tbuckley/cabot-search huggingface dataset:
TRANSCEND NHL 001: Health-related quality of life (HRQL) and symptom (Sx) impact in patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving lisocabtagene maraleucel (Liso-cel; JCAR017).
Authors: Donald L. Patrick, Karen C. Chung, Yeonhee Kim, Jacob Garcia, Christine Dehner, David G. Maloney
Journal: Journal of Clinical Oncology (2019)

e19052 Background: R/R DLBCL is associated with decreased HRQL. Liso-cel is an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells. In the ongoing TRANSCEND study, pts with R/R DLBCL achieved high best overall response rates with liso-cel, with low rates of severe cytokine release syndrome and neurological events (Abramson et al, ASCO 2018). We examined the impact of Sx and HRQL in pts with R/R DLBCL. Methods: Eligible pts with R/R DLBCL (≥18 yr, ≥2 prior therapy lines) received lymphodepletion followed by a single liso-cel infusion. The EORTC QLQ-C30 was administered at baseline (BL), day 29 (mo 1), and mo 2 and 3. Sx and functional scales and gIobal health status were analyzed. Increases from BL ≥10 points in functional and QL scores or decreases from BL ≥10 points in Sx scores were considered clinically meaningful improvement. Scores range from 0-100. Results: At data cutoff, 87/127 pts (mean [SD] age 62 [11] yr) were evaluable (BL+≥1 post-BL assessment). Sx scores generally improved postinfusion (Table). Mean global health status and emotional and cognitive function scores improved vs BL from mo 1-3 postinfusion, while physical, role, and social function scores declined at mo 1, followed by improvements vs BL in mo 2-3. The proportion of surviving pts achieving clinically meaningful improvement in key domains 3 mo postinfusion were: fatigue, 50%; pain, 51%; physical function, 22%; and global health status, 41%. Conclusions: In TRANSCEND, symptoms and HRQL improved in surviving pts, with clinically meaningful improvements in key domains, 2-3 mo after liso-cel infusion. Clinical trial information: NCT02631044. [Table: see text]
Preliminary study into the impact of immunotherapy on patterns of care and healthcare service utilization in stage IV non-small cell lung cancer in a tertiary hospital setting.
Authors: Xiao Yue Guo, Ben Gunawan, Jasotha Sanmugarajah
Journal: Journal of Clinical Oncology (2019)

92 Background: The advent of immunotherapy for Non-Small Cell Lung Cancer (NSCLC) has dramatically altered cancer care. There is increasing clinical evidence to support immunotherapy improving disease-free progression and survivorship. However, there is limited data on how this impacts healthcare in terms of service utilization. Methods: We conducted a retrospective study on patients newly diagnosed with Stage IV NSCLC at a tertiary referral hospital with a large catchment area in Australia. Data was collected for the years 2013 (pre-immunotherapy) and 2016 (immunotherapy in use) to investigate the impact of immunotherapy on treatment patterns, survivorship and healthcare service utilisation. A total of 62 patients were included in the study with equal numbers in both cohorts. Results: Preliminary analysis indicates that since the introduction of immunotherapy in NSCLC treatment protocols, there has been a trend towards improved survivorship. There was a 19% increase in the number of patients surviving to 12 months in the 2016 cohort compared with 2013 cohort patients. Median survival was 6 months and 8 months for 2013 and 2016 cohorts respectively. There was a significantly greater burden of visits to outpatient clinics and treatment day units in the 2016 cohort. We also found fewer Emergency Department presentations and hospital admissions in the 2016 cohort compared with their 2013 counterparts. Conclusions: In conclusion, our study demonstrates increasing healthcare utilisation in ambulatory cancer services with decreased Emergency presentations and hospital admissions following the introduction of immunotherapy for patients with advanced NSCLC. Although this preliminary study suggested important trends, our sample size was small and these effects need to be confirmed in a larger cohort. [Table: see text]
A validated miRNA expression profile for response to neoadjuvant therapy in esophageal cancer.
Authors: Heath D. Skinner, Enping Xu, Jeffrey H. Lee, Manoop S. Bhutani, Brian Weston, Akihiro Suzuki, Wayne Lewis Hofstetter, Ritsuko Komaki, Jaffer A. Ajani, Xifeng Wu
Journal: Journal of Clinical Oncology (2013)

4078 Background: For patients with esophageal adenocarcinoma (EAC) preoperative chemoradiation (trimodality therapy) is the preferred approach. We examined several patient cohorts to create and validate a miRNA signature predictive for response to this therapy in esophageal carcinoma. Methods: Pre-treatment tumor specimens from 10 patients with EAC treated with trimodality therapy were examined using a TaqMan Human MicroRNA Card Set (v3.0) for expression of 754 miRNAs, of which 306 were overexpressed. miRNA expression between patients with a pathologic complete response (pCR) and those with a non-pCR was then analyzed. 44 miRNAs differentially expressed between pCR and non-pCR patients were then examined in an additional 42 EAC patientsÕ tumors (model set) using the Fluodigm 48.48 Dynamic Array and were used to generate a miRNA expression profile (MEP) predicting for response in three groups: low, intermediate and high-risk. The MEP was then validated in an additional 72 EAC patients using the Illumina miRNA Expression Array. ROC curves were generated for clinical stage, MEP and a combination of both. Results: For the model set, pCR rates in low risk patients based on the MEP were 75%, 42.9% in intermediate risk and 12.5% in high-risk patients (p trend =0.008). In the validation set the pCR rates were 66.7%, 36.5% and 15.7% for low, intermediate and high-risk patients respectively (p trend =0.025). The AUC for the ROC using the MEP was 0.72 (p=7.8x10-12) in the model set, 0.69 (p=1x10-4) in the validation set and 0.7 for the two cohorts combined (p=1.4x10-18). When clinical stage was added to the predictive model, the ROC for each group was 0.79 (p=2.6x10-19), 0.75 (p=8.7x10-27) and 0.77 (p=2x10-41) respectively. Conclusions: The MEP represents the first validated miRNA signature for therapeutic response in esophageal carcinoma and improves significantly on clinical staging. Its use could select patients at high-risk for therapeutic resistance for trial-based therapy, as well as low-risk patients for whom resection may possibly be safely omitted.
The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness
Authors: Joseph Firth, Najma Siddiqi, Ai Koyanagi, Dan Siskind, Simon Rosenbaum, Cherrie Galletly, Stephanie Allan, Constanza Caneo, Rebekah Carney, Andre F Carvalho, Mary Lou Chatterton, Christoph U Correll, Jackie Curtis, Fiona Gaughran, Adrian Heald, Erin Hoare, Sarah E Jackson, Steve Kisely, Karina Lovell, Mario Maj, Patrick D McGorry, Cathrine Mihalopoulos, Hannah Myles, Brian O'Donoghue, Toby Pillinger, Jerome Sarris, Felipe B Schuch, David Shiers, Lee Smith, Marco Solmi, Shuichi Suetani, Johanna Taylor, Scott B Teasdale, Graham Thornicroft, John Torous, Tim Usherwood, Davy Vancampfort, Nicola Veronese, Philip B Ward, Alison R Yung, Eoin Killackey, Brendon Stubbs
Journal: The Lancet Psychiatry (2019)
Breast cancer: NICE approves new drug combination treatment
Authors: Elisabeth Mahase
Journal: BMJ (2019)

A new drug combination option for some patients with advanced breast cancer will now be available through the Cancer Drugs Fund, say new draft guidelines from the National Institute for Health and Care Excellence (NICE).1

The guidance has recommended ribociclib (Kisqali) with fulvestrant as an option for people with hormone receptor positive, human epidermal growth factor receptor 2 negative, locally advanced or metastatic breast cancer who have had previous endocrine therapy.

Ribociclib, a CDK4/6 …
The Gut Microbiome: A New Player in Breast Cancer Metastasis
Authors: Wendy V. Ingman
Journal: Cancer Research (2019)

Abstract There is increasing interest in the role of the gut microbiome in health and disease, and a number of observational and in vitro studies have suggested it may play a role in breast cancer development and progression. Buchta Rosean and colleagues present the first functional evidence that a preexisting disturbance in the gut microbiome leads to increased breast cancer cell metastasis in a mouse model. This discovery places the gut microbiome as a new player in breast cancer metastasis; however, further studies are required to determine the relevance of the findings in this mouse model to human disease. A better understanding of the relationship between the bacterial ecosystem of the gut and progression of breast cancer has enormous potential for improving treatment outcomes for patients with breast cancer. See related article by Buchta Rosean et al., p. 3662
David Oliver: Can apps relieve pressure on emergency departments?
Authors: David Oliver
Journal: BMJ (2019)

The recent announcement of a new “NHS waiting time app” prompted headlines in national print and broadcast media, with claims that it could “help patients find hospitals with the shortest A&E queue.”12

The current context makes this a compelling story. Performance against emergency departments’ waiting time goals has declined over several years, with targets serially missed.3 Bed occupancy in our acute hospitals is hovering around 90%.4 Media stories describe overcrowded departments, long trolley waits, and ambulances stacked outside. NHS England is piloting some new waiting time metrics.

Reading past the headlines, the story …
Patients to be asked what they need from doctors
Authors: Abi Rimmer
Journal: BMJ (2019)

The government has instructed Health Education England to consult patients and the public on what they need from “21st century” medical graduates.

The requirement is set out in the Department of Health and Social Care’s latest mandate for HEE, published on 12 July.1 Building on the interim workforce plan published in June,2 the mandate sets out the government’s ambitions for HEE over the coming year. It says that one of HEE’s “deliverables” for 2019-20 is to “launch a national consultation by November 2019 to establish …
Trends in the Inclusion of Black and Female Surgeons in Invited Visiting Professorships
Authors: Mika M. Tabata, Eben L. Rosenthal, Carlie J. Arbaugh, Cindy Kin, Emiley Kim, Laura A. Graham, Mary T. Hawn
Journal: JAMA Surgery (2019)

This study examines the changes in the composition of visiting professorships by race and sex at 25 academic surgical programs from 2007 through 2017.
Phase Ib: Preliminary clinical activity and immune activation for NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] in patients (pts) with locally advanced or metastatic solid tumors (REVEAL Phase Ib/II Trial).
Authors: Adi Diab, Mario Marcondes, Brian Kotzin, Mary Ann Tagliaferri, Ute Hoch, Yunfeng Li, Fiore Cattaruzza, Jonathan Zalevsky, Andrew Scott Brohl, James Brugarolas, Mehmet Asim Bilen, Shilpa Gupta, Evidio Domingo Musibay, Anthony Paul Conley, Erkut Hasan Borazanci, Sandra P. D'Angelo, Brendan D. Curti
Journal: Journal of Clinical Oncology (2019)

26 Background: NKTR-262 is a novel intratumoral prodrug designed to promote tumor antigen release, an immune stimulatory environment, and antigen presentation. NKTR-214 increases CD8+ T cells and NK cells in the tumor microenvironment. The combination of NKTR-262 with NKTR-214 accesses innate and adaptive immunity to provide an abscopal response and systemic tumor immunity. The Phase 1b/2 REVEAL trial is enrolling. Methods: In a 3+3 Phase 1 design, pts who are relapsed/refractory to ≥1 CPI receive escalating doses of intratumoral (IT) NKTR-262 followed by combined q3w treatment of IT NKTR-262 and fixed-dose intravenous (IV) NKTR-214 (0.006 mg/kg). Phase 1 will evaluate PK, safety, efficacy, and determine recommended Phase 2 dose. Scans are conducted every 9 wks (± 1 wk). Peripheral blood (PB) and tumor tissue are collected to measure biomarkers of immune activation. In Phase 2 expansion, NKTR-262 + NKTR-214 ± IV nivolumab (360 mg) will be assessed in specific tumor cohorts of IO-naïve and experienced pts. Results: As of 06 Nov 2018, 11 pts had received at least one cycle of NKTR-262 + NKTR-214 therapy. 7/11 pts were efficacy evaluable with at least one on-treatment scan (4 MEL, 2 SARC, 1 CRC). 2/4 R/R melanoma pts had uPRs with 100% (scan 2) and 40% (scan 1) reductions in target lesions per RECIST 1.1, respectively. Both patients remain on treatment. Two SARC pts had stable disease at scan 1. No pts experienced G3 or higher TRAEs or immune-related adverse events (AEs). Most common G1-2 AEs were transient flu-like symptoms. Gene expression analysis of tumor and PB show dose-dependent induction (4 to 16-fold) of TLR target genes. Consistent with the mechanism of action for NKTR-214, PB flow cytometry shows an average 13-fold increase from baseline in Ki67+ CD8+T cells in 6 pts. Conclusions: NKTR-262 + NKTR-214 engage the immune activation cascade from local tumor antigen production to anti-tumor T cell response. Initial dose levels of NKTR-262 with fixed-dose NKTR-214 were well-tolerated with early evidence of clinical activity. These data support continued evaluation of the combination +/- nivolumab. Clinical trial information: NCT03435640.
Abstract 5376: Whole-exome sequencing of acquired nevi identifies novel mechanisms for development and maintenance of benign neoplasms
Authors: Mitchell S. Stark, Jean-Marie Tan, Lisa Tom, Kasturee Jagirdar, Duncan Lambie, Helmut Schaider, H. Peter Soyer, Richard A. Sturm
Journal: Cancer Research (2018)

Abstract Background: Acquired melanocytic nevi (AMN) are often mimicking melanoma and ~30% of all melanomas arise within a pre-existing nevus. However, the melanoma transformation rate of each nevus is rare despite the detection of oncogenic mutations BRAF or NRAS mutations in 100% of nevi.Objective: To identify the underlying genetic mechanisms for nevus development.Methods: Nevi, adjacent normal skin, and saliva were sampled from a cross-sectional study. All nevi were clinically, dermoscopically, and histopathologically documented. Using whole-exome sequencing (WES) we assessed the somatic mutational landscape, mutation signatures and copy-number aberrations (CNA) in 30 acquired melanocytic nevi and matching normal skin.Results: In addition to identifying somatic mutations, we confirm the presence of mutational signatures relating to age and ultra-violet radiation (UVR) which mirrors those observed in melanomas of the skin. In matching normal skin of all nevi, we rarely observed the presence of a UVR mutation signature (10% vs. 97% in nevi) despite being exposed to the same amount of UVR as the associated naevus. Instead, we have identified the predominance of defective DNA repair mutation signatures (93%) which we postulate creates the environment for melanocyte transformation sufficient for nevi and perhaps de novo melanoma growth. In copy number aberration (CNA) analysis, in nevi with copy number loss of tumour suppressor genes (TSG), these were balanced by loss of potent oncogenes. Moreover, reticular and non-specific patterned nevi revealed an increased (p&amp;lt;0.0001) number of CNA as compared with globular patterned nevi. Conclusion: The mutation signature data generated in this study confirms that UVR and defective DNA repair mechanism strongly contributes to nevogenesis. The observed copy number changes reflect at a genomic level, the dermoscopic differences of AMN. Lastly, we propose that the balanced loss of TSGs and oncogenes is a protective mechanism of AMN. Citation Format: Mitchell S. Stark, Jean-Marie Tan, Lisa Tom, Kasturee Jagirdar, Duncan Lambie, Helmut Schaider, H. Peter Soyer, Richard A. Sturm. Whole-exome sequencing of acquired nevi identifies novel mechanisms for development and maintenance of benign neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5376.
Phase I/II trial of BMS-986205 and nivolumab as first-line therapy in hepatocellular carcinoma.
Authors: Justin Chen, Jingran Ji, May Thet Cho, Arta Monjazeb, Sepideh Gholami, Edward Jae-Hoon Kim
Journal: Journal of Clinical Oncology (2019)

TPS57 Background: Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death worldwide and incidence is rising. Sorafenib and lenvatinib are approved for first-line use in unresectable HCC; however, survival benefit remains low. Nivolumab, a human monoclonal antibody to programmed death-1 (PD1) receptor, has been approved as second-line therapy in patients with unresectable HCC refractory to sorafenib. BMS-986205 selectively inhibits human indoleamine-2,3- dioxygenase 1 (IDO1), an intracellular enzyme expressed in various malignancies that promotes immune tolerance. Thus, the combination of PD-1 antibody and IDO1 inhibitor is a promising strategy to augment immunotherapy against HCC. We aim to evaluate the combination of BMS-986205 with nivolumab 3 mg/kg every 2 weeks in unresectable and metastatic HCC. Methods: Primary objectives were to identify tolerable dosing of BMS-986205, and to evaluate safety, tolerability, and efficacy of combination therapy, the latter defined by objective response rate. Secondary objectives were to evaluate disease control rate, duration of response, progression free survival, and overall survival. Phase I (dose escalation phase) will monitor two dose levels of BMS-986205: 50mg daily with conditional escalation to 100mg daily depending on dose-limiting toxicity. Phase II (expansion phase) will begin after maximum tolerated dose is reached. The phase II cohort will be run as a Simon two-stage design to allow for early trial stoppage for futility. Estimated study duration is 36 months with a 24-month accrual period for a total of 17 patients. Patients will be followed for 100 days after the last dose of treatment or until all treatment-related clinical toxicities resolve to baseline or grade ≤ 1. Assessments prior to therapy include imaging, tissue biopsy, serum correlatives, and stool samples. Tissue biopsy will be repeated at 4 weeks. Imaging will be repeated at 8 and 16 weeks, then every 12 weeks until end of treatment. Serum correlatives will be repeated intermittently throughout. At progression, imaging, tissue biopsy, and serum correlatives will be repeated. Data will be reported using 95% confidence intervals, Kaplan-Meier estimates, and frequency tables. Clinical trial information: NCT03695250.
Upregulation of programmed death ligand 1 (PD-L1) on circulating epithelial tumor cells (CETCs) as consequence of adjuvant radiation therapy in primary breast cancer patients.
Authors: Monika Pizon, Dorothea Schott, Ulrich A. Pachmann, Katharina Pachmann, Matthias Maeurer
Journal: Journal of Clinical Oncology (2019)

3 Background: Radiation therapy (RT) is an integral part of the treatment of breast carcinoma but unfortunately many patients experience local recurrence. During the inflammatory response that accompanies radiation tumor cells may develop multiple resistance mechanisms for example the up-regulation of PD-L1 on tumor cells which leads to immune evasion. Since CETCs arise from the tumor it is conceivable that under evolutionary pressure they might share some of the immune escape mechanism inherent to tumor cells. In this study we demonstrate that RT leads to a transitory adaptive up-regulation of PD-L1 expression on CETCs. Methods: CETCs and the expression of PD-L1 and Ki-67 were analyzed from 25 patients with primary non-metastatic breast cancer using the maintrac method. The fraction of PD-L1 and Ki-67 positive CETCs were assessed at baseline, 3 and 6 weeks after start of RT and 6 weeks after end of therapy. Additionally, copy number status of PD-L1 was determined using FISH. Results: Fractionated-dose RT leads to a significant increase in PD-L1 expression on CETCs with the highest expression level midterm of irradiation as compared to baseline (49% vs. 74%, p &lt; 0.01). 6 weeks after end of RT the number of PD-L1 positive CETCs returned to baseline value. The up-regulation of PD-L1 was dose dependent. Patients who received higher total dose had significantly more PD-L1 positive CETCs as compared to patients treated with lower total dose midterm of RT (64% vs. 43, p &lt; 0.05). Before start of therapy there was a correlation between the fraction of PD-L1 and Ki-67 positive CETCs (r = 0.6, p &lt; 0.01). PD-L1 copy number gains were significantly associated with PD-L1 expression (r = 0.6, P &lt; 0.05). Conclusions: RT leads to an up-regulation of PD-L1 expression on CETCs, which could be a possible mechanism of acquired radioresistance. Combining immunomodulatory agents with radiation might have the potential to overcome this resistance and could improve clinical outcome in breast cancer.
Facile Fluorescence Monitoring of Gut Microbial Metabolite Trimethylamine <i>N</i>-oxide via Molecular Recognition of Guanidinium-Modified Calixarene
Authors: Huijuan Yu, Wen-Chao Geng, Zhe Zheng, Jie Gao, Dong-Sheng Guo, Yuefei Wang
Journal: Theranostics (2019)

Detection and quantification of trimethylamine
Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial
Authors: Robert Croop, Peter J Goadsby, David A Stock, Charles M Conway, Micaela Forshaw, Elyse G Stock, Vladimir Coric, Richard B Lipton
Journal: The Lancet (2019)
Daratumumab eradicates minimal residual disease in a preclinical model of pediatric T-cell acute lymphoblastic leukemia
Authors: Fotini Vogiatzi, Dorothee Winterberg, Lennart Lenk, Swantje Buchmann, Gunnar Cario, Martin Schrappe, Matthias Peipp, Paulina Richter-Pechanska, Andreas E. Kulozik, Jana Lentes, Anke K. Bergmann, Thomas Valerius, Fabian-Simon Frielitz, Christian Kellner, Denis M. Schewe
Journal: Blood (2019)
Abstract 14656: Effects of Ranolazine in Symptomatc Patients With Stable Coronary Artery Disease. A Meta-analysis of Randomized Clinical Trials
Authors: Gianluigi Savarese, Giuseppe Rosano, Carmen D'Amore, Donatella Ruggiero, Francesca Musella, Bruno Trimarco, Pasquale Perrone-Filardi
Journal: Circulation (2013)

Background: Ranolazine (R), as add-on therapy in symptomatic patients with chronic stable coronary artery disease (CAD), has been tested in randomized clinical studies. Aim of the study was to asse...
Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology
Authors: Xuanmao Jiao, Omar Nawab, Tejal Patel, Andrew V. Kossenkov, Niels Halama, Dirk Jaeger, Richard G. Pestell
Journal: Cancer Research (2019)

Abstract Experiments of nature have revealed the peculiar importance of the G-protein–coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and “stemness”. Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.