tbuckley/cabot-search huggingface dataset:
Talimogene laherparepvec with systemic immunotherapy in melanoma: A real-world experience.
Authors: Tapas Ranjan Behera, Yanwen Chen, Jung Min Song, Steve Shih-lin Huang, Pauline Funchain, Brian Gastman
Journal: Journal of Clinical Oncology (2021)

e21549 Background: Talimogene laherparepvec (TVEC) is an FDA approved oncolytic herpes virus for intralesional therapy in unresectable metastatic melanoma. Real world data is sparse regarding the efficacy of TVEC in combination with other systemic therapies used in melanoma. We present outcomes of the largest single institution observational study of the off-label use of TVEC in combination with systemic immunotherapy. Methods: Patients with metastatic melanoma receiving TVEC simultaneously with ipilimumab-nivolumab (Ipi/Nivo) or single agent immunotherapy (either nivolumab or pembrolizumab) were evaluated. The demographics, clinicopathological characteristics, responses to injected lesions and remote metastatic lesions were evaluated. Clinical documentation was used to assess improvement in injected lesion size; time points for initial response and best response were identified. Review of imaging by a radiologist was evaluated to assess responses in remote metastatic lesions. Results: A total of 67 patients receiving TVEC from 2016 to 2020 were evaluated, of which 50 remained evaluable after excluding Merkel cell carcinoma, patients on clinical trial, TVEC monotherapy or those on BRAF-MEK inhibitors, and patients lost to follow up. In total, 29 received systemic immunotherapy simultaneously with TVEC and had been followed for at least a year, with a median follow-up time of 34 months (range, 12-56). At the time of analysis, 14 of 29 patients were alive. 6 of the 29 patients had received prior lines of therapy. Four patients received Ipi/Nivo, while 25 patients received monotherapy including 9 on nivolumab and 16 on pembrolizumab. The median number of TVEC doses received was 6 (range, 2-55) with median average TVEC dose being 3.47 ml (0.5-4 ml). Median time to initial local response was 6 weeks, whereas time to best local response was 14 weeks. Overall response rate in the injected target lesions was in 19 (66%), with complete local response (CR) in 12 (41%), partial response (PR) in 7 (24%), and progressive disease (PD) in 8 (28%). The response rate in distant non-injected lesions was 4 out of 16 (25%), 2 of which had previously progressed on prior systemic therapy. Stable disease was observed in 8 (50%) patients, and progression of disease in 4 (25%). The 1-year overall survival rate in patients receiving TVEC with systemic monotherapy was 80%, 95% CI 0.651-0.9730. Progression free survival at 1-year in the monotherapy group was 71.6%, 95% CI 0.557-0.918. Conclusions: This is the largest single institution, real world experience to our knowledge, which assesses the efficacy of TVEC in combination with systemic immunotherapy. Our cohort suggests that TVEC is an effective treatment in combination with systemic immunotherapy, with a better overall survival observed with combination TVEC and anti-PD1 than seen with historical data from clinical trials of anti-PD-1 monotherapy.
The Evolving Impact on Survival Outcomes in Multiple Myeloma with Greater Access to Novel Treatment Regimens: Experience in a Real-World Cohort
Authors: Zack M. Breckenridge, Victor Jimenez-Zepeda, Nizar J. Bahlis, Paola Neri, Irwindeep Sandhu, Michael P. Chu, Ismail Ismail, Jason Tay, Peter Duggan, Andrew Belch, Joanne D. Hewitt, Linda M. Pilarski, Tatiana Nikitina, Christopher P. Venner
Journal: Blood (2017)
Gender and racial/ethnic disparities in academic oncology leadership.
Authors: Gavin Jones, Natasha Dhawan, Akansha Chowdhary, Trevor Joseph Royce, Kirtesh R. Patel, Arpit Chhabra, Miriam Knoll, Curtiland Deville, Karen Marie Winkfield, Neha Vapiwala, Narjust Duma, Mudit Chowdhary
Journal: Journal of Clinical Oncology (2021)

11009 Background: Gender &amp; racial/ethnic leadership disparities have been independently identified in academic hematology/oncology (HO) and radiation oncology (RO). Here, we evaluate gender and racial/ethnic intersectionality from the trainee to the leadership level. Methods: All ACGME accredited HO and RO training program websites were queried to identify constituent trainees, academic faculty, program directors (PD) and department chairs (DC), with a leadership position defined as PD or DC. Individual gender &amp; race/ethnicity was determined using externally validated software tools (Gender-API, NamSor, &amp; Onolytics), publicly available descriptors, and image review. We grouped individuals into 6 categories: White Male (WM), White Female (WF), Asian Male (AM), Asian Female (AF), Underrepresented Groups in Medicine (as defined by AAMC) Male (URMM) and Female (URMF). The chi-squared goodness-of-fit test was applied to examine if deviations exist between the observed vs. expected proportions of gender/race dyads in trainees, PD, and DC compared to academic faculty. Results: We identified 7,722 individuals from 2019-2020: 1,759 trainees (HO=1525; RO=234), 5,726 faculty (HO=4834; RO=892), 242 PD (HO=149; RO=93) and 237 DC (HO=144; RO=93). Leadership positions were most often comprised by WM (52.6%), and least often comprised by URMF (2.9%). Combined HO/RO analysis revealed significant differences in the observed representation of trainees &amp; DC vs expected levels based on total faculty, respectively: WM (33.7% &amp; 60.3% vs. 42.3%), WF (19.2% &amp; 13.9% vs. 22.3%), AM (20.75% &amp; 16.9% vs. 16.4%), AF (17.9% &amp; 2.5% vs. 12.7%), URMM (4.09% &amp; 5.5% vs. 3.5%) and URMF (4.3% &amp; 0.8% vs. 2.8%), p&lt;0.01. No differences were seen between PD vs total faculty. On subset analysis, there were significant differences observed in HO programs at the trainee, PD and DC levels compared to total faculty, whereas significant differences in RO programs were seen only at the DC level [Table]. Conclusions: Gender &amp; racial/ethnic disparity is present in academic oncology. Specifically, women of all races/ethnicities are proportionally underrepresented in DC positions in HO and RO programs. These data can serve as a benchmark to raise awareness and monitor progress towards a more balanced workforce in oncology.[Table: see text]
Pre-Transplant Transferrin Saturation Levels As a Predictive Marker for Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Satoru Nanno, Hideo Koh, Mitsutaka Nishimoto, Takahiko Nakane, Yasuhiro Nakashima, Yasunobu Takeoka, Mika Nakamae, Asao Hirose, Masayuki Hino, Hirohisa Nakamae
Journal: Blood (2017)
Code status transitions in patients with high-risk acute myeloid leukemia (AML).
Authors: Hannah Rebeccah Abrams, Ryan David Nipp, Lara Traeger, Mitchell W. Lavoie, Matthew J. Reynolds, Thomas William LeBlanc, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2021)

e19009 Background: Patients with high-risk AML often experience aggressive medical care at the end of life (EOL) such as hospitalization and intensive care unit (ICU) admission. Despite this, studies examining code status transitions in this population are lacking. Methods: We conducted a mixed methods study of 107 patients with high-risk AML enrolled in supportive care studies at Massachusetts General Hospital between 2014-2019. High-risk AML was defined as 1) new diagnosis &gt; 60 years or 2) relapsed/refractory AML. Two physicians used consensus-driven medical record review to characterize code status transitions. Code statuses were coded as ‘full’ (confirmed or presumed), ‘restricted’ (i.e., do not resuscitate), or ‘comfort measures only’ (CMO); confirmations of presumed status were not coded as transitions. Results: At diagnosis of high-risk AML, 91.9% of patients were ‘full code’ (48.5% presumed, 43.4% confirmed) and 8.1% had restrictions on life-sustaining therapies. Overall, 55.1% (59/107) of patients experienced a code status transition, with a median of two transitions (range 1-4). Median time from first to last transition was 11 days (range 1-306) and from last transition to death was 1 day (range 0-11). Most of these transitions (79.6%; 48/59) were transitions to CMO near EOL. We identified three processes leading to code status transitions (Table): 1) pre-emptive conversations prior to any clinical change (15.3%; 9/59); 2) anticipatory conversations at the time of acute clinical deterioration (15%; 9/59); and 3) futility conversations after acute clinical deterioration, focused on withdrawing life-sustaining therapy (64.4%; 38/59). Only 55.9% (33/59) of patients participated in their last code status transition and 22.0% (13/59) of these transitions occurred in the ICU or Emergency Room. Conclusions: Most patients with high-risk AML had code status transitions at EOL, often following clinical deterioration that limited their ability to engage in EOL discussions. Interventions to promote earlier and more specific code status conversations are needed to improve patients’ ability to voice their EOL preferences.[Table: see text]
PSMA-Ligand Uptake in Disseminated Epidermoid Cysts in a PSMA PET/CT of a Patient With Recurrent Prostate Cancer
Authors: Karl Peter Bohn, Ian Alberts, Clemens Mingels, Axel Rominger, Ali Afshar-Oromieh
Journal: Clinical Nuclear Medicine (2021)

PSMA PET/CT is routinely used for the detection of prostate cancer (PC). However, increased PSMA-ligand uptake has been described in a variety of benign and malignant tissues. A 71-year-old man with biochemical recurrence of PC initially treated with radical prostatectomy was referred for PSMA-ligand PET/CT. Apart from 1 lymph node with intense PSMA-ligand uptake, suspicious for metastasis, disseminated PSMA-ligand-avid subcutaneous lesions were seen. Histopathology of 1 of these lesions revealed an epidermoid cyst. Physicians should remain cognizant of non-PC-related causes of increased PSMA-ligand uptake, of which this case represent yet another example.
Genomic predictors of response to PD-1 axis inhibitors in metastatic urothelial cancer (mUC) patients using machine learning analysis of tissue comprehensive genomic profiling (CGP).
Authors: Raquel Reisinger, Victor Sacristan Santos, Roberto Nussenzveig, Sergiusz Wesolowski, Edgar Javier Hernandez, Alexander Ryan Henrie, Benjamin L. Maughan, Umang Swami, Mark Yandell, Petros Grivas, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2021)

4542 Background: Immune check point inhibitors (ICI), specifically PD-1 axis inhibitors, are an established treatment for mUC patients (pts), though molecular markers of response are not well-established. Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that machine learning analysis can reveal biomarkers of response to ICI beyond Tumor Mutational Burden (TMB) and PD-L1 expression. Methods: Pts with mUC receiving systemic therapy and available tumor CGP were included in the analysis. CGP was performed by a CLIA validated NGS panel (Foundation Medicine). 17 clinically relevant variables were included in the analyses. Multilevel molecular and clinical interdependencies between ICI response were assessed using a Bayesian network (BN) machine learning approach. To account for high computational cost of the BN dependence structure discovery, variables were selected based on primary and secondary dependencies to ICI Objective Response Rate (ORR) via Hill Climbing Algorithm. Genes selected for analysis included those present in &gt; 5% of the cohort . All variants of unknown significance were removed. Kaplan-Meyer (KM) survival analysis was also performed. Results: 174 pts were eligible and included: median age was 67 (33 – 86), 54.6% were smokers, 27.6% male, 14.4% had upper tract disease at diagnosis and 77 pts were treated with an approved ICI. Results from BN analysis revealed strong positive interdependencies between ICI ORR and TMB ≥ 10 or mutated PIK3CA gene. KM analysis was in agreement with BN results, a low TMB ( &lt; 10 muts/MB) and wild-type PIK3CA were predictive of poor PFS (Table). PGMs will be presented at the meeting. Conclusions: BN and KM survival analysis supported TMB ≥ 10 as a biomarker of improved outcomes to ICI. Moreover, these results reveal mutated PIK3CA as a novel biomarker of improved outcomes to ICI. Study has limitations as expected in a retrospective analysis. These hypothesis-generating data require external validation.[Table: see text]
Non-invasive transcutaneous vagal nerve stimulation improves myocardial performance in doxorubicin-induced cardiotoxicity
Authors: Yanqiu Lai, Xiaoya Zhou, Fuding Guo, Xiaoxing Jin, Guannan Meng, Liping Zhou, Hu Chen, Zhihao Liu, Lilei Yu, Hong Jiang
Journal: Cardiovascular Research (2021)

Abstract Aims The clinical use of antitumour agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity. Methods and results Healthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS, and DOX+tVNS groups. A cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30 min/day). After 6-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde and Interleukin-1β, and decreased superoxide dismutase were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were down-regulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly down-regulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group. Conclusion These results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodelling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms.
Gamma-interferon inducible lysosomal thiolreductase (GILT) effect on breast tumor microenvironment through regulating CXCR6/CXCL16 axis.
Authors: YinJiao Fei, MingXing Liang, Lei Li, Yuxin Song, Zhen Liu, Jinhai Tang
Journal: Journal of Clinical Oncology (2021)

e15081 Background: Gamma-interferon Inducible Lysosomal Thiolreductase (GILT) is constitutively expressed in most antigens endocytosed by antigen presenting cells (APCs), and its function is to catalyze the reduction of disulfide (S-S) bonds in protein substrates. The cytokine CXCL16 is one of the only two known plasma membrane chemokines which induces chemotaxis of activated T cells and bone marrow plasma cells in tumor microenvironment. It contains a free end folded by two sulfur bonds and therefore could also be a zymolyte of GILT. Previous studies found that specific receptor of CXCL16, CXCR6, was significantly overexpressed in breast cancer tissues and metastatic axillary lymph nodes. We suppose whether CXCR6/CXCL16 axis is regulated by GILT and affect tumor microenvironment, thereby eliciting specific anti-tumor immune responses in breast cancer (BC). Methods: GILT expression in BC was evaluated using publicly available data from The Cancer Genome Atlas (TCGA). GILT gene was analyzed in UALCAN ( http://ualcan.path.uab.edu/analysis-prot.html ) . In vitro, Immunohistochemistry (IHC) was conducted to examine the location and relation of GILT and CXCR6. Gene Set Enrichment Analysis (GSEA) was performed to mine the biological pathways involved in BC related GILT regulatory network. The expression of GILT at protein and RNA levels were detected by Western Blot and RT-PCR assay. Overexpression and knockdown of GILT in BC cell lines was carried out to further analyzed the correlation between GILT and CXCL16/CXCR6. Results: TCGA database showed that GILT expression was increased in the stroma of BC compared with normal, and was correlated to shorter BC overall survival. GSEA suggested that the expression of GILT was associated with chemotactic factors. Pearson analysis and IHC showed GILT had a strong correlation with CXCL16/CXCR6 axis in the aspect of angiogenesis and immunity. qRT-PCR and Western Blot assay also revealed that GILT had high expression in BC. Besides, patients with high expression of GILT in IHC simultaneously showed high immunoreactive to macrophage markers, which was related to neovascularization and anti-tumor immune responses. Compared with the normal breast cell line MCF-10A, GILT protein had high expression in Hs578T and low expression in MDA-MB-231 cell line. GILT was overexpressed in MDA-MB-231 and knockdown in Hs578T. Result showed that high level GILT promoted the production of CXCL16/CXCR6,while GILT siRNA knockdown inhibited the production of CXCL16/CXCR6. Conclusions: GILT could catalyze CXCL16 in BC, function as a key mechanism to affect tumor microenvironment through CXCR6/CXCL16 pathway. GILT-activated CXCL16 levels showed a strong connection with unfavorable outcomes in BC, which could be a potential biomarker of prognosis and a novel therapeutic target.
A Missense Mutation in the Loss-of-Function Intolerant Actr2 Gene Suppresses Thrombosis Via Multiple Mechanisms
Authors: Amy E Siebert, Linzi M Hobbs, Alexander J Johnston, Lena M Mishack, Marisa A Brake, Audrey Cleuren, Guojing Zhu, Randal Joseph Westrick
Journal: Blood (2017)
Prognostic Factors and Survival Outcomes in Blast Transformed Chronic Myelomonocytic Leukemia: A Mayo Clinic-MD Anderson Cancer Center Study of 171 Cases
Authors: Mrinal M. Patnaik, Ana Alfonso, Fevzi Yalniz, Tapan M. Kadia, Rangit Vallapureddy, Elias Jabbour, Terra L. Lasho, Curtis A. Hanson, Hagop M. Kantarjian, Ayalew Tefferi, Guillermo Garcia-Manero
Journal: Blood (2017)
V2 Trial: A phase I study of venetoclax and CPX-351 for young patients with relapsed/refractory acute leukemia.
Authors: Laura Agresta, Maureen Megan O'Brien, Eric Justin O'Brien, Robin Elizabeth Norris, Erin Haag Breese, Karen Cristly Burns, Benjamin Mizukawa, Thomas D Ryan, Pankaj B Desai, A.a. Vinks, H. Leighton Grimes, Michael Absalon, John Peter Perentesis
Journal: Journal of Clinical Oncology (2021)

TPS7052 Background: Despite significant advances in therapy for acute myeloid leukemia (AML), 30-40% of young patients will relapse, after which prognosis is poor. In young patients, curative-intent salvage therapy involves intensive re-induction followed by hematopoietic stem cell transplant. Recently, the COG Phase II study of CPX-351 (liposomal cytarabine:daunorubicin, Vyxeos™) in pediatric patients with AML in first relapse (NCT02642965) demonstrated a CR/CRi rate of 81.3%. Separately, our first-in-pediatrics CPX-351 Phase I (NCT01943682) showed 48% in a heavily pre-treated pediatric cohort with multiply relapsed and refractory (R/R) AML. Our integrated pilot study of single cell RNA sequencing (scRNA-seq) done before, during, and after CPX-351 showed p53 targets over time with enrichment for genes regulating apoptosis (ex.: FAS, BAX), suggesting blasts may be primed for apoptosis following CPX-351. Venetoclax is a small molecule inhibitor of the anti-apoptotic protein BCL-2, a regulator of apoptotic balance in some leukemias. Based on our preclinical data, we developed a Phase I study to investigate venetoclax with CPX-351 for the treatment of young patients with R/R acute leukemias. Methods: The V2 Trial (NCT03826992) is a single-institution Phase I study to evaluate the safety and tolerability of venetoclax with CPX-351 in patients ages 1-39 years with R/R acute leukemias. Inclusion diagnoses include AML, mixed phenotype acute leukemia (MPAL), KMT2A-rearranged acute lymphoblastic leukemia (ALL), and T-ALL. Exclusion criteria include CNS status 3, bone marrow failure syndromes, and prior cardiotoxic exposures above acceptable risk thresholds. Subjects receive a single course of CPX-351 at the FDA approved adult dose on Days 1, 3, 5 with concurrent daily venetoclax. In the dose exploration phase, venetoclax dosing is 400 mg daily (or allometrically-scaled equivalent) for 21 (Dose Level 0) or 14 days (Dose Level -1) using a rolling 6 design. Primary endpoints are determination of the recommended phase 2 dose of venetoclax in combination with CPX-351 and description of toxicities. Secondary endpoints include estimations of CR/CR p /CR i +/- MRD negativity in the context of a phase I study and evaluation of therapy-related cardiac dysfunction. Correlative studies include analysis of venetoclax pharmacokinetics with concomitant CPX-351. At the initial dose level, DLT were encountered and the study is now continuing enrollment at Dose Level -1. Clinical trial information: NCT03826992.
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
Authors: Yelena Y Janjigian, Kohei Shitara, Markus Moehler, Marcelo Garrido, Pamela Salman, Lin Shen, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Campos Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yanez, Mustapha Tehfe, Ruben Kowalyszyn, Michalis V Karamouzis, Ricardo Bruges, Thomas Zander, Roberto Pazo-Cid, Erika Hitre, Kynan Feeney, James M Cleary, Valerie Poulart, Dana Cullen, Ming Lei, Hong Xiao, Kaoru Kondo, Mingshun Li, Jaffer A Ajani
Journal: The Lancet (2021)