tbuckley/cabot-search huggingface dataset:
Motexafin gadolinium, a redox mediator, induces apoptosis in chronic lymphocytic leukemia B-cells and is additive or synergistic with fludarabine
Authors: Louie Naumovski, Nancy D. Bone, Mint Sirisawad, Richard A. Miller, Diane F. Jelinek, Renee C. Tschumper, Neil E. Kay
Journal: Cancer Research (2005)

5120  Motexafin gadolinium (MGd, (Xcytrin®) is a tumor-selective redox mediator that oxidizes intracellular reducing metabolites and protein thiols, thereby generating reactive oxygen species (ROS) through a process known as redox cycling. B-cell chronic lymphocytic leukemia (CLL) has elevated levels of the antioxidant ascorbate, and is known to be sensitive to redox stress. Since MGd can generate ROS through oxidation of ascorbate, we reasoned that MGd would be cytotoxic to CLL cells. Mononuclear cells were isolated from the blood of CLL patients (n=15) characterized by Rai Stage, CD38, FISH and immunoglobulin heavy chain variable (Ig VH) mutational status. CLL cells were incubated in vitro over 2-5 days with MGd at concentrations ranging from 0-50 μM. Cytotoxicity was assessed by flow cytometry using annexin V binding/propidium iodide uptake. Accumulation of MGd in CLL cells was demonstrated by flow cytometry using drug fluorescence (>650nm). MGd-induced cytotoxicity was found to be dose-dependent over a range of 2.5 to 50 μM in cells from 11 of 15 CLL patients. CLL cells from 11/15 patients treated with 50 μM MGd and 4/15 patients treated with 10 μM MGd had cytotoxicity levels at least 2 fold above baseline. MGd uptake was similar in sensitive and resistant CLL cells, implying that mechanisms other than uptake are responsible for the differential responses. CLL cells that were sensitive to MGd treatment showed an increase in caspase-3 activity and cleavage of the caspase substrate PARP was found by immunoblot suggesting that MGd induced apoptosis. The induction of apoptosis was found to be exclusive of Rai stage, CLL FISH defects, CD38 expression or Ig VH mutational status. Cells from 5 CLL patients were studied for drug synergy using seven concentrations of MGd (7.5 μm - 50 μM) and the active moiety F-ara-A of fludarabine (0.25 μm-2.0 μM). The cells were treated with each drug individually or both drugs for 48 hours prior to analysis for cytotoxicity. MGd was found to exhibit additive activity (N=4) or synergistic (N=1) effects on CLL B cytotoxicity when combined with fludarabine. Thus, our pre-clinical results reveal that MGd is cytotoxic to CLL cells in vitro through induction of apoptosis. Furthermore, MGd shows additive or synergistic activity when combined with fludarabine. These results support the evaluation of MGd in ongoing CLL clinical trials utilizing this agent alone or in combination with fludarabine.
<i>Dysosmobacter welbionis</i> is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice
Authors: Tiphaine Le Roy, Emilie Moens de Hase, Matthias Van Hul, Adrien Paquot, Rudy Pelicaen, Marion Régnier, Clara Depommier, Céline Druart, Amandine Everard, Dominique Maiter, Nathalie M Delzenne, Laure B Bindels, Marie de Barsy, Audrey Loumaye, Michel P Hermans, Jean-Paul Thissen, Sara Vieira-Silva, Gwen Falony, Jeroen Raes, Giulio G Muccioli, Patrice D Cani
Journal: Gut (2021)

To investigate the abundance and the prevalence of Dysosmobacter welbionis J115T, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic syndrome. To study the impact of this bacterium on host metabolism using diet-induced obese and diabetic mice.We analysed the presence and abundance of the bacterium in 11 984 subjects using four human cohorts (ie, Human Microbiome Project, American Gut Project, Flemish Gut Flora Project and Microbes4U). Then, we tested the effects of daily oral gavages with live D. welbionis J115T on metabolism and several hallmarks of obesity, diabetes, inflammation and lipid metabolism in obese/diabetic mice.This newly identified bacterium was detected in 62.7%-69.8% of the healthy population. Strikingly, in obese humans with a metabolic syndrome, the abundance of Dysosmobacter genus correlates negatively with body mass index, fasting glucose and glycated haemoglobin. In mice, supplementation with live D. welbionis J115T, but not with the pasteurised bacteria, partially counteracted diet-induced obesity development, fat mass gain, insulin resistance and white adipose tissue hypertrophy and inflammation. In addition, live D. welbionis J115T administration protected the mice from brown adipose tissue inflammation in association with increased mitochondria number and non-shivering thermogenesis. These effects occurred with minor impact on the mouse intestinal microbiota composition.These results suggest that D. welbionis J115T directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.
U.S. radiation oncology and medical oncology department faculty diversity trends by sex and underrepresented in medicine status over five decades.
Authors: Sophia C. Kamran, Andrzej Niemierko, Neha Vapiwala
Journal: Journal of Clinical Oncology (2021)

11010 Background: Academic faculty are critical in training future generations of oncologists to care for our increasingly diverse cancer patient population. It is unclear if the growing imperative to address disparities in racial/ethnic and gender representation in the medical field has resulted in corresponding progress in the composition of academic radiation and medical oncology (RO, MO) departments. Herein we report trends in faculty diversity, overall and by academic rank, among US radiation and medical oncologists over the past 5 decades. Methods: Data were acquired from the Association of American Medical Colleges (AAMC) Faculty Roster between 1970-2019 for academic RO and MO departments to determine sex and race/ethnicity trends over five decades. Underrepresented in Medicine (URM) was defined as individuals identifying as Black, Hispanic, and Native American. Linear regression models were used to estimate slopes and associated p-values. Results: Total faculty complements grew over time in both RO and MO departments. The number of URM female faculty increased by 0.85/year in RO and 0.79/year in MO (P-trend&lt;0.001), compared to non-URM female faculty, which increased by 11.3/year in RO and 7.9 in MO (P-trend&lt;0.001). URM male faculty increased by 1.4/year in RO and 1.1/year in MO (P-trend&lt;0.001), compared to non-URM male faculty, which increased by 25.5/year for RO and 12.2/year for MO (P-trend&lt;0.001). Males represented the majority of URM and non-URM faculty for both RO and MO. The proportion of females grew more than the proportion of URM faculty over the study period for both RO and MO. There were also significant differences in diversity by faculty rank. Although MO outperformed RO in terms of the proportion of female faculty members with more advanced rank, female faculty members had a lower academic rank than their male counterparts in both specialties. At every rank, there was a low number of URM faculty represented among both MO and RO (Table). Conclusions: Gender and racial/ethnic diversity of academic RO and MO faculty has increased over time but has not kept pace with the diversity of the US population served, particularly with respect to URM status. The proportion of female faculty in both specialties demonstrates more promising growth, and may inform measures to achieve similar progress in recruiting and retaining URM faculty in both MO and RO.[Table: see text]
Automated, IHC/FISH-free, H&amp;E histopathology image-based HER2 amplification, tumor infiltrating lymphocyte (TIL) and tumor heterogeneity profiling in breast cancer.
Authors: Satabhisa Mukhopadhyay, Tathagata Dasgupta, Nicolas M Orsi, Michele Cummings, Angelene Berwick
Journal: Journal of Clinical Oncology (2021)

593 Background: Digital pathology has fostered the development of automated diagnostic solutions. However, current technologies in breast cancer remain unable to determine HER2 amplification status, which is established by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH). These ancillary tests carry a significant cost, prolong diagnostic time and fail to capture HER2 tumor heterogeneity and tumor infiltrating lymphocyte (TIL) burden, both of which determine the effectiveness anti-HER2 targeted therapy. Methods: This study describes the real-life clinical context development and validation of a patented novel, universal, automated, white-box, scanning platform agnostic solution that determines HER2 amplification status, prognostically significant TIL levels and tumor heterogeneity index (HI) from hematoxylin and eosin (H&amp;E) stained malignant breast biopsy whole slide images (WSIs) alone. Unlike conventional artificial intelligence-based approaches, the underlying proprietary algorithm’s prediction criteria are explainable and are based on deterministic, hard-coded observational relationships of scale constructed from image morphological features mapped to observables representing underlying tumor-related perturbations in biological pathways/mitotic checkpoints.This includes G1/S deregulation signatures reflecting oncogenic HER2-neu. Results: Blinded validation of HER2 status prediction (n = 197 WSIs; 118 independent cases/patients) showed excellent diagnostic performance (κ = 0.85) relative to existing standard-of-care methodologies. This was independent of WSI file format, background histology, tumor subtype/grade or hormone receptor status. The device also displayed good accuracy (92%) in determining TIL profiles, and its combined HER2-TIL and HER2-HI prediction scales both exhibited a significant association with progression-free survival (CoxPH hazard ratio: 1.856; 95% CI: 1.002-3.438; p = 0.049 and CoxPH hazard ratio: 3.45; 95% CI: 0.95-12.55; p = 0.060). Conclusions: This technology opens up the future possibility of bypassing existing ancillary HER2 profiling investigations, thus potentially reducing laboratory workloads/healthcare costs while accelerating diagnostic turnaround times for patient benefit. In the interim, if used as an adjunct tool, this device could provide an objective HER2 testing reference scale while the robustness of its prediction of patient response to anti-HER2 targeted therapy is fully explored.
Parameters of local cellular immunity in patients with bladder cancer.
Authors: Lyubov I. Belyakova, Aleksandr B. Sagakyants, Alexey N. Shevchenko, Elena V. Filatova, Elena S. Bondarenko, Oksana G. Shulgina, Viktor K. Khvan, Dmitry A. Shvyrev, Irina A. Khomutenko
Journal: Journal of Clinical Oncology (2021)

e16508 Background: Bladder cancer (BC), which accounts for 4.5% of the total cancer incidence, is the cause of frequent severe disability and a significant deterioration in the quality of life of patients. BC development is determined by a number of factors, involving the immune system; however, its role is poorly understood. The purpose of the study was to determine characteristics of parameters of the cellular immunity in patients with non-muscle invasive BC. Methods: The study included 14 patients with newly diagnosed stage I BC. Patients were divided into two groups: with low-grade tumors (LG), n = 7, mean age 57 years; with high-grade tumors (HG), n = 6, mean age 60 years. All patients underwent transurethral resection of the bladder, and tumor tissues (TT, size up to 1.5 cm) and perifocal tissues (PT, at least 0.5 cm from the tumor) were obtained. The specimens were disintegrated to obtain the cell suspension. The relative numbers of the main populations of leukocytes and T- and B-lymphocytes, as well as some subpopulations of T-lymphocytes, were determined using the BD FACSCanto II flow cytometer and a panel of antibodies according to the manufacturer's instructions (Becton Dickinson, USA). Results: Reduction of lymphoid tissue infiltration by 78% was observed in TT in HG patients, compared to the LG group; levels of CD8+ lymphocytes, CD3+CD4-CD8- and CD3+CD4+CD8+ cells, NK- and B-lymphocytes were lower by 27%, 33%, 51%, 45% and 62%, respectively. Levels of Treg in HG TT were 32% lower than in LG. The numbers of activated CD4+, CD8+ cells were unchanged, but TT infiltration by naive lymphocytes of both populations was increased by 28% and 31%, respectively. In HG PT, a decrease in the total number of lymphocytes by 27% was observed, together with higher levels of CD3+CD4+CD8+ cells and NK- and B-lymphocytes by 200%, 213% and 31%, respectively. Conclusions: BC patients with various tumor grades demonstrate different distributions of lymphocyte populations in tumor and perifocal tissues; the functional activity of these cells can both contribute to the disease development and determine the risk of recurrence.
A nationwide analysis of population group differences in the COVID-19 epidemic in Israel, February 2020–February 2021
Authors: Khitam Muhsen, Wasef Na'aminh, Yelena Lapidot, Sophy Goren, Yonatan Amir, Saritte Perlman, Manfred S. Green, Gabriel Chodick, Dani Cohen
Journal: The Lancet Regional Health - Europe (2021)

Social inequalities affect the COVID-19 burden and vaccine uptake. The aim of this study was to explore inequalities in the incidence and mortality rate of SARS-CoV-2 infection and vaccine uptake in various sociodemographic and population group strata in Israel.
Investigation of measurable residual disease in acute myeloid leukemia by DNA methylation patterns
Authors: Tanja Božić, Chao-Chung Kuo, Jan Hapala, Julia Franzen, Monika Eipel, Uwe Platzbecker, Martin Kirschner, Fabian Beier, Edgar Jost, Christian Thiede, Wolfgang Wagner
Journal: Leukemia (2021)

Assessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.
Second-line nintedanib plus docetaxel for patients with lung adenocarcinoma after failure on first-line immune checkpoint inhibitor combination therapy: Initial efficacy and safety results from VARGADO Cohort C.
Authors: Christian Grohé, Thomas Wehler, Tobias Dechow, Sven Henschke, Wolfgang Schuette, Ina Dittrich, Stefan Hammerschmidt, Harald Müller-Huesmann, Christian Schumann, Stefan Krüger, Judith Atz, Rolf Kaiser
Journal: Journal of Clinical Oncology (2021)

9033 Background: The treatment landscape in advanced non-small cell lung cancer (NSCLC) has undergone significant changes, with immune checkpoint inhibitor (ICI) +/- chemotherapy now the preferred first-line (1L) regimen for metastatic, non-mutated NSCLC. However, only limited clinical data are available to guide subsequent treatment selection. Nintedanib (Vargatef), an oral triple angiokinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways, is approved in the EU and other countries in combination with docetaxel for the treatment of advanced adenocarcinoma NSCLC after failure on 1L chemotherapy. Methods: This analysis is part of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) of nintedanib + docetaxel. Here, we present initial efficacy and safety results from 100 patients (pts) with adenocarcinoma NSCLC in Cohort C, who received second-line (2L) nintedanib + docetaxel after failure on prior 1L ICI in combination with chemotherapy. Results: In Cohort C, the median age was 63 years (range: 43–84); 58 pts (58.0%) were men, and 71 pts (71.0%) had ECOG PS 0/1. Ninety-five pts (95.0%) had received prior 1L pembrolizumab-based combination therapy. Thirty-nine pts (39.0%) had progressed within 6 months after the start of 1L therapy, and 66 pts (66.0%) had progressed within 9 months. Objective response rate with 2L nintedanib + docetaxel was 37.3% (22/59 pts), disease control rate was 67.8% (40/59 pts), and median progression-free survival (PFS) was 4.4 months (95% confidence interval [CI]: 2.6–6.6). Among pts who had experienced disease progression &lt; 9 months after the start of 1L therapy (n = 66), median PFS from the start of 2L nintedanib + docetaxel was 4.1 months (95% CI: 2.5–6.6). Among pts with disease progression ≥9 months after the start of 1L therapy (n = 34), median PFS from the start of 2L nintedanib + docetaxel was 8.5 months (95% CI: 2.4–not estimable). Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were observed in 47 pts (47.0%), 37 pts (37.0%) and 28 pts (28.0%), respectively. Conclusions: Initial data from VARGADO Cohort C provide the first evidence that 2L nintedanib + docetaxel has encouraging and clinically meaningful efficacy, and a manageable safety profile in pts with advanced adenocarcinoma NSCLC following progression on 1L ICI in combination with chemotherapy. Clinical trial information: NCT02392455.
Molecular determinants of response to immune-oncology therapy in uterine carcinosarcoma.
Authors: Annelise M. Wilhite, Sharon Wu, Joanne Xiu, Britt Kristina Erickson, Rodney Paul Rocconi, Jubilee Brown, Thomas J. Herzog, Robert W. Holloway, John Wallbillich, Ira Seth Winer, Matthew A. Powell, Wolfgang Michael Korn, Nathaniel L. Jones
Journal: Journal of Clinical Oncology (2021)

5582 Background: Uterine carcinosarcoma (UCS) is subtype of endometrial cancer (EC) with aggressive behavior and poor prognosis. UCS has not traditionally been included in EC clinical trials and treatment options are limited. Immune-oncology (IO) therapy has shown promise UCS, but it is unknown which patients benefit most. We sought to identify immunogenic markers in UCS and explore treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off &gt;1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high &gt; 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be &lt;0.05. Results: A total of 1,144 UCS tumors underwent comprehensive tumor profiling. 68.4% of samples were obtained from primary tumors and 31.6% from metastatic sites. 21.6% of tumors expressed PD-L1, 8.5% were TMB-H and 6.8% were MSI-H/MMRd. UCS patients treated with IO had longer median overall survival than those not treated with IO (months: 31.2 vs 19.4; HR(95% CI): 0.39 (0.17-0.76) p=0.005). Median OS was also increased for dMMR/MSI-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.56 (0.36-0.92) p=0.019) and TMB-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.62 (0.38-0.99) p=0.047). More patients are needed to determine if these markers predict response to IO therapy. The most common mutations in UCS led to pathway dysregulation in the PI3K, RAS, chromatin remodeling, HR, and WNT pathways. dMMR/MSI-H tumors have distinct molecular profiles compared to MSS tumors (table). Additionally, dMMR/MSI-H tumors had higher TMB (96.9% vs 2.2%, q&lt;0.01) and increased frequency of PDL-1 (23.6% vs 13.8%; q=0.04). Immune checkpoint genes were more often expressed in MSI-H tumors, though this was non-significant except for IFNG (4.66-fold increase; q=0.01). Conclusions: IO therapy is associated with improved survival in USC. MSI and TMB are markers of improved OS in patients with UCS. MSI tumors have a distinct molecular profile compared to MSS tumors, and they appear to be more immunogenic, which could contribute to the improved survival seen in patients who received IO therapy.[Table: see text]
Cabozantinib in advanced HCC patients previously treated with immune checkpoint inhibitors: A territory-wide cohort study.
Authors: Jeffrey Sum Lung Wong, Yawen Dong, Vikki Tang, Thomas Wai-Tong Leung, Cynthia SY Yeung, Anna Tai, Ada Law, Tracy Cy Shum, Gin Wai Kwok, Bryan Li, Roland Ching-Yu Leung, Joanne Wing Yan Chiu, Ka Wing Ma, Wong-Hoi She, Wing Yan Josephine Tsang, Tan To Cheung, Thomas Yau
Journal: Journal of Clinical Oncology (2021)

e16179 Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.