tbuckley/cabot-search huggingface dataset:
Characterizing the gut microbiome of patients with triple-negative breast cancer.
Authors: April T. Swoboda, Anukriti Sharma, Olufunmilayo I. Olopade, Rita Nanda, Jack Gilbert
Journal: Journal of Clinical Oncology (2019)

e14186 Background: The human microbiome has been postulated to play a role in carcinogenesis, and there is evidence that commensal intestinal bacteria are capable of promoting tumor immunosurveillance and controlling the immune system’s response to therapy by modulating the tumor microenvironment. Methods: We characterized the stool microbiome of 30 patients (pts) with triple-negative breast cancer (TNBC) using 16S rRNA gene sequencing. Analysis of composition of microbiomes (ANCOM) was used to identify differential abundant exact-sequence-variants (ESVs) with p-values adjusted using Benjamini-Hochberg False Discovery Rate (pFDR) correction. We correlated the stool microbiome with clinicopathologic features and response to treatment. Results: The cohort included 7 pts with metastatic breast cancer and 23 pts with early-stage disease. 19 pts were treated with neoadjuvant chemotherapy (NACT). Bacteroides ovatus ESV was enriched (pFDR &lt; 0.05) in black pts (n = 14), whereas ESV from Prevotella copri was abundant (pFDR &lt; 0.05) in white pts (n = 13). ESVs from Clostridium and family Ruminococcaceae were enriched (pFDR &lt; 0.05) in pts with distant metastatic recurrence (n = 6) compared to pts without metastatic disease. Notably, we identified specific taxa that differentiated between pts with a pathological complete response to NACT (pCR, n = 6) and those with residual disease (n = 13). ESVs from Bacteroides and Ruminococcaceae were relatively more abundant in pts with a pCR (pFDR &lt; 0.05). Furthermore, among pts with residual disease after NACT, Bacteroides caccae was significantly enriched in pts with a partial response (n = 4) compared to pts with no response (n = 9). Conclusions: To our knowledge, this is the first time that 16S rRNA amplicon sequencing has been used to identify microbial signatures correlating with clinical phenotypes and response to treatment in pts with TNBC. This small study provides insight into the potential role of microbes in novel therapeutic interventions to correct dysbiosis and shift towards a gut microbial ecosystem that enhances the body’s immune response to TNBC.
Humanized immune system mouse models: progress, challenges and opportunities
Authors: Todd M. Allen, Michael A. Brehm, Sandra Bridges, Stacy Ferguson, Priti Kumar, Oleg Mirochnitchenko, Karolina Palucka, Roberta Pelanda, Brigitte Sanders-Beer, Leonard D. Shultz, Lishan Su, Mercy PrabhuDas
Journal: Nature Immunology (2019)
Case 31-1964
Authors: Morton N. Swartz, Benjamin Castleman
Journal: New England Journal of Medicine (1964)

Presentation of CaseA sixty-year-old man entered the hospital because of fever.He had been well until three days previously, when painless hematuria occurred; it cleared promptly but was followed by urinary frequency and nocturia. On the day of admission fever developed, accompanied by nausea and vomiting.The patient smoked 2 packages of cigarettes and drank 18 to 20 cups of coffee daily; he admitted ingesting "a little alcohol."Physical examination revealed a chronically ill man. The anteroposterior diameter of the chest was increased, and the heart was enlarged; a Grade 2 systolic, ejection-type murmur along the left sternal border . . .
Correlation of CD28 expression on CD8+ T cells with prognosis in advanced lung adenocarcinomas and squamous cell carcinomas.
Authors: Chao Liu, Wang Jing, Hui Zhu, Jinming Yu
Journal: Journal of Clinical Oncology (2019)

e14185 Background: Programmed death-1 (PD-1)-targeted therapies that treat non-small cell lung cancer (NSCLC) to salvage exhausted CD8 T cells depends on CD28 costimulatory pathway. However, the prognostic values of CD8+CD28+ T and CD8+CD28- T in advanced NSCLC and the impact of histological type on them remains unclear. Methods: Of 232 advanced NSCLC patients, 101 treatment-naïve individuals were eligible and included in our study. Flow cytometry was used to evaluate CD8+CD28+ T, CD8+CD28- T, CD4+CD25 hi T, B, natural killer, γδT, and natural killer T cells in patients’ peripheral blood. Results: Multivariate analysis showed that increased levels of CD8+CD28+ T cells independently predicted favorable overall survival (OS) [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.28-0.93, P = 0.034] and progression-free survival (PFS) (HR: 0.60, 95%CI: 0.27-0.98, P = 0.033) in ADs but not in SCCs. In addition, high levels of CD8+CD28- T cells independently predicted unfavorable OS (HR: 1.57, 95%CI: 1.13-3.34, P = 0.039) and PFS (HR: 2.08, 95%CI: 1.02-4.23, P = 0.043) in SCCs but not in ADs. ADs had higher levels of CD4+CD25 hi T and CD8+CD28- T, and lower NK (all P &lt; 0.05) cell counts than SCCs. Conclusions: The prognostic values of peripheral CD8+CD28+ and CD8+CD28- T cells in advanced NSCLC patients differ depending on histological type. These results could help refine the CD28-dependent PD-1-targeted therapies for advanced NSCLC with ADs and SCCs.
Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability.
Authors: Aurelie Moreira, Sophie Vacher, Claire Morel, Charlotte Lecerf, Maxime Frelaut, Marie Paule Sablin, Delphine Loirat, Francesco Ricci, Segolene Hescot, Edith Borcoman, Nouritza Torossian, Julien Masliah-Planchon, Celine Callens, Nicolas Servant, Anne Vincent- Salomon, Ivan Bieche, Christophe Le Tourneau, Maud Kamal
Journal: Journal of Clinical Oncology (2019)

e14750 Background: SIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. Methods: All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. Results: The 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1 mo in IIIA; 1.7 mo in IIIB, and 3.2 mo in IVA (p = 0.13). Median OS was 11.7 mo in tier II, 11.2 mo in IIIA, 6.3 mo in IIIB, and 12.1 mo in IVA (p = 0.002). Conclusions: The majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway.
Safety profile of midline catheters in patients with active malignancy.
Authors: Tiago Araujo, Vatsala Katiyar, Sanjay Patel
Journal: Journal of Clinical Oncology (2019)

e18046 Background: Patients with malignancy often require a safe and reliable intravascular access for disease management along the spectrum of diagnosis to end-of-life care. Despite a growing interest on the use of midlines, there is a scarcity of data on their safety in cancer patients. Data from observational studies suggest a lower rate of thrombotic and infectious complications when compared to peripherally-inserted central catheters (PICCs). However, there are no formal recommendations tailored to oncologic patients on when to prefer one type of vascular access versus another. Methods: We retrospectively gathered data from all midline catheters inserted in patients with active cancer at our institution from January 2016 to June 2017, totaling 159 procedures. Our primary analysis sought to determine the incidence of venous thromboembolism (VTE), CRBSI and bleeding. Results: Out of a total of 159 procedures performed in patients with solid tumor and hematologic malignancies, chemotherapy infusion was the indication in 17 (10.69%), with difficult intravenous access being the indication in 97 patients (61%) and prolonged antibiotic therapy in 44 patients (27.6%). Only one patient got a midline for peripheral parenteral nutrition. The mean dwell time of midline catheters was 9.4 days. A total of 5 patients (3.14%) developed catheter-associated thromboembolic episodes. All of them had metastatic solid tumors. No events were reported in patients with hematologic malignancies. Of note, 2 of these 5 patients had a prior history of VTE. The number of days from device insertion to VTE ranged from 2-14 days, with an average of 9.5 days. Catheter-related infection occurred in 1 patient (0.62% or 0.66 per 1000 catheter-days). No bleeding complications were reported. Conclusions: Midline catheters appear to be a safe and cost-effective alternative for secure vascular access, especially in patients with non-metastatic solid tumors and hematologic malignancies. Caution and close monitoring for occurrence of VTE are advised for those with high metastatic burden and prior history of VTE. The rate of infectious complications are low, which is in concordance with previous literature.
A TITE-CRM phase I/II study of disulfiram and copper with concurrent radiation therapy and temozolomide for newly diagnosed glioblastoma.
Authors: Jiayi Huang, Todd DeWees, Jian Li Campian, Milan G Chheda, George Ansstas, Christina Tsien, Gregory J. Zipfel, Gavin P. Dunn, Jospeh E Ippolito, J. Gregory Cairncross, Jacob C. Easaw, Josh Rubin, Albert H Kim
Journal: Journal of Clinical Oncology (2019)

2033 Background: Disulfiram (DSF) has shown promising activity against glioblastoma in preclinical studies and is more effective when combined with copper (Cu). Our previous phase I study established the maximum tolerated dose (MTD) of DSF when combined with adjuvant temozolomide (TMZ). This phase I/II study aims to establish the MTD when disulfiram and copper are combined with concurrent radiation therapy (RT) and TMZ for newly diagnosed glioblastoma and to explore preliminary efficacy. Methods: Eligible patients were treated with standard RT and TMZ plus escalating doses of DSF (250 mg - 375 mg PO QD) and Cu (2 mg PO TID), followed by adjuvant TMZ plus DSF (500 mg/day) and Cu. The time-to-event continual reassessment method (TITE-CRM) was used to continuously estimate the probability of dose-limiting toxicity (DLT) and to assign patients to doses with an estimated DLT probability of approximately 20% with a margin of 5%. Tumor mutations were evaluated with next-generation sequencing for all patients. Results: Eighteen glioblastoma patients were treated with the study therapy: 8 with DSF of 250 mg/day and 10 with 375 mg/day. Three DLTs were observed: 1 with 250 mg/day (grade 2 urinary incontinence and ataxia), and 2 with 375 mg/day (both grade 3 elevated liver enzymes). DSF had an estimated DLT probability of 10% (95% CI: 3-29%) at 250 mg/day, and 21% (95% CI: 7-42%) at 375 mg/day. After a median follow-up of 12.3 months, 1-year progression-free survival (PFS) was 57%, and 1-year overall survival (OS) was 69%. There was no significant difference in PFS/OS when stratified by DSF doses, surgical extent, or MGMT methylation status. However, glioblastomas with IDH1 (n = 6), BRAF (n = 2), or NF1 (n = 1) mutations had significantly better PFS and OS than those without the mutations: 1-year PFS: 100% vs 22%, respectively, p = 0.001; 1-year OS: 100% vs 42%, respectively, p = 0.006. Conclusions: The MTD of DSF with RT/TMZ/Cu for glioblastoma is 375 mg/day, and the recommended phase II dose is 250 mg/day. Although confirmation with larger sample size is needed, the combination demonstrates promising preliminary efficacy for the subset of glioblastoma with IDH1, BRAF, and NF1 mutations. Clinical trial information: NCT02715609.
Clinical significance of circulating tumor cells (CTCs) in hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients (pts) receiving letrozole (Let) or Let plus bevacizumab (Bev): CALGB 40503 (Alliance).
Authors: Mark Jesus Mendoza Magbanua, Oleksandr Oleksandr Savenkov, Erik Asmus, Karla V. Ballman, Janet H Scott, John Park, Maura N. Dickler, Ann H. Partridge, Lisa A. Carey, Eric P. Winer, Hope S. Rugo
Journal: Journal of Clinical Oncology (2019)

1049 Background: CALGB 40503 randomized HR+ MBC postmenopausal pts to Let alone or Let+Bev as first-line therapy. Adding Bev to Let prolonged progression-free survival (PFS) but not overall survival (OS) (Dickler JCO 2016). We performed a correlative study to assess prognostic and predictive value of CTCs in this population. Methods: Blood was collected prior to initiation of treatment. CTCs were enumerated using US FDA-cleared CellSearch assay; samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC-positive (CTC+). Correlation of CTCs with PFS and OS was assessed using Cox regression analysis. Median follow-up was 39 months (mo). Results: Of 343 pts treated, 294 had CTC data and were included in this analysis. Original study results that showed improved PFS (HR = 0.75; 95% CI: 0.59-0.96) but not OS (HR = 0.87; 95% CI: 0.65-1.18) in pts receiving Let+Bev compared to Let were recapitulated in this subset. In multivariable analysis, CTC+ pts (31%) had significantly reduced PFS (HR = 1.49; 95% CI: 1.12-1.97) and OS (HR = 2.08; 95% CI: 1.49-2.93) compared to CTC- pts. Moreover, CTC+ pts who did not receive Bev had worse PFS (HR = 2.31; 95% CI: 1.54-3.47) and OS (HR = 2.64; 95% CI: 1.59-4.40) (Table). CTC+ pts who received Bev had numerically longer median PFS (18.0 vs. 7.0 mo) and OS (33.6 vs. 27.1 mo) compared to CTC+ pts with no Bev; however, tests for interaction between CTC status and Bev (yes vs. no) were not statistically significant for PFS (p=0.70) or OS (p=0.84). Conclusions: CTCs were highly prognostic in this study involving addition of Bev to first-line Let in postmenopausal HR+ MBC. Further research to determine the potential predictive value of CTCs in the setting of both metastatic disease and early breast cancer is warranted. Support: U10CA180821, U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00601900. Survival in HR+ MBC pts receiving Let or Let+Bev stratified by CTC status. Clinical trial information: NCT00601900. [Table: see text]
Genetic determinants of adverse events in cancer patients receiving immune checkpoint inhibitors.
Authors: Noha Abdel-Wahab, Robert K Yu, Adi Diab, Ramona Dadu, Vickie Shannon, Andrew Futreal, Lindsey A. Criswell, Sanjay Shete, Maria E. Suarez-Almazor
Journal: Journal of Clinical Oncology (2019)

2586 Background: Immune checkpoint inhibitors (ICI) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAEs susceptibility as the phenotype of toxicity varies among patients (pts) and many pts do not develop toxicity despite continued inhibition. Methods: Genotyping was performed for 89 melanoma pts who received ICI using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data was extracted using PLINK (v1.90b3.34) and processed for quality control including on call rate (&gt;99%), genotyping rate (&gt;95%), minor allele frequency (no less than 5%), and Hardy-Weinberg Equilibrium (p&lt;1x10-6). The pairwise genetic distance was calculated using identity-by-state (IBS matrix) implemented in the genome option of PLINK, and the population-structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p&lt;1x10-3) and phenotype distribution for all pts, resulting in 7 structure groups. In the analytical stage, 602,463 variants in autosomal chromosomes were included for the association test. The test was performed using additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. Results: 44 pts had arthritis, colitis, hypohysitis, thyroiditis, or multiple irAEs (cases), and 45 did not have irAEs after a minimum of one year of treatment (controls); median age was 64 (23-92) years; 71% were male. A total of 30 variants/single nucleotide polymorphisms (SNPs) had p-value smaller than 10^-5 level were identified. The top variants/SNPs are listed in table. Conclusions: Genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings, and to establish their potential functional relevance.[Table: see text]
Cost-effectiveness analysis of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.
Authors: Wenqian Li, Rilan Bai, Lei Qian, Naifei Chen, Yuguang Zhao, Fujun Han, Ling Bai, Jiaxuan Li, Yu Yu, Jiuwei Cui
Journal: Journal of Clinical Oncology (2019)

e20556 Background: Non-small-cell lung cancer (NSCLC) patients with brain metastases had a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with WBI with or without chemotherapy for NSCLC patients with brain metastases. Methods: A markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]). Results: When considering progression as intracranial progression and overall progression respectively, the incremental cost-effectiveness ratio (ICER) was $930.17/QALY and $842.76/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (average CE) and net benefit showed advantage of icotinib (average CE: $2157.59/QALY for intracranial progression, $2285.16/QALY for overall progression; net benefit: $372153.35 for intracranial progression, $349938.32 for overall progression). One-way sensitivity analyses demonstrated the impact of the utilities of icotinib group. The probabilistic sensitivity analyses showed even at a WTP under $6000/QALY, icotinib could be cost-effective. Conclusions: Icotinib was cost-effective compared with WBI with or without chemotherapy. [Table: see text]
Eosinophilia during treatment of immune checkpoint inhibitors (ICIs) to predict succeeding onset of immune-related adverse events (irAEs).
Authors: Rika Kizawa, Yuji Miura, Yasuhiro Oda, Yukiko Nagaoka, Yukinori Ozaki, Chihiro Kondoh, Shuhei Moriguchi, Yui Takahashi, Kazumasa Ogawa, Yuko Tanabe-Hashimoto, Shuichi Taniguchi, Toshikazu Okaneya, Akiko Kishi, Nobukazu Hayashi, Kazuma Kishi, Toshimi Takano, Jun Masuda
Journal: Journal of Clinical Oncology (2019)

e14110 Background: ICIs such as anti-PD-1/-L1 Inhibitor and anti-CTLA-4 Inhibitor have been used in many types of cancer, and irAEs occur in a considerable proportion of patients. Predictive biomarkers could help us to manage irAEs promptly. Methods: We retrospectively analyzed the consecutive patients treated with nivolumab, pembrolizumab, atezolizumab or ipilimumab, not used as investigational drugs, between March 2015 and December 2018 based on the electric medical records in our institution. We evaluated the relationship between clinical and laboratory factors (gender, age, body mass index, lymphocyte-to-monocyte ratio and eosinophilia) and the occurrence of irAEs using univariate and multivariate analyses. Eosinophilia was defined as absolute eosinophil count over 500/mm 3 at least once between initiation of treatment and the occurrence of irAEs. We graded irAEs according to CTCAE v. 5.0. Results: Among 139 patients analyzed in this study, 136, 13 and 6 patients were treated with PD-1, PD-L1 and CTLA-4 inhibitors, respectively (cumulative total of 155 patients). This study included non-small cell lung cancer (n = 78; 56.1%), renal cell carcinoma (n = 17; 12.2%), melanoma (n = 16; 11.5%), gastric cancer (n = 15; 10.8%), Hodgkin lymphoma (n = 7; 5.0%), urothelial carcinoma (n = 3; 2.2%), head and neck carcinoma (n = 3; 2.2%) and mesothelioma (n = 1; 0.7%). Any grade and grade 3-5 irAEs occurred in 60 (38.7%) and 23 (14.8%) cumulative patients, respectively. The most common irAEs in any grade were endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 21) and skin disorders (n = 20). Eosinophilia occurred in 43 cumulative patients (27.7%). Eighteen patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.0193) and multivariate (p = 0.0464) analysis. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions: Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs.
Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis
Authors: Olena Gruzieva, Cheng-Jian Xu, Paul Yousefi, Caroline Relton, Simon Kebede Merid, Carrie V. Breton, Lu Gao, Heather E. Volk, Jason I. Feinberg, Christine Ladd-Acosta, Kelly Bakulski, Charles Auffray, Nathanaël Lemonnier, Michelle Plusquin, Akram Ghantous, Zdenko Herceg, Tim S. Nawrot, Costanza Pizzi, Lorenzo Richiardi, Franca Rusconi, Paolo Vineis, Manolis Kogevinas, Janine F. Felix, Liesbeth Duijts, Herman T. den Dekker, Vincent W. V. Jaddoe, José L. Ruiz, Mariona Bustamante, Josep Maria Antó, Jordi Sunyer, Martine Vrijheid, Kristine B. Gutzkow, Regina Grazuleviciene, Carles Hernandez-Ferrer, Isabella Annesi-Maesano, Johanna Lepeule, Jean Bousquet, Anna Bergström, Inger Kull, Cilla Söderhäll, Juha Kere, Ulrike Gehring, Bert Brunekreef, Allan C. Just, Rosalind J. Wright, Cheng Peng, Diane R. Gold, Itai Kloog, Dawn L. DeMeo, Göran Pershagen, Gerard H. Koppelman, Stephanie J. London, Andrea A. Baccarelli, Erik Melén
Journal: Environmental Health Perspectives (2019)

Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes.