tbuckley/cabot-search huggingface dataset:
Investigation of the immune infiltrate of melanoma metastases under immune checkpoint inhibition.
Authors: Jessica Cecile Hassel, Michael Flossdorf, Sonja Hänzelmann, Julia Winkler, Jasmin Roth, Claudia Lauenstein, Lena Appel, Enrico Streit, Niels Halama, Marta Faryna, Alexander Enk, Rienk Offringa, Ugur Sahin, Isabel Poschke
Journal: Journal of Clinical Oncology (2017)

9570 Background: Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers. Methods: We investigated metastases from 56 melanoma patients before and during treatment with immune checkpoint blockers (i) immunohistochemically, (ii) with TCR repertoire profiling and (iii) analysis of the transcriptome. The patients were treated with ipilimumab (n = 25) or pembrolizumab (n = 23) or ipilimumab/nivolumab (n = 7); half of them had a disease control, the other half progressed as best response to treatment. Results: In contrast to previous reports immunohistochemical analysis of the immune infiltrate revealed no significant difference in the number of CD8+ TILs in pretreatment samples of responders and non-responders. Instead, the number of CD4 + TILs including regulatory T cells (Treg) and the number of PD-1 + cells was higher in responders especially when receiving pembrolizumab. Samples taken at least 6 weeks after start of the immune checkpoint blocker showed a significant higher number of immune cells in responders through all T cell subsets (CD3,4,8,FoxP3, PD-1), B cells (CD20) as well as macrophages (CD68, CD163). TCR repertoire profiling by deep TCR sequencing demonstrated that responders develop a more diverse repertoire under treatment (p = 0.05). Pretreatment samples as well as the size of the top 10 TCR clones posttreatment did not differ significantly in responders and non-responders. By RNA sequencing no differential expression profiles between responders and non-responders was found pretreatment. Posttreatment samples expressed different genes compared to pretreatment samples in responders including MHC molecules, CDK2/4, Myc, TNF family members and different apoptosis-inducing genes. There was no differential gene expression in non-responders pre- and posttreatment. Conclusions: Pretreatment metastases from responders and non-responders do not differ much. With treatment responding patients have significant higher numbers of immune cells including T- and B- cells as well as macrophages and develop a more diverse TCR repertoire. RNA sequencing revealed a differential expression pre- versus posttreatment only in responding patients.
Preoperative hemoglobin-to-red cell distribution width ratio as a novel prognostic parameter in hepatocellular carcinoma after curative resection.
Authors: Ze-xiao Lin, Dan-yun Ruan, Yang Li, Dong-hao Wu, Tian-tian Wang, Jin-Xiang Lin, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2017)

e15634 Background: Cumulative evidence has demonstrated that interaction between tumor and the inflammatory microenvironment plays a critical role in the development and progression of hepatocellular carcinoma (HCC). This study aims to investigate the prognostic value of hemoglobin to red cell distribution width (RDW) ratio (HRR), as a novel and simple biomarker reflecting both the host inflammatory response and nutrition status, in patients with HCC undergoing curative hepatectomy. Methods: We retrospectively analyzed 373 HCC patients treated with hepatic resection between January 2004 and December 2012. Preoperative complete blood counts were used to calculate HRR. The best cut-off for survival analysis was determined by receiver operating characteristics (ROC) curve analysis. Univariate and multivariate analyses were applied to assess HRR and other clinicopathological variables. Results: The optimal cutoff value of HRR was 1.06 with an area under the curve (AUC) of 0.591 (95% CI, 0.540-0.642, p = 0.0072). A low preoperative HRR level ( &lt; 1.06) was significantly correlated with hypoalbuminemia, female sex, the presence of portal hypertension and elevated level of total bilirubin. After a median follow-up of 48.5 months (range, 2-148.2 months), patients with a low HRR had significantly worse 5-year overall survival (OS) (69.2% vs 83.9%, p = 0.002). However, no significant difference was observed between low and high HRR groups with respect to recurrence free survival. The HRR (p = 0.009), histological differentiation (p = 0.003), Barcelona Clinic Liver Cancer stage (p = 0.003), serum alkaline phosphatase level (p = 0.008) and serum alanine aminotransferase level (p = 0.041) were identified to be independent prognostic factors of OS by multivariate analysis. This cox model was validated by bootstrap resampling, confirming low HRR as an independent predictor of shorter OS after adjustment (p = 0.01). Conclusions: Our study demonstrates for the first time that preoperative HRR can serve as an independent prognostic maker in HCC patients after radical surgery. Incorporation of HRR into other indices may provide better prognostic stratification.
Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma
Authors: Lotte Spel, Joppe Nieuwenhuis, Rianne Haarsma, Elmer Stickel, Onno B. Bleijerveld, Maarten Altelaar, Jaap Jan Boelens, Thijn R. Brummelkamp, Stefan Nierkens, Marianne Boes
Journal: Cancer Research (2018)

Abstract Neuroblastoma is the second most common tumor in children. The cause of neuroblastoma is thought to lie in aberrant development of embryonic neural crest cells and is accompanied by low MHC-1 expression and suppression of the NF-κB transcription factor, thereby gearing cells toward escape from immunosurveillance. Here, we assess regulation of the MHC-1 gene in neuroblastoma to enhance its immunogenic potential for therapeutic T-cell targeting. A genome-wide CRISPR screen identified N4BP1 and TNIP1 as inhibitory factors of NF-κB-mediated MHC-1 expression in neuroblastoma. Patients with advanced stage neuroblastoma who expressed high levels of TNIP1 and N4BP1 exhibited worse overall survival. Depletion of N4BP1 or TNIP1 increased NF-κB and MHC-1 expression and stimulated recognition by antigen-specific CD8+ T cells. We confirmed that TNIP1 inhibited canonical NF-κB member RelA by preventing activation of the RelA/p50 NF-κB dimer. Furthermore, N4BP1 inhibited both canonical and noncanonical NF-κB through binding of deubiquitinating enzyme CEZANNE, resulting in stabilization of TRAF3 and degradation of NF-κB-inducing kinase NIK. These data suggest that N4BP1/CEZANNE or TNIP1 may be candidate targets for immunotherapy in neuroblastoma tumors and should lift NF-κB suppression, thereby triggering increased peptide/MHC1-mediated tumor reactivity to enhance therapeutic T-cell targeting. Significance: Aberrant regulation of NF-κB and MHC-1 in neuroblastoma tumors provides new targets for immunotherapeutic approaches against neuroblastoma.
Abstract 11919: Dementia and Stroke Rates Were Lower Among Patients Receiving Long-term Anticoagulation Therapy With Novel Oral Anticoagulants Compared to Warfarin
Authors: Victoria Jacobs, Heidi T May, Tami L Bair, Jeffrey L Anderson, Brian G Crandall, Michael Cutler, John D Day, Charles D Mallender, Jeffrey S Osborn, Scott M Stevens, J P Weiss, Scott C Woller, T J Bunch
Journal: Circulation (2015)

Introduction: Patients with atrial fibrillation (AF) are at an increased risk of developing dementia, and this risk appears sensitive to quality of warfarin control. Longstanding warfarin use predisposes AF patients to the development of microbleeds if they are over-anticoagulated and microemboli if they are under-anticoagulated. The novel oral anticoagulants (NOACs) offer an alternative to warfarin with a predictable anticoagulant effect, and comparatively favorable intracranial bleeding and thrombosis rates which may lower the risk of dementia. Hypothesis: The use of NOACs will be associated with a lower risk of stroke, TIA, and dementia compared to warfarin. Methods: Patients receiving long-term anticoagulation therapy with either warfarin or a single NOAC for thromboembolism prevention were studied (June 2010-December 2014). NOAC and warfarin patients were matched 1:1 by index date (± 6 months) and propensity score (±0.01). Multivariable Cox hazard regression was performed to evaluate the association of NOAC compared to warfarin use for the composite outcome of dementia, stroke, and TIA. Results: A total of 5,254 (2,627 per group) patients were studied, and those receiving NOACs included: apixaban= 590 (22.5%), dabigatran=583 (22.2%), and rivaroxaban=1,454 (55.3%). Average age was 72.4±10.9 and 59.0% were male. The majority of patients were receiving long-term anticoagulation for AF (warfarin: 96.5% vs. NOAC: 92.7%, p&lt;0.0001). History of a prior stroke/TIA were similar between the groups (warfarin: 10.7% vs. NOAC: 10.8%, p=0.89). Dementia incidence alone was lower in the NOAC group compared to the warfarin group (0.3% vs. 1.6%, p&lt;0.0001). The composite outcome of dementia, stroke, and TIA occurred in 4.7% of warfarin patients and 1.8% of NOAC patients (p&lt;0.0001). After adjustment, patients taking NOACs had a 51% decreased risk of dementia incidence or subsequent stroke or TIA compared to patients taking warfarin (HR=0.49 (0.35, 0.69), p&lt;0.0001). Conclusions: This study shows the use of NOACs in a community setting to be superior to that of warfarin for the composite outcome of dementia, stroke, and TIA among patients receiving long-term oral anticoagulation.
Management of stage II nasopharyngeal carcinoma (NPC) in the US population: Retrospective analysis of the National Cancer Database (NCDB).
Authors: Omer Toor, Lara Ann Kujtan, Zaheer Ahmed, Kevin F Kennedy, David A. Schomas, Valerie Wood, Ashiq Masood, Janakiraman Subramanian
Journal: Journal of Clinical Oncology (2018)

e18088 Background: Concurrent chemotherapy with definitive radiation is the standard of care treatment for locally advanced NPC. However, there is limited data on the optimal management of stage II or intermediate NPC. We performed a retrospective analysis of the NCDB to evaluate the role of chemotherapy and definitive radiation in the management of stage II NPC. Methods: We identified 702 patients diagnosed with T1-2, N0-1, M0 NPC , from 2004 to 2013. 5-year survival was calculated using Kaplan Meier (KM) analysis. Multivariate analysis was used to obtain hazard ratios (HR). Results: Of the 702 patients, 620 underwent CT+RT and 82 received RT only. The majority of patients (n = 485; 69%) were white. KM analysis showed improved 5-year survival in the CT+RT group as compared to RT only (78.4% vs 61.6%; p = 0.001). Multivariate analysis (table 1) also showed improved survival with the addition of chemotherapy. (HR, 0.54; 95% CI, 0.36 to 0.81; p-value = 0.0029). Elderly patients with age > 65 (HR, 2.3; 95% CI, 1.67 to 3.15; p-value = < 0.0001) and Charlson-Deyo co-morbidity score > 1 (HR, 2.96; 95% CI, 1.6 to 5.49; p-value = 0.0006) were predictors of poor survival. Conclusions: In this retrospective database analysis, patients with stage II nasopharyngeal cancer had improved survival with chemoradiation compared to those who underwent radiation only. Elderly patients with comorbidities had worse outcomes. Table 1. Multivariate analysis for predictors of overall survival in patients with stage II NPC Variable HR (95% CI) p-value Age ≥ 65 2.3 (1.67 - 3.15) < .0001 CT 0.54 (0.36 - 0.81) 0.0029 CDC Score 1 vs 0 1.31 (0.85,2.02) 0.2233 CDC Score > 1 vs 0 2.96 (1.6 - 5.49) 0.0006 Clinical N1 vs N0 Clinical T2 vs T1 1.72 (1.16 - 2.57) 1.37 (0.96 - 1.95) 0.0074 0.0855 Clinical N1 vs N0 1.72 (1.16 - 2.57) 0.0074 Others vs White 0.77 (0.51 - 1.18) 0.2267 Grade: 2 vs 1 0.91 (0.32 - 2.59) 0.8534 Grade: 3 vs 1 0.58 (0.21 - 1.62) 0.2994 Grade: 4 vs 1 0.48 (0.16 - 1.49) 0.2060
Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma
Authors: Julien Calderaro, Eric Letouzé, Quentin Bayard, Anais Boulai, Victor Renault, Jean-François Deleuze, Oriol Bestard, Dominique Franco, Elie-Serge Zafrani, Jean-Charles Nault, Michel Moutschen, Jessica Zucman-Rossi
Journal: New England Journal of Medicine (2018)

AA Amyloidosis Caused by Hepatocellular Adenoma A woman presented with AA amyloidosis that was found to be caused by a genetic lesion in an inflammatory hepatocellular adenoma that led to overprodu...
Using patient satisfaction to predict readmissions in cancer patients.
Authors: Lisa Diamond, Scott Ogden, John Frame, Patrick Samedy, James N Masciale, Svetlana Granovsky, Kent Sepkowitz
Journal: Journal of Clinical Oncology (2018)

e18870 Background: Thirty-day unplanned readmissions are a fundamental indicator of hospital quality. Current models used to predict readmissions perform poorly in cancer patients. We explored how patient-reported satisfaction on the HCAHPS hospital survey correlates with and improves predictive models on 30-day readmissions. Methods: We used data from HCAHPS responses (n = 26,044) between January 2010 and June 2017 from a single, urban comprehensive cancer center. We correlated all HCAHPS questions to readmissions, replicating a previous study’s analysis of 8 HCAHPS questions. Next, we created a prediction model for each HCAHPS questions using binomial logistic regression on clinical variables (MDC, Service, length of stay, number of medications at discharge, history of adverse events, an adverse event on their current visit, hour of discharge, history of readmissions) and satisfaction results. Finally, we performed a factor analysis to determine if latent subscales exist among the highly correlated HCAHPS questions. Results: Among the 21 HCAHPS questions analyzed, 15 had significant associations with readmissions, after controlling for clinical variables. For 14 of these items, patients who selected the top scores on these questions were less likely to be readmitted. For example, patients who selected the top score for the item “Did you have help when you pressed the call button?” were significantly less likely to be readmitted (OR = .69). Non-intuitively, patients who selected the the top score for the item “Did staff talk to you about whether you would have help after you left?” were more likely to be readmitted (OR = 1.31). Our final model accounts for 89.7% of the variance in readmissions when accounting for clinical factors as well as our decided-upon HCAHPS questions. Conclusions: Patient satisfaction ratings offer unique information on the probability that a cancer patient will be readmitted to the hospital. This novel source of data can help improve prediction models and may be considered when designing interventions. As patient satisfaction is increasingly offered in real-time and online, these data could be used to target interventions for cancer patients at high risk of readmissions.
Association between phase angle and survival in patients with advanced cancer admitted to an acute palliative care unit (APCU).
Authors: David Hui, Jessica Anne Moore, Minjeong Park, Diane D. Liu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2018)

10023 Background: Many complex healthcare decisions in the last weeks and days of life are dependent on accurate prediction of survival. Phase angle, a novel measure of cellular function, has been found to be prognostic in patients with months of survival; however, its utility has not been examined in patients with weeks/days of survival. We determined the association between phase angle and survival in advanced cancer patients admitted to an APCU. Methods: In this prospective cohort study, we assessed phase angle with bioelectric impedance analysis in consecutive patients with advanced cancer admitted to our APCU. Survival analysis was conducted using the Kaplan Meier method, log rank test and multivariate Cox regression analysis, adjusting for established prognostic factors including the Palliative Prognostic Score and delirium. We identified the optimal phase angle cutoff using the Contal and O’Quigley method. Subgroup analysis was conducted in patients without peripheral edema. Results: Among 204 patients, the median overall survival was 10 days (95% confidence interval 8-11 days). 74 (36%) did not have edema. The median phase angle was 3.7° for the entire cohort and 3.9° for the no edema cohort. In univariate analysis, a low phase angle was associated with decreased survival for the entire cohort (≤3° vs. > 3°, median survival 7 vs. 10 days; P = 0.045) and for the no edema cohort (5 vs. 18 days; P < 0.001). In multivariate Cox regression analysis adjusting for known prognostic factors, phase angle was not significant for the entire cohort but remained significant in the no edema cohort (hazard ratio 2.46, 95% confidence interval [CI] 1.14, 5.31; P < 0.001). Specifically, phase angle ≤3° had an accuracy of 86% (95% CI 77%-93%) for 3 day survival among patients without edema, with a sensitivity of 50%, specificity of 90%, positive predictive value of 30%, negative predictive value of 95% and positive likelihood ratio of 5.2. Conclusions: We identified phase angle as a novel, independent prognostic factor even among patients with a short survival. Phase angle ≤3° was predictive of impending death within 3 days. Our findings suggest that phase angle may be best used among patients without edema.
Safety and feasibility of adding tumor debulking to palliative chemotherapy in multi-organ metastatic colorectal cancer: The ORCHESTRA trial.
Authors: Elske C. Gootjes, Eric P. van der Stok, Lotte Bakkerus, Tineke E Buffart, Barbara M Zonderhuis, Martijn R. Meijerink, Cornelis J Haasbeek, Peter M van de Ven, Albert J. Ten Tije, Jan Willem De Groot, Sandra A Radema, Esther Van Meerten, Joost Nuyttens, Cornelis Verhoef, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2017)

3553 Background: For selected patients with oligometastatic colorectal cancer (mCRC), local treatment of metastases is standard of care based on retrospective reports showing long term survival rates. Local treatment of metastases is technically feasible in an increasing number of patients with multi-organ mCRC. It is unknown if patients with extensive disease will benefit from tumor debulking when added to first line palliative chemotherapy. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival (OS) benefit from tumor debulking in patients with multi-organ mCRC. Methods: Patients with multi-organ mCRC were eligible if &gt; 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. All patients received oxaliplatin based chemotherapy ± bevacizumab. In case of stable disease or response at first evaluation (9 weeks), patients were randomized to continuation of chemotherapy or tumor debulking followed by chemotherapy. Adverse events were reported. If patient withdrawal after randomization was &lt; 10%, the study was deemed feasible. Study continuation was based on the interim report on safety and feasibility after inclusion of 100 (of 478) patients. Results: Patients were randomized to the standard (N = 43) or intervention arm (N = 45). No patients withdrew after randomization. In 6.8% of patients debulking was not performed due to progressive disease (N = 5) or death (N = 1) prior to local treatment. Two patients had no lesions left to treat, 37 patients underwent tumor debulking. In 15 patients (40%) 21 serious adverse events related to debulking were reported, 83.7% of patients had no SAEs or recovered within 30 days. Postoperative 90-day mortality was 2.7% (N = 1). Chemotherapy was resumed in 86.5% of patients, median time to restart was 12.7 weeks (SD 5.6) and 78.4% completed ≥24 weeks of chemotherapy. Conclusions: Tumor debulking is feasible and safe and does not prohibit administration of palliative chemotherapy in the majority of patients with multi-organ mCRC. The ORCHESTRA trial will continue accrual to determine whether the aim of &gt; 6 months OS benefit from tumor debulking will be achieved. Clinical trial information: NCT01792934.
Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Safety analysis from an expanded access study.
Authors: Joaquim Bellmunt, Sumanta K. Pal, Hanzhe Zheng, Darren Tayama, Dannis Chang, Jean H. Hoffman-Censits
Journal: Journal of Clinical Oncology (2017)

4532 Background: A majority of mUC pts progress on standard platinum-based chemo regimens. Atezo (anti–PD-L1) was approved in the US for mUC in the post-platinum setting. Here we report the preliminary safety results from an expanded access program conducted to grant access to atezo, prior to commercial availability, to a broader range of mUC pts than are typically eligible for Phase I-III studies. Methods: From Nov 2015-Aug 2016, this study (NCT02589717) enrolled mUC pts who progressed during or following platinum. Atezo was given 1200 mg IV q3w, and pts could be treated post RECIST v1.1 PD until lack of clinical benefit (per investigator). Safety and clinical activity were key endpoints. PD-L1 expression on immune cells (IC) was assessed with the VENTANA SP142 IHC assay on the first 73 pts prior to protocol amendment omitting this requirement. This study was ended early following FDA approval of atezo. Results: 218 pts were enrolled at 36 sites in the US, with 214 treated pts comprising the safety/efficacy population (Table). Median treatment duration was 9 wks (range 3-26), corresponding to a median of 3 doses of atezo (range 1-8). Overall, 89% of pts had an AE. Treatment-related AEs (TRAEs) occurred in 46% (any Gr) and 7% (Gr3-4) of pts; 2 treatment-related Gr 5 AEs were seen (ileus; acute respiratory failure). TRAEs ≥ 5% were fatigue, decreased appetite and anemia. TRAEs leading to dose interruption or discontinuation occurred in 11% and 6% of pts, respectively. Investigator-assessed RECIST v1.1 ORR was 15% (95% CI: 9, 23), and disease control rate (ORR + SD) was 49% (95% CI: 40, 59). Additional clinical data will be reported. Conclusions: In this expanded access study, atezo was administered to &gt; 200 mUC pts. Overall, atezo was safe and tolerable, supporting its use in a wider platinum-based population. Clinical trial information: NCT02589717. [Table: see text]