tbuckley/cabot-search huggingface dataset:
Assessment of ethnic difference in the incidence of thrombocytopenia induced by trastuzumab emtansine (T-DM1): A meta-analysis.
Authors: Jingyi Zhang, Yaning Yang, Ru Chen, Shanshan Chen, Jiayu Wang, Yang Luo, Fei Ma, Binghe Xu, Ying Fan
Journal: Journal of Clinical Oncology (2021)

e15096 Background: Trastuzumab emtansine (T-DM1) has been proved its value and efficacy in advanced metastatic cancer disease as well as in the adjuvant setting. However, there is an increasing concern in T-DM1-induced thrombocytopenia (TCP), which also showed difference of incidence in races. This meta-analysis, combining available data from all single-agent T-DM1 studies to date, aimed to evaluate the incidence of treatment-related thrombocytopenia of T-DM1 and the differences between Asian and non-Asian patients. Methods: We conducted a systematic search of the relevant published clinical studies of T-DM1 that reported safety profile including thrombocytopenia, from 1980 to March of 2020 using PubMed, Embase, and the Cochrane database. Screening and data extraction were conducted by two independent reviewers. Pooled-effect estimates calculated with fixed-effects or random-effects model were expressed as incidence with 95% CIs. Results: A total of 29 studies involving 6188 patients were included. The incidence of all-grade thrombocytopenia in Asian patients was 0.39 (95%CI 0.11-0.67) and 0.29 (95%CI 0.23-0.35) in non-Asian patients. And the incidence of the grade 3 or higher thrombocytopenia in Asians was 0.20 (95%CI 0.10-0.29), in non-Asians was 0.02 (95%CI 0.01-0.03). Gastrointestinal cancer type and the dose of 2.4 mg/kg Q3W T-DM1 treatment were both associated with the higher incidence of grade 3 or higher thrombocytopenia. Conclusions: Asian patients have the higher risk of thrombocytopenia induced by T-DM1. Clinicians should have an awareness of careful observation in platelet counts when patients receive T-DM1 therapy.
Retrospective validation of a pretreatment serum protein profile in metastatic non-small cell lung cancer patients treated with a pembrolizumab containing regime as first line of treatment.
Authors: Wouter W. Mellema, Edwin A. Basak, Heinrich Roder, Joanna Roder, Robert W. Georgantas, Egbert F. Smit, Joachim Aerts
Journal: Journal of Clinical Oncology (2021)

e21135 Background: There is an unmet need for reliable biomarkers predictive of treatment outcome with immunotherapy in patients with non-small cell lung cancer (NSCLC). The aim of our study is to examine, in front-line patients, the potential utility of a proteomic signature, PIR (primary immune response), developed and validated in 2 nd line patients (M. Muller Clin Cancer Res. 2020 Oct 1;26(19):5188-5197. doi: 10.1158/1078-0432.CCR-20-0538. Epub 2020 Jul 6) as a predictive biomarker of response to treatment with pembrolizumab in a first-line setting. Methods: Pretreatment serum samples were collected from stage IV NSCLC patients treated with a pembrolizumab-containing regimen in first-line at the Netherlands Cancer Institute and Erasmus Medical Center between 2016 and 2020. Data on demographics, ECOG performance status (PS), PD-L1 expression, treatment, progression free survival (PFS) and overall survival (OS) were collected. The PIR test was performed and classified in two groups: resistant vs. intermediate/sensitive (not-resistant). Results: Serum samples of 119 patients were available for analysis. Median age was 65 (36-82) years; 49% female; PS 0-1 80%. 45 samples failed QC and were excluded allowing for the analysis of 74 patients: 24 receiving pembrolizumab monotherapy, and 50 receiving a combination of chemotherapy and pembrolizumab. Overall, median PFS was 5.3 months in the resistant group vs. 9.0 months in the not-resistant group (HR 0.60 (95%CI 0.33-1.08; p = 0.09). In patients receiving pembrolizumab monotherapy, the resistant group had a trend toward shorter PFS (median PFS 3.4 months vs. 10.3 months) then the non-resistant group, (HR 0.42 (95% CI 0.15-1.21; p = 0.11))). No difference was observed in patients treated with a combination of chemotherapy and pembrolizumab (median PFS 5.8 months vs. 9.0 months, respectively; HR = 0.65 (95% CI 0.31-1.36; p = 0.25). Median OS was not reached vs 17.0 months, respectively (HR 0.90 (95% CI 0.34-2.36; p = 0.83)). We did not observe any significant association between performance score and PD-L1 expression, and the PIR test. Conclusions: These data encourage further study of PIR as a predictive biomarker for first-line treatment with pembrolizumab in NSCLC patients.
Effect of paracentesis on the survival of patients with terminal cancer and ascites: A propensity score-weighted analysis of the EASED study.
Authors: Ken Masuda, Hiroto Ishiki, Naosuke Yokomichi, Takuhiro Yamaguchi, Tetsuya Ito, Hana Takatsu, Koji Amano, Shuji Hiramoto, Takuhiro Yamaguchi, Takashi Kawaguchi, Masanori Mori, Yosuke Matsuda, Takashi Yamaguchi
Journal: Journal of Clinical Oncology (2021)

e24063 Background: Malignant ascites (MA) is associated with progressive deterioration in quality of life and poor prognosis of patients with cancer. Paracentesis is among the most widely utilised treatments for MA. However, reports on the usefulness of paracentesis in patients with MA are limited. Thus, this study aimed to investigate whether paracentesis affects the duration of survival in such patients. Methods: We performed a post - hoc analysis of a prospective multicentre observational study that investigated the dying process and end-of-life care in patients with terminal cancer, who were admitted to 23 palliative care units in Japan. Survival duration was compared between patients who did (paracentesis group) and did not undergo paracentesis (non-paracentesis group). We used the inverse probability of treatment weighting (IPTW) method to control for baseline covariates between the two groups. Furthermore, subgroup analyses were performed to investigate the IPTW-adjusted hazard ratio (HR) of the paracentesis and non-paracentesis groups according to some of the baseline covariates, including age, sex, Karnofsky Performance Status, primary tumor site, liver dysfunction, and renal dysfunction. Results: Among the 1,896 patients, who were initially enrolled, 568 with ascites were included in the study cohort. Eighty-five (15.0%) patients underwent paracentesis. The most common primary tumour site was the gastrointestinal tract (51.9%, n = 295), followed by the pancreas (22.7%, n = 129). The non-adjusted median durations of survival were 22 days (95% confidence interval [CI]: 16–25) and 12 days (95% CI: 11–13) in the paracentesis and non-paracentesis groups, respectively (HR: 0.69, [95% CI: 0.54–0.88]; p = 0.003). The IPTW-adjusted median durations of survival were 22 days (95% CI: 16–25) and 16 days (95% CI: 12–22) in the paracentesis and non-paracentesis groups, respectively (HR: 0.89, 95% CI: 0.64–1.24; p = 0.492). There were no serious adverse events in the paracentesis group. According to the baseline covariates, a weighted subgroup analysis was performed to compare the survival of patients in the non-paracentesis and paracentesis groups. There was no significant heterogeneity across all subgroups. Paracentesis was not associated with a significant survival risk in any of the subgroups. Conclusions: Paracentesis does not negatively affect the survival of patients with cancer and MA; hence, it can be used as a standard treatment in palliative care settings.
Genomic alterations for novel targeted therapies in pancreatobiliary cancers from real-world data.
Authors: Kumiko Umemoto, Hiroyuki Yamamoto, Ritsuko Oikawa, Hiroyuki Takeda, Ayako Doi, Yoshiki Horie, Takashi Ogura, Takuro Mizukami, Naoki Izawa, Jay A. Moore, Ethan Sokol, Yu Sunakawa
Journal: Journal of Clinical Oncology (2021)

4124 Background: Cancers of the pancreas and biliary tract remain one of the unfavorable malignant tumors with few driver genomic alterations. Tumor-agnostic approaches are promising for cancers with poor prognosis, with some potentially actionable alterations, such as BRCA1/2 mutations, ERBB2 amplification, MSI-High, or tumor mutational burden (TMB)-High. However, co-existing alterations, clinical significance of other genomic alterations, or frequency of alterations by clinical and genomic background are unclear. Here we investigated the genomic profile in a large cohort of advanced pancreatobiliary cancers to help refine and discover new targets for improved cancer therapies. Methods: Comprehensive genomic profiling was performed at Foundation Medicine, on patients with RWD tested during the course of routine clinical care. Hybrid capture was carried out on up to 395 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. 16,913 pancreatic cancer (PC) patients and 3,031 biliary tract cancer (BTC) patients were available for analyses and were stratified by age (≥40/ &lt; 40), MSI status, TMB status (High ≥10/Low &lt; 10 Muts/Mb), and select gene alterations. Using a chi-square test with Yate’s correction, frequencies of genetic alterations were analyzed according to clinical or genomic background. Results: KRAS (84.8%), TP53 (73.3%), CDKN2A (51.2%), CDKN2B (26.5%), and SMAD4 (23.2%) were frequently altered in PC patients, versus TP53 (60.6%), CDKN2A (33.5%), KRAS (27.1%), CDKN2B (20.6%) and SMAD4 (16.9%) in BTC patients. The frequency of MSI-High and TMB-High in BTC was 1.2% and 5.7%, respectively, while these were lower in PC (0.48% and 2.1%, respectively). In PC patients, the KRAS alteration rate was significantly lower in both MSI-High (57.3%, P&lt; 0.001) and TMB-High populations (51.3%, P&lt; 0.001). In BTC patients, the rate of ERBB2 amplification was 6.4% in TMB-High and 8.6% in TMB-Low population. Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplified tumors but not in those without ERBB2 amplified tumors. In patients of pediatric/adolescents and young adults ( &lt; 40 years old), the mutation rate of KRAS/ TP53/ CDKN2A/ SMAD4 was lower, and FGFR2 rearrangement (4%) was observed in PC patients; GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%), FGFR2 (5.6%) were observed in BTC patients. Conclusions: A large real-world dataset showed differences in genomic landscape according to clinical or genomic background, and some potential targets for the development of novel drugs in advanced pancreatobiliary cancers. These findings may lead to the improvement of cancer therapies in PC and BTC patients with poor prognosis.
Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom
Authors: Emma Pritchard, Philippa C. Matthews, Nicole Stoesser, David W. Eyre, Owen Gethings, Karina-Doris Vihta, Joel Jones, Thomas House, Harper VanSteenHouse, Iain Bell, John I. Bell, John N. Newton, Jeremy Farrar, Ian Diamond, Emma Rourke, Ruth Studley, Derrick Crook, Tim E. A. Peto, A. Sarah Walker, Koen B. Pouwels
Journal: Nature Medicine (2021)

The effectiveness of COVID-19 vaccination in preventing new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the general community is still unclear. Here, we used the Office for National Statistics COVID-19 Infection Survey-a large community-based survey of individuals living in randomly selected private households across the United Kingdom-to assess the effectiveness of the BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca; ChAdOx1) vaccines against any new SARS-CoV-2 PCR-positive tests, split according to self-reported symptoms, cycle threshold value (<30 versus ≥30; as a surrogate for viral load) and gene positivity pattern (compatible with B.1.1.7 or not). Using 1,945,071 real-time PCR results from nose and throat swabs taken from 383,812 participants between 1 December 2020 and 8 May 2021, we found that vaccination with the ChAdOx1 or BNT162b2 vaccines already reduced SARS-CoV-2 infections ≥21 d after the first dose (61% (95% confidence interval (CI) = 54-68%) versus 66% (95% CI = 60-71%), respectively), with greater reductions observed after a second dose (79% (95% CI = 65-88%) versus 80% (95% CI = 73-85%), respectively). The largest reductions were observed for symptomatic infections and/or infections with a higher viral burden. Overall, COVID-19 vaccination reduced the number of new SARS-CoV-2 infections, with the largest benefit received after two vaccinations and against symptomatic and high viral burden infections, and with no evidence of a difference between the BNT162b2 and ChAdOx1 vaccines.
Association of Fetal Exposure to Newer Antiseizure Medications With Neurodevelopment
Authors: Torbjörn Tomson, Rebecca Bromley
Journal: JAMA Neurology (2021)

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BMP4 to increase connexin43 expression and interaction with β-catenin in glioblastoma stem cells.
Authors: Natalia Sutherland, Stacie Deaver, Taylor Wynne, Christina Wheeler, Samy Lamouille
Journal: Journal of Clinical Oncology (2021)

e14045 Background: Glioblastoma multiforme (GBM) is the most commonly occurring and most lethal primary central nervous system tumor. Treatment for GBM involves an aggressive combination of surgical resection, radiotherapy, and temozolomide chemotherapy. While intensive therapy has shown marginal improvement in prognosis, the median survival for GBM patients remains between twelve to fourteen months. The aggressiveness of GBM is attributed to the cellular heterogeneity and the invasive nature of the tumor, as well as the presence of glioblastoma cancer stem cells (GSCs). GSCs are a subpopulation of slowly dividing cells within GBM tumors that can survive chemotherapy and irradiation treatments targeting proliferating cells. The remaining quiescent GSCs can then enter an active state of self-renewal and differentiation through asymmetric division that contributes to tumor recurrence by recapitulating the heterogeneous tumor in relatively short order. Previously, we have identified a non-junctional, tumorigenic function for the gap junction protein connexin43 (Cx43) through its interaction with microtubules in GSCs. However, when GSCs are differentiated, this interaction decreases while Cx43 expression increases, suggesting an alternate function for Cx43. Bone Morphogenic Proteins (BMPs) have been implicated in GSC differentiation and their role in human tumorigenesis has remained largely unknown in GSCs. In this study, we aim to determine the effect of BMP on Cx43 expression and localization in GSCs. Methods: In this study, we used GBM patient-derived GSCs isolated from two GBM tumors following resection at Carilion Clinic, and maintained in stem cell medium. The effect of BMP4 signaling on Cx43 expression and localization in GSCs was determined using RT-qPCR, immunofluorescence, western blot, and co-immunoprecipitation. Results: Preliminary data show that BMP4 treatment increases Cx43 expression at the protein and mRNA levels through nuclear translocation and transcriptional activity of β-catenin. In addition, BMP4 treatment increases the interaction between Cx43 and β-catenin at the plasma membrane. Further studies are underway to determine the implications of disrupting Cx43/β-catenin interaction in GSC differentiation. Conclusions: While additional experiments are needed, our findings may be adapted as a prognostic indicator to determine patients’ susceptibility to traditional GBM therapies, and aid in novel therapeutic development to eradicate GSCs in GBM and prevent tumor recurrence following treatment.
Association of genomic characterization with clinical benefits of anti-PD-1 antibody combined with FOLFOX as neoadjuvant therapy on locally advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Ying Liu, Guangsen Han, Hongle Li, Yuzhou Zhao, Zhi Li, Zhentian Liu, Jing Zhuang, Gangcheng Wang, Baodong Li, Jinbang Wang, Zhimeng Li, Qingxin Xia, Chengjuan Zhang, Juan Yu, Xuan Gao, Ke Li, Shuning Xu, Lei Qiao, Gaizhen Kuang, Danyang Li
Journal: Journal of Clinical Oncology (2021)

e16025 Background: Anti-PD-1 antibody combined with chemotherapy showed promising efficacy in gastric adenocarcinoma. However, little is known about biomarkers that identify clinical response. Here, we focus on genomic alteration patterns to predict response of neoadjuvant immunotherapy in patients with locally advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). Methods: Patients with locally advanced GC/GEJC were received 4 cycles of FOLFOX plus anti-PD-1 antibody (camrelizumab) as neoadjuvant therapy in the study. We prospectively conducted whole exome sequencing (WES) in paired biopsy specimens from enrolled patients at baseline. According to Tumor Regression Grading (TRG) assessment by postoperative pathology, patients were classified into group A (TRG0 &amp; TRG1) and group B (TRG2 &amp; TRG3). Results: We eventually performed WES in 23 patients who had adequate available tumor tissues. The clinical characterizations were not significantly different between two groups. All 23 cases were microsatellite stable (MSS). Alterations of AHNAK2 (50.0%/6.67%), TG (50.0%/6.67%), CTNNB1 (37.5%/0.0%) and ZFHX2 (37.5%/0.0%) significantly enriched in group A (n = 8) compared to group B (n = 15).Furthermore, we inspecting 10 hallmark oncogenic pathways, alterations of WNT pathway also occurred more frequently in group A than those of group B. Genomic alterations in WNT pathway were identified in 5 of 23 cases (21.74%), of which the most frequently mutated genes were CTNNB1 (13.04%), LRP5 (8.69%) and RNF43 (8.69%). Tumor mutation burden (TMB, p = 0.357), whole genome duplication (WGD) status (p = 0.667), copy number variant burden (p = 0.825), fraction of loss of heterozygosity (LOH) in chromosome level (p: 0.07-1), tumor neoantigen burden (TNB) (p = 0.65), HLA type (p: 0.49-1) and HLA LOH status (p: 0.37-1) were not significantly associated with neoadjuvant therapy response. Conclusions: Aberrant activation of WNT pathway was reported to be associated with immune evasion. Our study demonstrated that CTNNB1/WNT-pathway-mut may be a promising predictor for clinical response of neoadjuvant immutherapy in GC/GEJC. Clinical trial information: NCT03939962.
The SGLT-2 inhibitor dapagliflozin reduces cell death and apoptosis in cardiomyocytes exposed to trastuzumab and doxorubicin through NLRP3-mediated pathways.
Authors: Nicola Maurea, Vincenzo Quagliariello, Michelino De Laurentiis, Ernesta Cavalcanti, Andrea Paccone, Simona Buccolo, Martina Iovine, Gerardo Botti
Journal: Journal of Clinical Oncology (2021)

e15041 Background: The clinical trial “DECLARE-TIMI 58” (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. We aimed to study if dapagliflozin could exerts cardioprotective and anti-inflammatory effects in doxorubicin and trastuzumab-induced cardiotoxicity through the analysis of multiple biochemical mechanisms. Methods: HL-1 adult cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity (MTS assay), study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), and of intracellular Ca 2+ homeostasis. Moreover, anti-inflammatory studies were also performed (protein expression of NLRP3 inflammasome; p65/NF-κB and cytokines involved in cardiotoxicity (interleukins 1β, 8 and 6). Results: Dapagliflozin increases significantly the cardiomyocytes viability during exposure to doxorubicin and trastuzumab. Its cardioprotective properties are explainable by the reduction of intracellular Ca 2+ overload (-47,6% vs cells treated only to anticancer drugs; p&lt;0,001), of the lipid peroxidation phenomena (mean reduction of 35-43 % compared to cells exposed only to anticancer drugs; p&lt;0,001). Moreover, cardiomyocytes exposed to dapagliflozin during anticancer drugs have a reduced expression of pro-inflammatory cytokines involved in cardiotoxicity (- 37,3 % for interleukin-1β; -39,5 for Interleukin 8 ; -41,3 % for Interleukin 6 ; p&lt;0,001 for all). Notably, dapagliflozin reduces p65-NF-κB activation (- 36,5% vs cells treated only to anticancer drugs) and inhibits of 27,8 % the expression of NLRP3 inflammasome that consequently improves the mitochondrial homeostasis of cardiomyocytes. Conclusions: Dapagliflozin demonstrated cardioprotective properties during doxorubicin and trastuzumab exposure. Dapagliflozin improves the Ca 2+ homeostasis and inhibits the pro-inflammatory “NLRP3- NF-κB –cytokines” pathways. The overall picture obtained provides the proof of concept for translational studies designed to investigate the cardioprotective use of dapagliflozin in HER2+ breast cancer patients.
Multisystem Inflammatory Syndrome in Children — Initial Therapy and Outcomes
Authors: Mary Beth F. Son, Nancy Murray, Kevin Friedman, Cameron C. Young, Margaret M. Newhams, Leora R. Feldstein, Laura L. Loftis, Keiko M. Tarquinio, Aalok R. Singh, Sabrina M. Heidemann, Vijaya L. Soma, Becky J. Riggs, Julie C. Fitzgerald, Michele Kong, Sule Doymaz, John S. Giuliano, Michael A. Keenaghan, Janet R. Hume, Charlotte V. Hobbs, Jennifer E. Schuster, Katharine N. Clouser, Mark W. Hall, Lincoln S. Smith, Steven M. Horwitz, Stephanie P. Schwartz, Katherine Irby, Tamara T. Bradford, Aline B. Maddux, Christopher J. Babbitt, Courtney M. Rowan, Gwenn E. McLaughlin, Phoebe H. Yager, Mia Maamari, Elizabeth H. Mack, Christopher L. Carroll, Vicki L. Montgomery, Natasha B. Halasa, Natalie Z. Cvijanovich, Bria M. Coates, Charles E. Rose, Jane W. Newburger, Manish M. Patel, Adrienne G. Randolph
Journal: New England Journal of Medicine (2021)

The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy.