tbuckley/cabot-search huggingface dataset:
Activation of B-1 Cells Promotes Tumor Cell Killing in the Peritoneal Cavity
Authors: Marcela A. Haro, Allison M. Dyevoich, James P. Phipps, Karen M. Haas
Journal: Cancer Research (2018)

Abstract Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6′-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer–induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell–produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases. Significance: This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential. See related commentary by Tripodo, p. 5
The Role of Weight Management in the Treatment of Adult Obstructive Sleep Apnea. An Official American Thoracic Society Clinical Practice Guideline
Authors: David W. Hudgel, Sanjay R. Patel, Amy M. Ahasic, Susan J. Bartlett, Daniel H. Bessesen, Melisa A. Coaker, P. Michelle Fiander, Ronald R. Grunstein, Indira Gurubhagavatula, Vishesh K. Kapur, Christopher J. Lettieri, Matthew T. Naughton, Robert L. Owens, Jean-Louis D. Pepin, Henri Tuomilehto, Kevin C. Wilson
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Overweight/obesity is a common, reversible risk factor for obstructive sleep apnea severity (OSA). The purpose of this guideline is to provide evidence-based recommendations for the management of overweight/obesity in patients with OSA.The Grading of Recommendations, Assessment, Development and Evaluation approach was used to evaluate the literature. Clinical recommendations were formulated by a panel of pulmonary, sleep medicine, weight management, and behavioral science specialists.Behavioral, pharmacological, and surgical treatments promote weight loss and can reduce OSA severity, reverse common comorbidities, and improve quality of life, although published studies have methodological limitations. After considering the quality of evidence, feasibility, and acceptability of these interventions, the panel made a strong recommendation that patients with OSA who are overweight or obese be treated with comprehensive lifestyle intervention consisting of 1) a reduced-calorie diet, 2) exercise or increased physical activity, and 3) behavioral guidance. Conditional recommendations were made regarding reduced-calorie diet and exercise/increased physical activity as separate management tools. Pharmacological therapy and bariatric surgery are appropriate for selected patients who require further assistance with weight loss.Weight-loss interventions, especially comprehensive lifestyle interventions, are associated with improvements in OSA severity, cardiometabolic comorbidities, and quality of life. The American Thoracic Society recommends that clinicians regularly assess weight and incorporate weight management strategies that are tailored to individual patient preferences into the routine treatment of adult patients with OSA who are overweight or obese.
Paradoxical expressions of hypoxia-inducible factor-1α and apelin affecting cervical carcinogenesis and prognosis.
Authors: Hee Seung Kim, Jae-Weon Kim
Journal: Journal of Clinical Oncology (2016)

e17006 Background: Hypoxia-inducible factor-1α (HIF-1α) is a well-known biomarker affecting tumor angiogenesis under decreased oxygen tension by chronic hypoxia. Moreover, apelin is also an factor stimulating angiogenesis in cardiac disease and some types of malignancies. However, there is no evidence of the role of apelin, especially compared with HIF-1α, in cervical cancer. Thus, we investigated their expressions affecting cervical carcinogenesis and prognosis. Methods: We collected paraffin-embedded blocks including cervical tissues of 178 patients who received loop electrosurgical excision procedure or hysterectomy between 2006 and 2010. All tissues consisted of three groups: group 1 (normal, n = 24; cervical intraepithelial neoplasia [CIN] 1, n = 16; CIN 2, n = 32); group 2 (CIN 3, n = 20; cervical carcinoma in situ, n = 16); group 3 (invasive squamous cell carcinoma, n = 70). We made tissue microarray using them, and performed immunohistochemistry using mouse monoclonal antibody for HIF-1 α (1:30) and rabbit polyclonal antibody (1:100) for apelin. Results: Higher expression of HIF-1α was observed more commonly in groups 2 (75%) and 3 (65.7%) than group 1 (37.5%), whereas higher expression of apelin was shown more frequently in groups 1 (20.8%) and 2 (22.2%) than group 3 (15.7%) (p < 0.05). Moreover, patients with higher expression of HIF-1α showed poor progression-free survival than those with lower expression of HIF-1α (mean, 84.2 and 94.3 months; p < 0.05). However, higher expression of apelin was related with improved PFS (mean, 92.3 and 79.4 months, p < 0.05). Conclusions: Although both HIF-1α and apelin were related with tumor angiogenesis, we found that they showed paradoxical expressions affecting cervical carcinogenesis and progression-free survival in patients with invasive squamous cell carcinoma.
Three-year survival after combined treatment with induction chemoimmunotherapy in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Yuriy N. Lazutin, Sergey P. Pyltsin, Anna Pavlovna Kharitonova, Tamara G. Ayrapetova, Igor A. Leyman, Anna V. Chubaryan, Pavel A. Anistratov, A. S. Shogenov, M. A. Gappoeva, M. Kh. Afaunov
Journal: Journal of Clinical Oncology (2017)

e20064 Background: Induction chemotherapy (iCT) for NSCLC has potential advantages over adjuvant CT, high therapeutic compliance, the ability to influence the primary tumor and metastatic disease. Standard approaches to iCT improving are largely exhausted. However, the development of iCIT techniques using recombinant cytokines and assessment of the effectiveness of its clinical application remains poorly understood. Methods: Clinical trial included 65 pts. with stage IIB, IIIA (N2), IIIB (T4 ipsi. nod.) NSCLC, randomized in main (n = 33) and control (n = 32) groups with comparable clinical and pathological characteristics: m 23 (69.7) vs. 23 (71.8%), W 10 (30,3%) vs. 9 (28.2%); stage IIB - 8 (24.4%) vs. 9 (28.6%), IIIA - 22 (66.6%) vs. 19 (59.4%), IIIB - 3 (9%) vs. 4 (12.5%); 40-49 years 5 (15,5%) vs. 5 (15,6%), 50-59 14 (42,4%) vs.15 (46,8%), 60 years and older 14 (42,4%) vs. 12 (37,8%). Pts. of the control group received 2 iCT cycles: cisplatin 75 mg / m 2 i.v. 1 day and gemcitabine 1000 mg / m 2 i. v. 1 and 8 days; pts. of the main group additionally received recombinant tumor necrosis factor coupled with thymosin (TNF-T Farmaclon Russia) 50. 000 ED / m 2 i.v. 3, 5 and 7 days of the cycle. The direct results were evaluated 3 weeks after completion of induction. Pts. who underwent radical surgery received 2 cycles of platinum-based adjuvant CT. DFS was studied by the method of Kaplan-Meier. Results: 3-year DFS in the main group was 72% vs. 48% in the control group (p = 0.10603). Conclusions: Clinical trial of the effectiveness of iCIT with using immune drug TNF-T demonstrated a tendency to improve 3-year DFS by 24%, which favors further studies on a larger number of pts.
Successful automated normalization of cancer outcomes for half a million patients across four disparate health systems.
Authors: Paul D. Tittel, Ali Zaman, James E. Shima, David Leal, James Lin Chen, Aradhana Ghosh, Jonathan Hirsch, Jonathan C. Trent, Bat-Ami Gordon, Jared Cotta, Michael A. Thompson, Jennifer Godden, Antony Ruggeri, James Leighton Weese, Nadia Z Haque, Spencer C. Hoover, Steven N. Kalkanis
Journal: Journal of Clinical Oncology (2018)

e18763 Background: The lack of interoperability among different electronic medical record (EMR) systems remains a challenge to fulfilling the promises of precision oncology. Typically, cancer outcomes data is stored as unstructured information in a multitude of inconsistent fields across EMRs. This prevents the integration of outcomes into the treatment decision-making process. To overcome this challenge, we leveraged the Syapse ontology, a data model that unifies biomedical data. We report our successful efforts to unify outcomes data across a large network of health systems. Methods: Health system participants included Providence St. Joseph Health, Aurora Healthcare, Henry Ford Health System, and University of Miami Sylvester Comprehensive Cancer Care. Data integration efforts were initiated with each health system between 1/2015 and 1/2018. Syapse aggregated clinical data sources and automated outcomes calculation. Source datasets within the health system included the EMR, enterprise data warehouse, tumor registry, and health system databases. Outcome measures included time on treatment, defined as the time between treatment start date and treatment end date; and overall survival, defined as the time between treatment start date and the patient’s date of death. Results: Across these four health systems, as of 2/6/2018, 613,575 individual patient records were automatically extracted and normalized using Syapse. These patients include 178,333 males, 435,242 females and represent 70 anatomical cancer types. There were 35,850 patients with a recorded date of death, and 298,792 patients with medication order information. Overall survival, defined as time between treatment start date and date of death, was calculated for 15,968 cases, and time on treatment, defined as time between treatment start date and treatment end date, was calculated 47,579 cases. Conclusions: This collaboration represents one of the largest efforts to structure cancer outcomes data across health systems for clinical purposes in an automated fashion. Pursuant to data availability, this initiative will expand to other outcomes and will integrate outcomes information into clinical decision making.
Proteogenomic characterization and comprehensive integrative genomic analysis of human colorectal cancer liver metastasis
Authors: Yu-Shui Ma, Tao Huang, Xiao-Ming Zhong, Hong-Wei Zhang, Xian-Ling Cong, Hong Xu, Gai-Xia Lu, Fei Yu, Shao-Bo Xue, Zhong-Wei Lv, Da Fu
Journal: Molecular Cancer (2018)

Proteogenomic characterization and integrative and comparative genomic analysis provide a functional context to annotate genomic abnormalities with prognostic value.Here, we analyzed the proteomes and performed whole exome and transcriptome sequencing and single nucleotide polymorphism array profiling for 2 sets of triplet samples comprised of normal colorectal tissue, primary CRC tissue, and synchronous matched liver metastatic tissue.We identified 112 CNV-mRNA-protein correlated molecules, including up-regulated COL1A2 and BGN associated with prognosis, and four strongest hot spots (chromosomes X, 7, 16 and 1) driving global mRNA abundance variation in CRC liver metastasis. Two sites (DMRTB1R202H and PARP4V458I) were revealed to frequent mutate only in the liver metastatic cohort and displayed dysregulated protein abundance. Moreover, we confirmed that the mutated peptide number has potential prognosis value and somatic variants displayed increased protein abundance, including high MYH9 and CCT6A expression, with clinical significance.Our proteogenomic characterization and integrative and comparative genomic analysis provides a new paradigm for understanding human colon and rectal cancer liver metastasis.ClinicalTrials, NCT02917707. Registered 28 September 2016, https://clinicaltrials.gov/ct2/show/NCT02917707 .
Immune microenvironment in mesothelioma: Looking beyond PD-L1.
Authors: Bibhusal Thapa, Marzena Walkiewicz, Gareth Rivalland, Carmel Murone, Khashayar Asadi, Stephen Barnett, Simon Knight, Neil Watkins, Prudence A Russell, Thomas John
Journal: Journal of Clinical Oncology (2017)

8515 Background: Studies using immune checkpoint inhibitors in mesothelioma (MM) have shown promise. Differences in response to PD-L1 and PD-1 inhibitors (10% vs 25%) have been reported. Also, expression of PD-L1 alone appears to be a limited predictor. As the roles of the multiple check point receptors and their ligands become defined, an understanding of their expression and interplay in the mm tumour microenvironment, which could affect suitability for checkpoint inhibition therapy, has become necessary. Methods: Tissue microarrays were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. Tumour infiltrating lymphocytes (TILs) were assessed in the stroma and expressed as a % of stromal area within invasive tumour. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. To quantify the immunosuppressive milieu, we combined our assessment of PD-L1, PD-L2 and TIM3 expression to derive an “Immune checkpoint score (ICS)” and explored its correlation with the tumour microenvironment and clinicopathological covariates. We are also exploring its predictive value in an independent cohort of mm patients who have received anti-PD-1 treatment. Results: Amongst 329 patients evaluated, PD-L1 was positive (+) in 41.7% and PD-L2+ in 24.5%. TIM3+ lymphocytes were found in 99.4% but LAG3+ lymphocytes in only 0.2%. 28/173 (16%) of PD-L1- patients were PD-L2+ and 31/136 (22%) PD-L1 and PD-L2 negative patients had high infiltration with TIM3+ lymphocytes. High ICS was associated with non-epithelioid histology, increased TILs and poorer survival. On multivariate analysis, high TILs, non-epithelioid histology and poor physiological status remained significantly associated with poorer survival. Data on the predictive role of ICS score will also be reported. Conclusions: While co-expression of PD-L1, PD-L2 and TIM3 can occur, their expression is mutually exclusive in a large proportion of patients. The expression of PD-L2 may explain differences in responses seen between PD-1 compared to PD-L1 inhibitors. A comprehensive assessment of these multiple immunosuppressive pathways may be necessary to truly gauge the immunosuppressive environment and tailor immunotherapy for individual cases.
Correction: Clinical utility of novel ultrathin single-balloon enteroscopy: a feasibility study
Authors: Kaoru Takabayashi, Naoki Hosoe, Ryoichi Miyanaga, Seiichiro Fukuhara, Kayoko Kimura, Shinta Mizuno, Makoto Naganuma, Naohisa Yahagi, Haruhiko Ogata, Takanori Kanai
Journal: Endoscopy (2018)

Correction to: Clinical utility of novel ultrathin single-balloon enteroscopy: a feasibility studyEndoscopy 2019; 51(05): 468-471DOI: 10.1055/a-0656-5622
Definitions of value among patients with breast cancer.
Authors: Joanne S. Buzaglo, Ellyn Specker Charap, Linda House, Niraj K. Gupta, Margaret Longacre
Journal: Journal of Clinical Oncology (2016)

e18259 Background: Value in health care is the nexus of best care and lowest cost. How patients define value is key to measuring health care value in this era of shared decision making. Very little is understood about how patients define value and how disease stage may influence their attributions of value. We report on how persons diagnosed with metastatic (MBC) and non-metastatic breast cancer (non-MBC) define value. Methods: We asked registrants in the online Cancer Experience Registry: “When considering your cancer experience, how would you define value?” This analysis includes persons diagnosed with breast cancer who answered (n=651), comparing MBC (n=415) to non-MBC (n=236). (MBC response rate = 54%; non-MBC response rate = 49%.) Two researchers coded responses by categories, including: 1) personal benefit, 2) health care benefit. Subcategories are reported in Table 1. Interrater reliability was 90%. Table 1 shows responses by category for MBC and non-MBC. Results: Average age was 57 for MBC patients and 56 for non-MBC patients. Among those with non-MBC, 53% defined value as personal benefit. Among these patients, most defined value as a learned principle (42%; “Live each day to its best”). Findings are similar to patients with MBC for these sub-categories (Table 1). A nearly equal proportion of patients with MBC (28%) and non-MBC (29%) defined value in terms of health. Among those with non-MBC who defined value relative to health (n=68), most (43%) cited relationship with one’s health care team. Conclusions: These findings provide further support that patients may define value differently from HCPs, which may lead to a lack of alignment between HCPs and patients about what matters most in delivery of patient-centered care. Response by cancer type. Response* MBC (n=415) W/in MBC Non-MBC (n=236) W/in non-MBC Personal 60.2% n=250 52.9% n=125 Practical .72% 1.2% 2.9% 5.6% Existential 21% 35% 14% 26% Relational 11% 18% 13% 24% Principle 24% 40% 22% 42% Spiritual 3.6% 6% .85% 1.6% Health 28.4% n=118 28.8% N=68 Practical 6.2% 22% 11% 35% Relational 8.1% 29% 12% 43% Tx trade off .48% 1.6% 1.6% 5.8% QOL 9.1% 32% 2.1% 7.3% Shared decision making .72% 2.5% 2.5% 8.8% *Remaining responses were unclear or stated not to understand.
Abstract 15557: Left Ventricular Mechanics as an Independent Risk Predictor of Atrial Fibrillation
Authors: Satish Ramkumar, Hong Yang, Ying Wang, Mark Nolan, Kazuaki Negishi, Thomas H Marwick
Journal: Circulation (2016)

Introduction: The incidence of atrial fibrillation (AF) in the community is increasing, and AF affects up to 20% of patients over the age of 80. Myocardial mechanics can be used to identify patient...
A prospective phase 2/3 multicenter study of <sup>18</sup>F-DCFPyL PET/CT imaging in patients with prostate cancer: Examination of diagnostic accuracy (OSPREY).
Authors: Michael J. Morris, Peter Carroll, Stephan Probst, Frederic Pouliot, Lawrence Saperstein, Barry A. Siegel, Ajjai Shivaram Alva, Mark A. Preston, Akash Patnaik, Michael A. Gorin, Jeremy C. Durack, Melissa Nichols, Tess Lin, Thomas Strack, Vincent A. DiPippo, Jessica Donato Jensen, Syed Mahmood, Vivien Wong, Kenneth J. Pienta
Journal: Journal of Clinical Oncology (2018)

TPS5092 Background: Accurate localization of sites of disease is essential for delivering optimal care to patients with prostate cancer. This is especially true for patients who may have distant disease either at initial staging or at relapse and may benefit from curative local primary or salvage treatments. 18F-DCFPyL (PyL) is a novel, high specific activity, highly selective, low-molecular weight prostate-specific membrane antigen (PSMA)-targeted PET radiopharmaceutical. This trial seeks to analytically validate the performance characteristics of PyL PET/CT for the detection of metastatic and/or recurrent prostate cancer. Methods: This is a multi-center, open-label, phase 2/3 study evaluating the diagnostic performance of PyL PET/CT in patients with at least high-risk (as defined by NCCN guideline v3.2016) prostate cancer prior to radical prostatectomy [cohort A] or radiologically confirmed metastatic/recurrent prostate cancer [cohort B]. A total of approximately 400 subjects will be enrolled in the study. All patients must be at least 18 years of age with histologically confirmed adenocarcinoma of the prostate. A single administration of PyL (9 ± 1 mCi [333 ± 37 MBq]) is administered 1-2 hours prior to PET/CT imaging on Day 1. The primary objective is to assess the diagnostic performance (sensitivity and specificity) of PyL PET/CT in the detection of metastatic prostate cancer within the pelvic lymph nodes relative to histopathology in pre-prostatectomy patients [cohort A], as determined by independent central review. Key secondary objectives include safety and tolerability of PyL, diagnostic performance of PyL PET/CT in the detection of prostate cancer within sites of distant metastasis or local recurrence [cohort B], and pharmacokinetic parameters of PyL in a subset of subjects. The clinical impact of PyL PET/CT imaging on the intended management of prostate cancer patients will also be assessed as an exploratory endpoint. Clinical trial information: NCT02981368.
Development of genetic profiles-based nomograms for predicting survival among EGFR-mutant lung cancer.
Authors: Rui-lian Chen, Haiyan Tu, Huajun Chen, Qing Zhou, Yi-Long Wu, Hong-Hong Yan, Xuchao Zhang, Zhou Zhang, Junyi Ye, Wenzhao Zhong, Jian Wu, Jinji Yang
Journal: Journal of Clinical Oncology (2018)

e21219 Background: Not all advanced non-small-cell lung cancer (NSCLC) patients respond equally to tyrosine kinase inhibitor (TKI) treatments, despite the presence of sensitizing epidermal growth factor receptor (EGFR) mutations. Approximately 20-30% show minimal response to TKIs. However, there is few information on predicting the responsiveness to EGFR TKI and prognosis in EGFR-mutant patients. In this study, we profiled all baseline tissues from the previously published phase III study (CTONG0901, NCT01024413) of erlotinib vs gefitinib using next-generation sequencing (NGS) and developed nomograms to predict both progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with advanced NSCLC. Methods: A total of 191 eligible patients from this phase III trial with sufficient baseline tissues for NGS were included in the present study. Multivariate Cox models were established using both the clinical and genetic variables that were significantly associated with PFS and OS univariately. The nomograms, which assigned points as weighted sum of relative significance of each variable, were derived and tested using 10-fold cross-validation. Results: The prediction model for PFS included PIK3CA, RB1, TP53 mutations, gender, prior radiotherapy, prior chemotherapy and prior surgery history. The resulting nomogram was able to distinguish low (n = 90) and high (n = 101) risk groups (C-index: 0.62; 95%CI: 0.57-0.67) with median PFS values of 13.8 and 9.7 months respectively (p<0.0001. Predictive variables in the nomogram of OS included RB1, TP53 mutations, gender and prior radiotherapy history, with C-index of 0.61 (95% CI: 0.56-0.66). Median OS values in the low (n = 78) and high (n = 113) risk groups were 24.5 and 18.5 months respectively (p<0.0001). Conclusions: We established nomograms based on both clinical and genetic features that could predict survival for EGFR-mutant patients with advanced NSCLC who treated with first generation EGFR TKIs treatment, providing more precise prognosis for this population.