tbuckley/cabot-search huggingface dataset:
Interrogating the sarcoma immune microenvironment (iME) using multiplex immunohistochemistry (mIHC).
Authors: Andrew Silverman, Matthew Ingham, Robyn Denise Gartrell, Douglas Kanter Marks, Hojung Rachel Park, Thomas D Hart, Camden L Esancy, Yan Lu, Fabrizio Remotti, Helen Elaine Remotti, Yvonne M. Saenger, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2018)

11536 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy including more than 50 molecularly distinct subtypes. Undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS) are common subtypes with limited treatment options. LMS can be divided into two distinct subsets: uterine (uLMS) and retroperitoneal (rpLMS). STS subtypes have differing levels of immune infiltration and show variable response to checkpoint blockade. We hypothesize that immune infiltration of cytotoxic T lymphocytes (CTLs) and macrophages will differ among subtypes of STS. Methods: 30 patients with sarcoma, naïve to systemic treatment, were identified, 10 cases each: UPS, uLMS and rpLMS. 5µm slides were stained using qmIF protocol for DAPI, CD3 (T cells), CD8 (CTLs), CD68 (macrophages), vimentin (tumor marker), HLA-DR (activation) and PD-L1 (immune suppression). Tumor areas were chosen by a pathologist, multiplex images acquired using Vectra, then processed and analyzed using inForm software. Genomic analysis to be performed using nanoString. Results: All cases have been stained and are now being analyzed. Preliminary analysis was performed by qualitative grading of stains (Table 1). We find increased CTL infiltration and HLA-DR expression in UPS as compared to either LMS group. uLMS appears to exhibit higher CTL infiltration and HLA-DR expression than rpLMS. QmIF and genomic analysis is ongoing. Conclusions: Qualitative analysis of UPS, uLMS, and rpLMS immune TME finds that UPS appears to have higher levels of CTLs and PD-L1 expression, consistent with results from other studies using conventional immunohistochemistry. Subtypes of LMS harbor distinct immune TME features, as uLMS as higher CTL and HLA-DR expression than rpLMS. These findings could have therapeutic implications. This study is currently ongoing; multi-parameter immune phenotyping, spatial localization, and genomic analysis will be reported at the meeting. Quantitative qmIF analysis. Group CD3 CD8 CD68 HLA-DR PD-L1 rpLMS + - + ++ ++ UPS ++ ++ ++ +++ +++ uLMS ++ + ++ +++ ++ - no cells, + few cells, ++ some cells, +++ many cells
Role of immune checkpoint inhibitor, tumor vaccine and cellular immunotherapy in advanced non-small-cell lung cancer.
Authors: Yunfang Yu, Ying Wang, Shengbo Liu, Qiyun Ou, Tuping Fu, Dagui Lin, Quanlong Gao, Zhaoying Zhan, Herui Yao
Journal: Journal of Clinical Oncology (2018)

e21056 Background: We previously identified that immunotherapy including immune checkpoint inhibitor (ICI), tumor vaccine (TV) and cellular immunotherapy (CIM) improved overall survival (OS) and progression-free survival (PFS) compared with non-immunotherapy in advanced non-small-cell lung cancer (NSCLC). This update aims to confirm the role of immunotherapy with the inclusion of new trials. Methods: We searched for randomised trials in patients with advanced NSCLC until February 2018 and calculated hazard ratios (HRs) and differences in OS and PFS using random-effects model. Quality of evidence was appraised with GRADE criteria. PROSPERO registry number is CRD42017075610. Results: 24 RCTs including a total of 8,968 patients were identified. Patients treated with immunotherapy obtained prolonged median PFS (5.32 months vs. 4.75 months; difference, 1.22 months, 95% confidence interval [CI] 0.71 to 1.72, P < 0.0001; and HR, 0.78, 95% CI 0.71 to 0.87, P < 0.0001), and median OS (13.18 months vs. 10.03 months; difference, 2.59 months, 95% CI 1.80 to 3.37, P < 0.0001; and HR, 0.78, 95% CI 0.72 to 0.85, P < 0.0001) compared with non-immunotherapy. In stratified analysis, ICI or TV or CIM combined with chemotherapy as first-line therapy had significantly benefits than those treated with chemotherapy alone (ICI HR, 0.80, 95% CI 0.67 to 0.95 for PFS; TV HR, 0.72, 95% CI 0.58 - 0.91 for PFS; and CIM HR, 0.48, 95% CI 0.27 to 0.87 for OS). Compared with single-agent chemotherapy, ICI as first-line monotherapy had a similar PFS (HR = 0.76, 95% CI 0.34 to 1.73) and OS (HR = 0.80, 95% CI 0.48 to 1.34). TV as maintenance therapy after first-line therapy had prolonged PFS (HR = 0.89, 95% CI 0.81 to 0.99) and OS (HR = 0.83, 95% CI 0.74 to 0.92) compared with non-TV. ICI as second-line monotherapy, compared with single-agent chemotherapy, resulted in prolongation of PFS (HR = 0.79, 95% CI 0.66 to 0.94) and OS (HR = 0.70, 95% CI 0.64 to 0.77). Conclusions: This study provided more precise evidence that immunotherapies are associated with significantly prolonged OS and PFS in patients with advanced NSCLC. Future prospective biomarker-driven trials are needed to identify patients for which immunotherapy is most efficacious.
Etanercept biosimilar <scp>SB</scp> 4 in the treatment of chronic plaque psoriasis: data from the Psobiosimilars registry
Authors: P. Gisondi, L. Bianchi, P. Calzavara‐Pinton, A. Conti, A. Chiricozzi, M. Fimiani, M. Pellegrino, A. Giunta, F. Prignano, R. Tiberio, M. Venturini, G. Girolomoni
Journal: British Journal of Dermatology (2018)
A phase iia trial of acupuncture to reduce chemotherapy-induced peripheral neuropathy severity during neoadjuvant or adjuvant weekly paclitaxel chemotherapy in breast cancer patients.
Authors: Ting Bao, Andrew David Seidman, Lauren Piulson, Xi Chen, Andrew J. Vickers, Emily Vertosick, Victoria Susana Blinder, Wanqing Iris Zhi, Qing Susan Li, Linda T. Vahdat, Maura N. Dickler, Mark E. Robson, Jun J. Mao
Journal: Journal of Clinical Oncology (2018)

e22201 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapy for cancer patients. We evaluated the preliminary efficacy of acupuncture in preventing worsening CIPN in patients receiving paclitaxel. Methods: In this phase IIA single-arm clinical trial, we screened stage I-III breast cancer patients receiving neoadjuvant/adjuvant weekly paclitaxel for development of CIPN. The primary objective was to assess acupuncture's efficacy in preventing the escalation of National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0 grade 2 CIPN to higher grades. Acupuncture would be deemed worthy of further study if 23 or more of the 27 enrolled patients did not develop grade 3 CIPN. Outcome measures (NCI-CTCAE CIPN grade, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), Neuropathic Pain Scale (NPS)) were obtained weekly during the intervention. Results: Of 104 patients screened, 37 developed grade 2 CIPN (36%) and 28 (27%) enrolled into the intervention phase; one was removed due to protocol violation. Of 27 patients receiving acupuncture, 26 completed paclitaxel treatment without developing grade 3 CIPN, meeting our pre-specified success criteria for declaring acupuncture worthy of further study. FACT/GOG-Ntx and NPS scores remained stable during the intervention while continuing weekly paclitaxel. Acupuncture treatment was well tolerated; 4/27 (15%) patients reported grade 1 bruising. Conclusions: Acupuncture was safe and showed preliminary evidence of effectiveness in reducing the incidence of high grade CIPN during chemotherapy. A follow-up randomized controlled trial is needed to establish definitive efficacy in CIPN prevention for patients at risk. Clinical trial information: NCT02364726.
ADVL1513: Results of a phase 1 trial of entinostat, an oral histone deacetylase inhibitor, in pediatric patients with recurrent or refractory solid tumors.
Authors: Suman Malempati, Bill H. Chang, Joel M. Reid, Xiaowei Liu, Charles G. Minard, Charles Keller, Elizabeth Fox, Brenda Weigel
Journal: Journal of Clinical Oncology (2018)

10556 Background: Histone modification plays a key role in oncogenesis and progression of malignancy. Histone deacetylase (HDAC) inhibition has shown promise as anti-cancer therapy. Entinostat is an oral small molecule inhibitor of class I and IV HDACs that has not previously been evaluated in pediatric patients. We report the results of a phase 1 study of entinostat in children and adolescents with solid tumors. Methods: Children and adolescents (age £ 21 years) with relapsed or refractory solid tumors, including CNS tumors were eligible. Body-surface area ³ 1.17 m2 was required. Entinostat (1 or 5 mg tablets) was administered orally, once weekly, in 4-week cycles. A rolling 6 design was used to evaluate two dose levels of 3 or 4 mg/m2. A pharmacokinetic (PK) cohort was enrolled at the recommended dose. Results: Twenty eligible patients (10 male, 10 female), median (range) age 14.4 (8 -20) years were enrolled. Diagnoses included patients with CNS tumors (n = 11), sarcomas (n = 6) or other solid tumors (n = 3). Twelve patients were evaluable for DLT. Eight patients were not evaluable due to progression of disease prior to receiving the required percent of protocol prescribed therapy. No DLTs were observed at 3 mg/m2 (n = 3) or among 9 patients (6 in dose escalation and 3 in the PK cohort) at the 4 mg/m2 dose level. Grade 3 toxicities included neutropenia (n = 4), lymphopenia (n = 1), and leukopenia (n = 1). Most common non-hematologic toxicities (all grade £ 2) were elevated AST, fatigue, and hypophosphatemia (n = 4 each) and elevated ALT, hypoalbuminemia, and vomiting (n = 3 each). Pharmacokinetics of entinostat were evaluated and will be reported. Conclusions: Entinostat was well-tolerated with no DLTs observed. The recommended phase 2 dose in pediatric patients with solid tumors is 4 mg/m2. Evaluation of entinostat in combination with other agents is planned. Clinical trial information: NCT02780804.
CD15 expression to predict outcome in patients with Hodgkin lymphoma.
Authors: Dahlia Sano, Tarik H. Hadid, Baljit Singh, Uqba Khan, Zyad Kafri, Ayad M. Al-Katib
Journal: Journal of Clinical Oncology (2016)

e19010 Background: CD15 is a carbohydrate attached to the surface glycoprotein of malignant lymphocytes. It is encoded by fucosyltransferase 4 or 9 genes. CD15 regulates phagocytosis and chemotaxis but it may also affect how the immune system reacts to malignant lymphocytes. It is expressed in 66% of patients with Hodgkin lymphoma (HL); and 20% of those with non-Hodgkin's lymphoma. Studies investigated the prognostic value of CD15 expression in patients with head and neck and colorectal cancers. In this study, we evaluate the prognostic value of CD15 expression in patients with HL. Methods: We conducted a retrospective review of all patients with HL treated at our institution between 2006 and 2014. Primary end-points were to assess overall survival and progression-free survival. Data were analyzed with Students t-test, chi-squared test, Fisher exact test, analysis of variance and Kaplan Meier survival analysis. Results: Of the 60 patients evaluated, 86.4% expressed CD15. Median follow-up time was 44.4 months. CD15- group were slightly older than the CD15+ group (47 vs 34 years). The overall response rate (ORR) to first-line therapy was lower in the CD15- patients compared to the CD15+ patients (50% vs 85%, p = 0.04). Complete remission rates in the CD15- and CD15+ patients were 50% and 81%, respectively (p = 0.079). Progression-free survival (PFS) was shorter for CD15- patients compared to CD15+ patients (4 years vs 36 years; p = 0.01). Median survival was not reached in both groups. Overall survival at the end of the study was 87% for the CD15- group and 92% in the CD15+ group (p = 0.68). Conclusions: Lack of expression of CD15 was associated with lower ORR rate and PFS in patients with HL. OS was not different due to the presence of effective salvage therapy. Further studies should investigate the biological significance of these findings and explore alternative therapeutic approaches for patients with CD15- HL.
Abstract 10411: Significance of Inflammation and Neoangiogenesis of Epicardial Adipose Tissue on Coronary Atherosclerosis Based on Computed Tomography Analysis
Authors: Toshiro Kitagawa, Hideya Yamamoto, Hiroshi Tsushima, Atsuhiro Senoo, Kazuhiro Sentani, Wataru Yasui, Yasuki Kihara
Journal: Circulation (2015)

Background: Previous studies indicate that epicardial adipose tissue (EAT) biologically contributes to coronary atherosclerosis progression. The inflammation and neoangiogenesis have been reported to be biological markers of ‘diseased’ adipose tissues. We evaluated the relation of EAT pathologies, represented by inflammation and neoangiogenesis, to computed tomography (CT)-based coronary atherosclerosis. Methods: We enrolled 45 patients undergoing cardiac CT examination before elective cardiac surgery (coronary artery bypass graft [CABG], n = 21; non-CABG, n = 24). Each patient was evaluated with visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and presence of non-calcified coronary plaque (NCP) on CT angiography. During each cardiac surgery, histological samples for immunohistochemistry were obtained from EATs adjacent to the left anterior descending and right coronary arteries. Each patient was assessed with the numbers of CD-68+ individual macrophages and CD-31+ neovessels in a total of 6 random high-power fields (x400) of EAT samples. Results: The EAT volume had no correlation with macrophage infiltration (r = 0.09, p = 0.53) or neoangiogenesis (r = 0.08, p = 0.59) in EAT. In the comparisons of EAT pathologies based on CCS levels or NCP presence, the moderate CCS (101-400) or NCP present group had more macrophage infiltration and neoangiogenesis in EAT (Fig 1). On multivariate analyses adjusting for age, sex, CABG vs. non-CABG, VAT area, and EAT volume, both the moderate CCS and NCP presence showed significant correlation with increased macrophage infiltration (β = 0.65; p &lt; 0.0001, and β = 0.49; p = 0.0089, respectively) and neoangiogenesis (β = 0.55; p = 0.0011, and β = 0.53; p = 0.012, respectively) in EAT (Fig 2). Conclusions: The EAT biological activities independently correlate with moderate, rather than severe, coronary calcium and NCP formation, suggesting the stage in the process of coronary atherosclerosis growing.
Abstract 12756: 11 year Trends and Utilization Patterns of Cardiac Implantable Electronic Devices in Patients Diagnosed With Sick Sinus Syndrome
Authors: Avirup Guha, Xiao Xiang, Dilesh Patel, Vadim V Fedorov, Emile G Daoud
Journal: Circulation (2016)

Background: CIEDs (cardiac implantable electronic devices) are commonly used for managing sick sinus syndrome (SSS). Hypothesis: Compare features of SSS patients (pts) who did and did not receive CIED. Methods: Pts were identified from the National Inpatient Sample dataset (2003-13). Included pts were ≥18, had a primary diagnosis of sinus node dysfunction and atrial arrhythmia (hence SSS). Pts who died, transferred out or had prior CIED were excluded. Included pts were then stratified by implantation of a CIED. Data regarding SSS and weighted multivariable model of factors associated with CIED implantation are presented. Results: Over 11 years, 421,535 pts were diagnosed with SSS (mean annual incidence of 38,321 ± 4,258) and the trend for SSS hospitalization fell 19% (p &lt; 0.001). CIED were implanted in 353,247 pts (83.8%) and the annual trend of CIED use was decreasing (p &lt; 0.001). Of 39 variables analyzed, the attached forest plot shows only those variables that were either associated with a lower likelihood (down arrow) or with a higher likelihood (up arrow) for CIED implantation. Lower likelihood for CIED was associated with young age, female, African American race, self-pay, heart failure, COPD, kidney disease, emergency room admission, weekend admission, public/rural/urban nonteaching/small/medium hospitals, midwest/south/west regions and reduced inpatient and procedural volume. Greater likelihood for CIED implant was associated older age, Hispanic race, HTN, hyperlipidemia, coronary artery disease, and increased procedure volume. Conclusions: Analyzing a large US database over 11 years demonstrates falling hospitalizations and CIED implantation for SSS. There are a number of relevant variables that impact if a CIED is utilized that include not only clinical features but also nonclinical variables such as socioeconomic status, gender, type and location of hospital and hospital procedure volume.
Next-generation sequencing (NGS) survey of biliary tract cancer (BTC) to reveal the association between tumor somatic variants and chemotherapy resistance.
Authors: Daniel H. Ahn, Milind M. Javle, Chul Ahn, Apurva Jain, Sameh Mikhail, Rachna T. Shroff, Kristen Keon Ciombor, Anne M. Noonan, Christina Sing-Ying Wu, James Lin Chen, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2016)

4079 Background: BTC are uncommon and associated with a dismal prognosis. Gemcitabine and platinum-combinations (GP) form the standard approach for treating advanced BTC with a modest improvement in survival. To identify potential biomarkers for response to GP in BTC, we used NGS to evaluate the genomic BTC landscape and identify whether mutations affecting DNA repair were associated with GP resistance. Methods: Pretreatment formalin-fixed, paraffin-embedded (FFPE) samples from 183 patients (pts) with BTC treated with GP were analyzed with a commercial targeted NGS platform. Genes with incidence > 10% were included in our analysis. Cox regression models were used to determine the association between mutations, progression free survival (PFS) and overall survival (OS). Survival was estimated using the Kaplan Meier method and compared by the log-rank test. Results: Of the 183 pts analyzed, 181 (99%) had at least one actionable mutation. The most common mutations included CDKN2A (29%), TP53 (27.9%), KRAS (22.4%), and ARID1A (13.7%). Considering genes with an incidence > 10%, no individual gene was independently predictive of GP response. In pts with unresectable BTC who received GP as first-line therapy, the joint status of CDKN2A, TP53 and ARID1A were associated with PFS (P = 0.0004) and OS (P = < 0.0001). Pts with mutations in CDKN2A and TP53 with wild-type ARID1A were identified as a poor prognostic cohort with a median PFS of 2.63 months (mos) and OS 5.22 mos. Pts with mutant ARID1A regardless of the single mutational status of TP53 or CDKN2A had statistically similar PFS and OS. In a single pt who exhibited mutations in all three genes, the median PFS was 20.37 mos and median OS not reached. Conclusions: In the largest exploratory analysis of this nature to date in BTC, we found that the presence of three prevalent and mutually exclusive mutations (TP53, CKDN2A and ARID1A) represent distinct pt cohorts. These mutations are prognostic and may represent a predictive biomarker to GP response. Prospective studies are needed to validate these findings, including the incorporation of novel agents that exploit the genomic instability observed with these mutations with GP in BTC.
The appliances and prospects of aurum nanomaterials in biodiagnostics, imaging, drug delivery and combination therapy
Authors: Dan Yang, Feiyang Deng, Dechun Liu, Bo He, Bing He, Xing Tang, Qiang Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Aurum nanomaterials (ANM), combining the features of nanotechnology and metal elements, have demonstrated enormous potential and aroused great attention on biomedical applications over the past few decades. Particularly, their advantages, such as controllable particle size, flexible surface modification, higher drug loading, good stability and biocompatibility, especially unique optical properties, promote the development of ANM in biomedical field. In this review, we will discuss the advanced preparation process of ANM and summarize their recent applications as well as their prospects in diagnosis and therapy. Besides, multi-functional ANM-based theranostic nanosystems will be introduced in details, including radiotherapy (RT), photothermal therapy (PTT), photodynamic therapy (PDT), immunotherapy (IT), and so on.
Impact of prophylactic bilateral salpingo-oophorectomy on bone health in <i>BRCA</i> mutation carriers: A prospective cohort study.
Authors: Elizabeth Hall, Joanne Kotsopoulos, Amy Finch, Islay Thompson, Barry Rosen, Joan Murphy, Steven Narod, Angela Cheung
Journal: Journal of Clinical Oncology (2018)

1566 Background: Women who inherit a deleterious mutation in BRCA1 or BRCA2 face a high lifetime risk of ovarian cancer. Prophylactic bilateral-salpingo oophorectomy (PBSO) is recommended prior to natural menopause; however, the impact of abrupt hormonal withdrawal on bone health in this high-risk population is not known. We conducted a longitudinal study to evaluate the impact of PBSO on bone mineral density (BMD) in BRCA mutation carriers. Methods: The study population included women who underwent PBSO at the University Health Network (Toronto, Canada) between January 2000 and May 2013. Eligibility criteria included having a BRCA mutation, at least one ovary prior to surgery, and no personal cancer history other than breast cancer. Information regarding medical history, medication use, and lifestyle factors was collected via questionnaire. BMD measurements using dual x-ray absorptiometry were collected at baseline (prior to surgery) and follow-up. The % change in BMD from baseline to follow-up was calculated for the lumbar spine, femoral neck, and total hip. Results: A total of 103 women had baseline and follow-up BMD measurements available. Mean age at PBSO was 49 years (range 37-52). Mean time to first follow-up was 2.04 years (range 0.98-4.74). Among women premenopausal at the time of surgery (n = 58), there was a significant change in BMD from baseline to first follow-up in the lumbar spine (-5.32%; 95% CI -7.17 to -3.48), femoral neck (-2.94%; 95% CI, -4.62 to -1.26), and total hip (-2.75%; 95% CI, -3.82 to -1.68) respectively. Among the women who were postmenopausal at the time of surgery (n = 45), there was a significant change in BMD across the lumbar spine (-2.41%; 95% CI, -4.41 to -0.41), and femoral neck (-2.73%; 95% CI, -4.86 to -0.60), but not for total hip (-0.78%; 95% CI, -2.40 to 0.85). Conclusions: These preliminary findings suggest significant post-operative bone loss, particularly among women who were premenopausal prior to PBSO. Targeted interventions as well as routine BMD measurements may be needed to improve management of bone health in this population. Additional analyses evaluating the impact of supplement use, body mass index, as well as hormone replacement therapy are underway.