tbuckley/cabot-search huggingface dataset:
Characterization of mechano-microenvironment of acral melanoma and its potential impact on tumor cell invasion.
Authors: Xin Yi, Jia yong Liu, Jie Dai, Jun Guo, Cong ying Wu, Lu Si, Lili Mao, Zhong Hui Qi
Journal: Journal of Clinical Oncology (2019)

e21062 Background: Acral melanoma is the main subtype in Asia, and tends to be insensitive to conventional and novel therapies compared with cutaneous melanomas. It has been proved that biomechanical alterations inside the tumor microenvironment significantly affect tumor progression in breast, pancreatic and other cancers(Hepatology. 2016 July ; 64(1): 261–275; Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXXI) . Hence, we hypothesized that the biomechanical microenvironment plays critical roles in proliferation and invasion in acral melanoma. In this study, the main purpose is to observe whether melanoma cells have the same ability called “durotaxis” as other tumors, which to respond to a gradient of extracellular stiffness and migrate in a directed fashion. Methods: In this study, the stiffness was compared between the acral melanoma tissue and the normal tissue by using the atomic force microscope (AFM) with fresh samples and the freezing microtome sectioning specimen (J. Matthew Barnes et al., Nature Cell Biology 2018.) . A stiffness gradient polyacrylamide hydrogel system was constructed to observe how the acral melanoma cells response. Using automated tracking (Curr Protoc Cell Biol. ; 76: 12.12.1–12.12.16.) of positional data for large sample size of single migrating cells to systematically analyze polarized melanoma cell migration in response to stiffness gradient. Results: The results showed that 1) all the acral melanoma cell lines tested displayed strong anti-durotactic migratory response, which was in accordance with the AFM measurement that the melanoma microenvironment gradually softened; 2) Acral melanoma cells tend to move toward softer areas on gradient gels, which is contrary to the migration behavior of most other tumor cells. Conclusions: In this study, we presented the different migratory pattern of acral melanoma cells. It may illustrate the invasion mechanism for aral melanoma cells. It could also herald that extracellular matrix may be a potential therapeutic target in acral melanomas.
Abstract 19912: Direct Current Block of the Paravertebral Chain Stabilizes Ventricular Electrical Function Post-Myocardial Infarction
Authors: Una Buckley, Ray W Chui, Pradeep S Rajendran, Tina Vrabec, Kalyanam Shivkumar, Jeffrey L Ardell
Journal: Circulation (2016)

Background: Surgical sympathetic decentralization has evolved to effectively treat refractory ventricular arrhythmias but has irreversible off target side effects. Bioelectric therapies applied to ...
Sarcopenia as a predictor of survival in patients with epithelial ovarian cancer (EOC) receiving platinum and taxane-based chemotherapy.
Authors: Stuart-Allison Moffat Staley, Katherine Tucker, Meredith Newton, Michelle Ertel, Yingao Zhang, Irene Doherty, Paola A. Gehrig
Journal: Journal of Clinical Oncology (2019)

e17030 Background: Severe skeletal muscle loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased treatment toxicity. This relationship has recently been demonstrated in women with metastatic breast cancer, but there is a paucity of data regarding this correlation in women with EOC. Thus, our goal was to evaluate if sarcopenia, as assessed by computed tomography (CT) morphometric measurements, was associated with worse survival outcomes in EOC patients undergoing primary platinum and taxane-based chemotherapy. Methods: EOC patients diagnosed between 06/2000 and 02/2017 who received treatment with platinum and taxane-based chemotherapy were included. CT abdominal images closest to the time of diagnosis were retrospectively evaluated for skeletal muscle area at the 3 rd lumbar vertebrae. Measurements were obtained with use of TomoVision® radiological software (SliceOmatic – version 5.0, Quebec, Canada). Sarcopenia was defined as Skeletal Muscle Index (SMI = SMA/height 2 ) ≤ 41. Data analysis included Kaplan-Meier plots to assess survival, and descriptive statistics was utilized to describe characteristics between the two groups. Results: 201 EOC patients were evaluated. Sixty-four percent (128/201) met criteria for sarcopenia (SMI ≤ 41) at time of diagnosis. Seventy-six percent of patients were diagnosed with Stage III or IV disease, with high-grade serous as the most common histology (74%). Median age at diagnosis was 61 years. Approximately one third were obese. Body mass index was greater in the SMI &gt; 41 group compared to the SMI ≤ 41 group (31.3 vs 26.3, p &lt; 0.001). There was no difference in the prevalence of chronic conditions, including diabetes, coronary artery disease, hypertension, chronic kidney disease, or tobacco use, between the two groups. The mean overall survival did not differ between patients with SMI &gt; 41 and SMI ≤ 41 (36.5 vs 40.8 months, p = 0.4, respectively). Conclusions: Based on this patient cohort, sarcopenia was not associated with worse survival outcomes in EOC patients receiving first-line platinum and taxane-based chemotherapy. Further prospective studies are needed to explore other diagnostics that may allow us to provide improved accuracy and individualization in the care of women with advanced ovarian cancer.
The impact of geography and center volume on access to care and outcomes in advanced hepatocellular carcinoma (HCC): A retrospective population based study.
Authors: Irene S. Yu, Shiru Lucy Liu, Valeriya O. Zaborska, Tyler Raycraft, Howard John Lim, Sharlene Gill, Janine Marie Davies
Journal: Journal of Clinical Oncology (2019)

e15597 Background: Treatment of advanced HCC is complex and involves specialized multidisciplinary care. We aimed to characterize the impact of geography and center volume on access to care and outcomes in HCC patients (pts). Methods: HCC pts who received sorafenib in British Columbia from 2008 to 2016 were included. Pts were stratified by rural vs urban status (distance from cancer center), and high volume (HVC) vs lower volume (LVC) centers. Chi-square tests and Kaplan Meier were used to test for differences between groups. Results: Of 288 pts identified, median was age 62 (IQR 56-72), 81% male, 40% Asian, 82% ECOG 0/1 and 90% Child Pugh A. Hepatitis C (32%), hepatitis B (31%) and alcohol (25%) related liver disease were most common. Most pts resided within 100 km (85%) and 173 (60%) were treated at HVC. Ethnicity, liver disease etiology, ECOG and M1 disease varied by stratification (Table). Rural pts were more likely to see an internist (30% vs 16%, p=0.04); access to other subspecialists was similar (all p&gt;0.05). HVC pts were more likely to see a hepatologist (83% vs 19%), hepatobiliary surgeon (57% vs 42%), and/or interventional radiologist (32% vs 13%) compared to LVC pts (all p&lt;0.01). Number of specialists seen correlated with survival (36.4 vs 20.3 vs 12.6 mo for ≥ 3 vs 2 vs 1 specialist(s), p&lt;0.01). Median OS from time of diagnosis was higher for HVC pts (24.7 vs 13.2 mo, p&lt;0.01), but similar when stratified by distance (p=0.44) and from sorafenib initiation (p=0.66). Conclusions: HCC patients treated at a HVC are more likely to see specialized clinicians and have improved survival outcomes. Further research is needed to understand social and clinical factors that influence these findings. [Table: see text]
Abstract 18867: Long Term Outcome With Left Cardiac Sympathetic Denervation in Patients With Long QT Syndrome
Authors: Yitschak Biton, Wojciech Zareba, Valentina Kutyifa, Steven Lubitz, Bronislava Polonsky, Scott Mcnitt, Arthur J Moss
Journal: Circulation (2017)

Introduction: Beta-blocker (BB) therapy is very effective in preventing Sudden Cardiac Death (SCD) and syncope in patients with Long QT Syndrome (LQTS). In patients who had cardiac events while tre...
Changes in insomnia severity with advanced PAP therapy in patients with posttraumatic stress symptoms and comorbid sleep apnea: a retrospective, nonrandomized controlled study
Authors: Barry J. Krakow, Natalia D. McIver, Jessica J. Obando, Victor A. Ulibarri
Journal: Military Medical Research (2019)

Sleep disorders frequently occur in posttraumatic stress disorder (PTSD) patients. Chronic insomnia is a common feature of and criteria for the diagnosis of PTSD. Another sleep disorder, obstructive sleep apnea (OSA), also occurs frequently in PTSD, and emerging research indicates OSA fuels chronic insomnia. Scant research has investigated the impact of OSA treatment on insomnia outcomes (Insomnia Severity Index, ISI) in trauma survivors. OSA patients with moderately severe posttraumatic stress symptoms were studied in a retrospective chart review. Ninety-six patients who failed CPAP therapy due to expiratory pressure intolerance or complex sleep apnea or both underwent manual titration with advanced PAP modes [autobilevel (ABPAP); adaptive servo-ventilation (ASV)], which were subsequently prescribed. PAP use measured by objective data downloads divided the sample into three groups: compliant regular users (C-RU): n = 68; subthreshold users (SC-RU): n = 12; and noncompliant users (NC-MU): n = 16. The average follow-up was 11.89 ± 12.22 months. Baseline and posttreatment ISI scores were analyzed to assess residual insomnia symptoms as well as cure rates. The C-RU group showed significant improvements in insomnia with very large effects compared to those in the NC-MU reference group (P = 0.019). Insomnia severity significantly decreased in all three groups with large effects (C-RU, P = 0.001; SC-RU, P = 0.027; NC-MU, P = 0.007). Hours of weekly PAP use and insomnia severity were inversely correlated (P = 0.001, r = − 0.321). However, residual insomnia symptoms based on established ISI cut-offs were quite common, even among the C-RU group. Post hoc analysis showed that several categories of sedating medications reported at baseline (hypnotics, anti-epileptic, opiates) as well as actual use of any sedating medication (prescription or nonprescription) were associated with smaller insomnia improvements than those in patients not using any sedating agents. In a retrospective, nonrandomized analysis of a select sample of sleep clinic patients with OSA and PTSD symptoms, advanced PAP therapy was associated with significant improvement in insomnia severity for both compliant and partial users. However, residual insomnia symptoms persisted, indicating that PAP therapy provides only limited treatment. RCTs are warranted to assess the effect of ABPAP and ASV modes of therapy on adherence and sleep outcomes, and their potential impact on posttraumatic stress symptoms. Treatment arms that combine PAP with CBT-I would be expected to yield the greatest potency.
Alpha-1-acid glycoprotein 1 (AGP1) as a novel biomarker for pancreatic cancer.
Authors: Qimin Zhou, Roland Andersson, Dingyuan Hu, Monika Bauden, Agata Sasor, Thomas Bygott, Krzysztof Pawłowski, Indira Pla_Parada, György Marko-Varga, Daniel Ansari
Journal: Journal of Clinical Oncology (2019)

e15708 Background: Pancreatic cancer is a heterogeneous disease with an aggressive clinical course. Most patients are detected late due to the insidious onset of symptoms and lack of effective molecular markers. The purpose of this study was to develop protein markers for improved prognostication and non-invasive diagnosis. Methods: A mass spectrometry (MS)-based discovery approach was applied to pancreatic cancer tissues and healthy pancreas. In the verification phase, extracellular proteins with differential expression were further quantified in targeted mode using parallel reaction monitoring (PRM). Next, a tissue microarray (TMA) cohort including 140 pancreatic cancer resection specimens was constructed, in order to validate protein expression status and investigate potential prognostic implications. The levels of protein candidates were finally assessed in a panel of 80 serum samples with ELISA. Results: Protein sequencing with nano-liquid chromatography tandem MS (nano-LC-MS/MS) and targeted PRM identified alpha-1-acid glycoprotein 1 (AGP1) as a potential pancreatic cancer biomarker. Using TMA and immunohistochemistry, AGP1 expression was significantly associated with shorter overall survival (HR = 2.217; 95% CI 1.296-3.794, p = 0.004). Multivariable analysis confirmed the results (HR = 1.867; 95% CI 1.078-3.235, p = 0.026). Circulating levels of AGP1 yielded an area under the curve (AUC) of 0.85 for the discrimination of resectable pancreatic cancer and IPMN from healthy controls. Combining AGP1 with CA 19-9 displayed an AUC of 0.98 with an overall sensitivity of 96% at 90% specificity. Conclusions: This study suggests that AGP1 is a valid biomarker for pancreatic cancer.
Abstract 14090: Direct Cardiac Positive Inotropic and Lusitropic Effect of Colforsin Daropate is Enhanced While Isoproterenol is Attenuated in Hypothyroidism
Authors: Qun Shao, Tiankai Li, Heng-Jie Cheng, Wei-Min Li, Che Ping Cheng
Journal: Circulation (2013)

Background: Thyroid hormone (TH) has profound effects on the modulation of cardiac β-adrenergic regulation. In addition to β-adrenergic receptor (β-AR), Adenylate Cyclase (AC) is an important targe...
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with metastatic breast cancer.
Authors: Xiaoxiang Guan, Hong Zhu, Wenzhuan Xie, Jing Zhao, Guoqiang Wang, Yuzi Zhang, Zhengyi Zhao, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

e12569 Background: Breast cancer is the most common malignancy among women worldwide. It is particularly important to provide precise therapies based on genomic alterations, especially for metastatic breast cancers (MBC), which exhibit a high tumor heterogeneity and dynamic changes during the course of disease progression. However, genomic sampling upon metastatic tissue biopsy frequently encountered difficulties due to its inherent invasive approach such as insufficient samples and clinical risks. Our study aims to assess the genomic alternation landscape of metastatic breast cancer detected by blood-based circulating tumor DNA (ctDNA) and evaluate the assay performance. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 150 genes on ctDNA from 203 female patients with MBC. The mean sequencing depth was more than 3000×. The results were compared with our internal tissue genomic database (297 female patients with MBC) tested by NGS and TCGA database (N=982) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Genomic data from 203 female patients with metastatic breast cancer were analyzed via ctDNA [median age 53 years (range, 46–61 years)]. Evidence of ctDNA as estimated by the maximum somatic allele frequency (MSAF) was detected in 95.6% of the patients (median=7.1 alterations/patient), and 97.0% of the patients had at least one characterized altered gene. The most frequently mutated genes identified for SNV occurred in TP53 (47.8%), PIK3CA (36.0%), and ESR1 (16.3%) upon ctDNA analysis and TP53 (73.2%), PIK3CA (38.4%), and ESR1 (4.0%) from our internal tissue database. However, in TCGA cohort, where most patients were presented with early stage diseases, the most mutated gene in terms of SNV was PIK3CA (32.5%), followed by TP53 (30.7%) and TTN (16.0%). The status of ERBB2 amplifications had a high concordance among ctDNA (14.8%), tissue (14.9%), and TCGA database (13.5%). The MSAF level was significantly higher for the fusion-present cases (P=0.048) or amplification cases (p&lt;0.0001) than non-fusion or non-amplification cases. Conclusions: Our study has suggested that ctDNA profiling is a feasible approach for the molecular analysis in metastatic breast cancer and may better capture the mutational landscape of MBC for further clinical implications.
Association between human papillomavirus (HPV) status and duration of response of anti-programmed cell death protein-1 (PD-1) inhibitors in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Kedar Kirtane, Jameel Muzaffar, Robbert Slebos, Christine H. Chung
Journal: Journal of Clinical Oncology (2019)

6044 Background: Human papillomavirus status is known to be prognostic for patients with HNSCC. Current data suggests that HPV-positive HNSCC tumors exhibit increased infiltration of immune cells and higher levels of T-cell exhaustion markers compared with HPV-negative tumors, possibly suggesting a difference in response patterns to immunotherapy. We evaluated whether HPV status is associated with duration of response in patients receiving anti-PD-1 inhibitors. Methods: We performed a retrospective chart review of 54 patients at Moffitt Cancer Center who received either pembrolizumab (N = 32) or nivolumab (N = 22) from February 2016 to July 2018 for R/M HNSCC. We collected the following data for our patient population: primary site of disease, stage, smoking status, duration of treatment, and overall survival (OS). Overall survival time was defined as the date of starting anti-PD-1 inhibitors to death. Primary disease site was oropharynx (N = 25), oral cavity (N = 13), larynx (N = 11), nasopharynx (N = 3) and unknown primary (N = 2). HPV status was available for 37 patients. Analysis of survival and time on treatment was done using log-rank test. Results: Overall survival was not different with respect to primary site of disease, smoking, ECOG status, or type of anti-PD-1 inhibitor, but was significantly longer for patients with HPV-positive vs HPV-negative HNSCCs (17 months vs 4.5 months; log rank p &lt; 0.001). Time on anti-PD-1 inhibitor was also significantly longer for patients with HPV-positive HNSCCs (7 months vs 3 months; log rank p &lt; 0.001). Conclusions: Our data suggests patients with HPV-positive R/M HNSCCs have longer duration of response and OS on anti-PD-1 inhibitors compared to HPV-negative patients.
Utilization of mental health services among survivors of testicular cancer: A population-based study.
Authors: Christopher M. Booth, Michael J. Raphael, Xuejiao Wei, Claudio Soares, Philippe L. Bedard, Michael Leveridge, D. Robert Siemens, Andrew George Robinson
Journal: Journal of Clinical Oncology (2019)

e16062 Background: Testicular cancer survivors may experience long-term psychological distress related to their diagnosis and treatment. Measurement of mental health service use (MHS) is an objective way to quantify the incurred burden of psychological distress. Here we describe patterns of MHS use among survivors of testicular cancer in a single-payer health system. Methods: The Ontario Cancer Registry was linked to electronic treatment records to identify all incident cases of testicular cancer treated with orchiectomy in the Canadian province of Ontario during 2004-2010. Mental health clinical visits were identified from records of hospital admission, emergency room visits and out-patient physician billing records. Results: The study cohort included 1877 patients; mean age was 35 and 61% had pure seminoma. Two thirds of patients (66%, 1230/1877) were initially treated with active surveillance. In the 2-year period prior to orchiectomy, 24% (443/1877) of patients had MHS use. Post-orchiectomy, the prevalence of MHS use was 18% (331/1877), 23% (431/1877) and 30% (572/1877) at 6, 12 and 24 months, respectively. The use of MHS was greatest in the peri-diagnostic/surgical period. Rates of MHS visits, 3 months before, 0-3 months after, 4-6 months after and 2 years after orchiectomy were 11%, 14%, 10%, and 6%, respectively. Post-orchiectomy MHS use was greatest among those with baseline MHS use. The prevalence of MHS use for patients with and without baseline MHS use was 40% (175/443) vs 11% (156/1434, p &lt; 0.001) at 6 months; 51% (225/443) vs 14% (206/1434, p &lt; 0.001) at 12 months; and 61% (271/443) vs 21% (301/1434, p &lt; 0.001) at 24 months post-orchiectomy. Post-orchiectomy MHS use did not vary by initial treatment strategy (active surveillance vs upfront treatment, p = 0.435). Older patients were more likely to have MHS visits at all time periods than younger patients; MHS rates at 6 months were 15% (93/631) vs 18% (112/625) vs 20% (126/621) for ages 16-29, 30-39, and 40+ years respectively (p = 0.035). Conclusions: MHS use among survivors of testicular cancer is common, particularly in the peri-diagnostic and surgical period. The rate of MHS use is highest among those patients with a history of prior MHS use. Clinicians should screen for the presence of psychological distress among survivors of testicular cancer.
Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab.
Authors: Michael E. Hurwitz, Daniel C. Cho, Arjun Vasant Balar, Brendan D. Curti, Arlene O. Siefker-Radtke, Mario Sznol, Harriet M. Kluger, Chantale Bernatchez, Christie Fanton, Ernesto Iacucci, Yi Liu, Tuan Nguyen, Willem Overwijk, Jonathan Zalevsky, Mary Ann Tagliaferri, Ute Hoch, Adi Diab
Journal: Journal of Clinical Oncology (2019)

2623 Background: PIVOT-02 is an ongoing phase 1/2 study of bempegaldesleukin (NKTR-214), a CD122-preferential IL-2 pathway agonist, plus nivolumab in patients with advanced solid tumors. Bempegaldesleukin (NKTR-214) increases proliferative tumor infiltrating lymphocytes (TIL) and cell surface PD-1 on immune cells and PD-L1 on tumor cells, demonstrating potential synergy with anti-PD-1 therapy. Pre-treatment tumor biopsies from metastatic 1L melanoma (MEL) and urothelial carcinoma (UC) patients were analyzed to correlate baseline immune phenotype to response. Methods: Pre-treatment TIL (CD8+ T cells/mm 2 and %CD3+ by IHC; 29 MEL; 22 UC) were measured and divided into high and low groups based on median values. PD-L1 (% PD-L1 on tumor cells by IHC [28-8 PharmDx]; 33 MEL; 23 UC) was scored negative (&lt;1%) or positive (≥1%). Interferon gamma gene score (IFNG; 11 MEL) was scored as high or low based on median p value of &lt;0.1 for 15 genes (EdgeSeq). High and low groups were correlated with responses per RECIST 1.1. Results: Baseline demographics and prognostic factors were balanced in the biomarker subgroups. Response rates for response evaluable MEL and UC were 53% (SITC 2018) and 48% (ASCO-GU 2019), respectively. In MEL, median values of CD3-TIL and CD8-TIL were 19% and 203 cells/mm 2 , respectively. Response rate correlations were 67% and 20% with IFNG high and low, 79% and 29% with CD3-TIL high and low, 79% and 33% with CD8-TIL high and low, and 68% and 43% with PD-L1 positive and negative. Most importantly, responses were observed in patients with the least favorable tumor microenvironment, characterized as both PD-L1 negative and TIL low, with responses of 17% (1/6 CD8-TIL), and 25% (2/8 CD3-TIL), respectively. Similar correlative trends were observed in UC, with 50% (4/8 CD8-TIL) and 38% (3/8 CD3-TIL) responses in patients with least favorable microenvironment. Conclusions: The biomarker program included in PIVOT-02 identified baseline immune signatures correlated with response for MEL and UC. The response rates observed in both the favorable and unfavorable tumor microenvironments indicate the potential of this combination and support its broad development. Clinical trial information: NCT02983045.