of EpiAge from ChronAge. We compared EpiAgeAccel across the 3 HIV/ICC groups using multiple linear regressions adjusting for ChronAge, education, parity, employment, cancer stage, body mass index, and study site. Among the ICC women, we compared EpiAgeAccel between 26 tumor tissues and their surrounding normal tissues using paired t-tests, stratified by HIV status. Results: EpiAgeAccel among HIV positive women with ICC was 4.5 years higher than HIV positive and cancer-free women (p=0.019). We did not find substantial differences in EpiAgeAccel between HIV-positive women with ICC and HIV-negative women with ICC. EpiAgeAccel was 7.9 and 2.9 years higher in tumor tissues compared to the surrounding normal tissues among HIV positive women (p=0.021) and negative women (p=0.295), respectively. Conclusions: EpiAge is accelerated in cervical tissue of HIV-infected women with ICC. EpiAgeAccel may be a potential biomarker for ICC screening and early detection for women living with HIV in low- and middle-income countries.
Cold Spells and Cause-Specific Mortality in 47 Japanese Prefectures: A Systematic Evaluation
Authors: Chaochen Ma, Jun Yang, Shoji F. Nakayama, Miyuki Iwai-Shimada, Chau-Ren Jung, Xian-Liang Sun, Yasushi Honda
Journal: Environmental Health Perspectives (2021)

Many studies have investigated the devastating health effects of heat waves, but less is known about health risks related to cold spells, despite evidence that extreme cold may contribute to a larger proportion of deaths.We aimed to systematically investigate the association between cold spells and mortality in Japan.Daily data for weather conditions and 12 common causes of death during the 1972-2015 cold seasons (November-March) were obtained from 47 Japanese prefectures. Cold spells were defined as ≥2 consecutive days with daily mean temperatures ≤5th percentile for the cold season in each prefecture. Quasi-Poisson regression was combined with a distributed lag model to estimate prefecture-specific associations, and pooled associations at the national level were obtained through random-effects meta-analysis. The potential influence of cold spell characteristics (intensity, duration, and timing in season) on associations between cold spells and mortality was examined using a similar two-stage approach. Temporal trends were investigated using a meta-regression model.A total of 18,139,498 deaths were recorded during study period. Mortality was significantly higher during cold spell days vs. other days for all selected causes of death. Mortality due to age-related physical debilitation was more strongly associated with cold spells than with other causes of death. Associations between cold spells and mortality from all causes and several more specific outcomes were stronger for longer and more intense cold spells and for cold spells earlier in the cold season. However, although all outcomes were positively associated with cold spell duration, findings for cold spell intensity and seasonal timing were heterogeneous across the outcomes. Associations between cold spells and mortality due to cerebrovascular disease, cerebral infarction, and age-related physical debility decreased in magnitude over time, whereas temporal trends were relatively flat for all-cause mortality and other outcomes.Our findings may have implications for establishing tailored public health strategies to prevent avoidable cold spell-related health consequences. https://doi.org/10.1289/EHP7109.
Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.
Authors: Laercio Lopes Da Silva, Robin Park, Pedro Nazareth Aguiar, Eduardo Edleman Saul, Benjamin Haaland, Gilberto Lopes
Journal: Journal of Clinical Oncology (2021)

e16032 Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.
Imatinib Suspension and Validation Study: Results from the Isav Study at 62 Months
Authors: Silvia Mori, Philipp D. le Coutre, Elisabetta Abruzzese, Bruno Martino, Ester Pungolino, Chiara Elena, Micaela Bergamaschi, Sarit Assouline, Eros Di Bona, Antonella Gozzini, Marcio Andrade, Fabio Stagno, Alessandra Iurlo, Michela Luciani, Eleonora Parisse, Dong-Wook Kim, Alessandra Pirola, Michela Viltadi, Maria Luisa Bonanomi, Patrizia Crivori, Rocco Piazza, Carlo Gambacorti-Passerini
Journal: Blood (2017)