tbuckley/cabot-search huggingface dataset:
Immunomarker combined with clinical features to support vector machines classifier for prediction of gastric cancer survival and adjuvant chemotherapeutic benefits.
Authors: Tuanjie Li, Yuming Jiang, Guoxin Li, Jiang Yu
Journal: Journal of Clinical Oncology (2018)

e16098 Background: Currently, gastric cancer (GC) prognosis evaluation is based primarily on the TNM staging system. However, the TNM staging system can not provide adequate information for prediction of prognosis and chemotherapeutic benefits. Methods: The study enrolled 3 independent cohorts of patients with GC from 2 medical centers of China. We detected expression of 15 immunohistochemistry (IHC) features in GC tumors from 251 patients who underwent total or partial radical gastrectomy between January 2005 and August 2007, at Nanfang Hospital in Guangzhou, China; and evaluated the association of their expression level with overall survival (OS) and disease-free survival (DFS). Then, integrating multiple clinicopathologic features and IHC features, we used support vector machine (SVM) –based methods to develop a prognostic classifier for GC (GC-SVM classifier) with eleven features. Further validation of the GC-SVM classifier was performed in an internal cohort of 248 patients who met the inclusion criteria and underwent surgery at Nanfang Hospital, and an external cohort of 287 patients who underwent surgery at First Affiliated Hospital in Guangzhou, China. Results: The GC-SVM classifier integrated patient sex, CEA, lymph node metastasis and the protein expression level of eight features, including CD3invasive margin (IM), CD3center of tumor (CT), CD45ROCT, CD57IM, CD66bIM, CD68CT and CD34. Significant differences were found between the high- and low- GC-SVM patients in 5-year OS and DFS in training and validation cohorts. Multivariate analysis revealed that the GC-SVM classifier was an independent prognostic factor. The classifier had higher predictive accuracy for OS and DFS than TNM stage and can complement the prognostic value of the TNM staging system. Further analysis revealed that stage II and III GC patients with high- GC-SVM were pone to benefit from adjuvant chemotherapy. Conclusions: The newly developed GC-SVM classifier was a powerful predictor of OS and DFS among patients with GC. Moreover, the GC-SVM classifier might be able to predict which patients with stage II and III GC benefit from adjuvant chemotherapy.
Abstract 13658: The Clinical Impact of Diabetes Mellitus on Outcome After Transcatheter Aortic Valve Replacement
Authors: Yigal Abramowitz, Hasan Jilaihawi, Tarun Chakravarty, Mohammad Kashif, Yoshio Maeno, Yoshio Kazuno, Nobuyuki Takahashi, Hiroyuki Kawamori, Justin Cox, Rahul P Sharma, Wen Cheng, Raj R Makkar
Journal: Circulation (2015)

Background: DM adversely affects morbidity and mortality for cardiovascular diseases and procedures. DM has been independently associated with increased morbidity and mortality after surgical aortic valve replacement. There is limited data on the impact of DM on the prognosis of patients with severe aortic stenosis that undergo TAVR. In a sub-study of the PARTNER trial, 1-year mortality was significantly higher in patients without DM compared to patients with diabetes, although multivariable analysis was not performed. We aimed to evaluate the clinical characteristics and the early and midterm outcomes after TAVR according to DM status. Methods &amp; Results: We examined 802 consecutive patients that underwent TAVR: 548 patients without DM, 177 patients with orally treated DM and 77 with insulin treated DM. Patients with DM were younger (mean age 80±8.4 vs. 82.9±8.8; p&lt;0.01), had higher BMI (29±6.8 vs. 25.8±5; p&lt;0.01), had higher incidence of CAD (70.9% vs. 61.5%; p=0.01) and lower incidence of frailty (28% vs. 37.6%; 0=0.01). Device success, postprocedural perivalvular leak and 30-days mortality and major complications rates were similar between groups (Table). In a Cox multivariable regression analysis including age, BMI, CAD and frailty, DM was associated with decreased overall survival. This was driven by increased overall mortality of the insulin treated DM subgroup (Figure). Conclusions: DM does not significantly affect short term mortality or rates of complications in patients who underwent TAVR. Insulin treated DM, but not orally treated DM, is independently associated with death at midterm follow up and should be included into future TAVR dedicated scores.
Phosphoproteomic analysis of matched primary breast cancer (BC) and lymph node (LN) metastases.
Authors: Corinne Ramos, Nicholas N Hoke, Maren K. Levin, Michael D Grant, Sarah Hippely, Rohan Thamby, Mariaelena Pierobon, Elisa Baldelli, George J Snipes, Emanuel Petricoin, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2017)

11620 Background: Therapeutic recommendations are often based on molecular markers expressed in primary BCs. However, LN metastases (mets) may more accurately reflect the lethal potential of the disease (Ries 2007). Whether activated oncogenic pathways in axillary LN mets can be reliably identified in the associated primary BCs is unknown. We evaluated the activation of key signaling pathways in pts’ matched primary BC and axillary LN mets using reverse phase protein array (RPPA). Methods: 60 pts’ matched FFPE primary BC and axillary LN mets (20 TN, 20 ER+/HER2-, 20 HER2+) are to be evaluated by RPPA at a CLIA-certified laboratory. The first 20 matched BC/LN (3 TN, 14 ER+/HER2-, 3 HER2+) and 7 unmatched (1 TN LN, 1 ER+/HER2- BC, 5 ER+/HER2- LN) results are reported here. Immunostaining of 14 HER1/2/3 and downstream pathway proteins was performed. Mann-Whitney U tests (p value) were utilized to compare BC vs LN mets protein level. Results: Increased expression of HER1 (6-fold) and p-Akt (2-fold) was observed in TN compared to Luminal (Lum) and HER2+ primary BCs. AR expression was upregulated in TN and HER2+ (2-fold) compared to Lum primary BCs. The LN mets showed higher expression of HER1 (p = 0.004), p-HER3 (p = 0.040), p-IGFR (p = 0.009), p-S6 (p = 0.033), p-4EBP1 (p = 0.027) and p-MEK1/2 (p = 0.023) compared to primary BCs. TN had higher level of p-Akt T308 (p = 0.077) in the LN mets compared to the primary BCs while HER2+ showed a downregulation of p-Akt T308 (p = 0.049) in the LN mets. HER2+ also had higher level of HER1 (p = 0.049), p-HER3 (p = 0.049), p-FGFR (p = 0.083), and p-4EBP1 (p = 0.049) in the LN mets compared to primary BCs. Higher levels of HER1 (p = 0.043) and p-MEK1/2 (p = 0.027) were observed in Lum B LN mets compared to p-IGFR (p = 0.041), p-Akt S473 (p = 0.088), p-S6 (p = 0.063) and p-4EBP1 (p = 0.097) in Lum A LN mets. Conclusions: In TNBC, preliminary results show that p-Akt is differentially upregulated in LN mets while HER1, p-HER3 and p-4EBP1 are overexpressed in HER2+ LN mets. Lum A LN mets showed higher levels of p-IGFR, p-Akt, p-S6 and p-4EBP1 vs Lum B LN mets which had higher levels of HER1 and p-MEK1/2. These data suggest different signaling pathways in BC LN mets compared to primary BCs. Analyses of 60 pts’ matched primary BC/LN samples will be presented.
Abstract 10452: The SYMPLICITY HF Feasibility Study: Twelve Month Outcomes of Renal Denervation in Patients With Chronic Heart Failure and Renal Impairment
Authors: Henry Krum, Sidney A Cohen
Journal: Circulation (2015)

Introduction: Renal dysfunction often develops in patients with heart failure with low ejection fraction due to hemodynamic and neurohumoral dysfunction leading to increased risk for mortality. Methods: The multi-center, prospective, open label Renal Denervation in Patients With Chronic Heart Failure &amp; Renal Impairment (SYMPLICITY HF) trial enrolled NYHA Class II-III patients with left ventricular ejection fraction (LVEF) &lt;40% and estimated glomerular filtration rate (eGFR) 30 to 75 mL/min/1.73m 2 . Subjects with systolic blood pressure &lt; 90 mm Hg were excluded. The primary objective was to evaluate both the safety and physiologic response of renal denervation therapy on cardiac and renal function with the Symplicity™ renal denervation system using the Symplicity Flex™ catheter (Medtronic, Inc). Results: A total of 39 patients were enrolled (Table). No vascular complications occurred during the procedure. Available at AHA 2015 will be outcomes to 12 months follow up, including safety, cardiac function by echocardiography, and renal function by eGFR. Additionally, 9 subjects participated in a sub study that evaluated cardiac and renal noradrenaline spillover, muscle sympathetic nerve activity, and electrophysiological parameters by Holter monitor. Conclusions: Twelve-month outcomes in SYMPLICITY HF will provide initial insights into the safety and cardiac and renal physiologic impact of renal denervation in patients with heart failure.
Association of length of hospice enrollment with regional variation in end-of-life care expenditures.
Authors: Shi-Yi Wang, Siwan Huang, Sylvia H. Hsu, Cary Philip Gross
Journal: Journal of Clinical Oncology (2016)

10030 Background: Marked regional variation exists in end-of-life (EOL) care intensity and expenditures. Hospice use is expected to reduce EOL care expenditures, but literature provided mixed results on its financial impact. Determining the interplay of length of hospice enrollment on EOL care expenditures among regions with different levels of EOL care intensity could shed light on the relationship between hospice enrollment duration and cost saving. Methods: Using the Surveillance, Epidemiology, and End Results–Medicare database, we identified 90,465 decedents who had cancer diagnosed in 2004-2011 and died within 3 years of diagnosis as a result of cancer. We calculated decedents’ last 6 months expenditures in the hospital referral region (HRR) areas, and assigned HRRs into five quintiles. We also calculated each decedent’s length of hospice enrollment. Using hierarchical generalized linear models, we estimated risk-standardized EOL expenditures for each HRR and determined the associations between length of hospice enrollment and EOL expenditures across quintiles. Results: Compared with decedents in the lowest quintile expenditure areas, decedents in the highest quintile expenditure areas had shorter average hospice enrollment (8.3 days vs. 13.7 days; p < .001). Among decedents residing in the highest areas, increased hospice enrollment were associated with a decrease in the mean adjusted expenditure per decedent, from $59,167 for not hospice users, $52,456 for hospice users less than 3 days, $48,784 for hospice users 4-7 days, $45,393 for hospice users 8-56 days, to $41,713 for hospice users more than 56 days. However, there was no substantial difference in expenditures by length of hospice enrollment in HRRs with low levels of end-of-life expenditures ($37,731, $34,561, $32,759, $32,787, and $33,265, respectively). Length of hospice enrollment could explain 7.8% of variation in EOL expenditures between the highest and lowest quintile areas. Conclusions: Substantial geographic variation in length of hospice enrollment among cancer decedents exists. Early hospice enrollment has the potential to decrease expenditures in areas with high EOL expenditures, but not in areas with low EOL expenditures.
Prognostic gene signatures for lung adenocarcinoma using digital multiplexed gene expression in formalin-fixed paraffin embedded tissue.
Authors: Ping Wei, Xiang Du
Journal: Journal of Clinical Oncology (2017)

e20050 Background: The outcome after resection of non-small-cell lung cancer (NSCLC) patients are poor, even in the early stage, there still has 35-50% recurrence rates. Current staging methods are not inadequate for predicting the outcome of NSCLC patients. Methods: 396 lung adenocarcinoma specimens were obtained for this study, of whom 78 frozen specimens (corhort1) and 223 FFPE specimens (corhort2) were from Shanghai Cancer Center, Fudan University and 85 FFPE specimens (independent corhort) were from Shanghai Pulmonary Hospital. The RNA was extracted from corhort1 and used in the microarray gene expression analysis to derive prognostic associated genes. The digital multiplexed technology (Nanostring) was then used to determine the expression of these genes in FFPE-derived RNA from corhort2. For validation, we used the random patients from the independent corhort. Results: Through microarray assay, the top 18 survival and 19 metastasis associated gene were chosen to digital multiplexed gene expression analysis using FFPE-derived RNA from corhort2. Four genes that correlated with the survival were then identified by risk scores. Kaplan-Meier analysis showed that patients of high risk scores had longer OS and DFS compared with patients of low risk scores in the corhort2. The four-gene signature was an independent predictor of OS and DFS. We validated the four-gene model in the independent corhort. Conclusions: Our results suggest that the four gene signature is a new biomarker for the prognosis of patients with NSCLC, enabling more accurate prediction of prognosis.
Bag to school
Authors: Johannes Zwerver, Robert-Jan de Vos
Journal: British Journal of Sports Medicine (2018)

Childhood and adolescence are characterised by marked somatic growth, and significant musculoskeletal, physiological and pubertal development. Musculoskeletal conditions become increasingly prevalent when growing up, and are thought to predict pain and disability later in life.1 However, Swain et al ( see page 1246 ) dispute that there is a meaningful association between biological maturation, growth and musculoskeletal conditions in adolescence. They advise clinicians to refrain from inferring a causal relationship between maturity, growth and musculoskeletal conditions in adolescents. This raises the question of the specific role of loading in the growing child.

Heavy schoolbags have traditionally been linked to back pain in children and adolescents, leading to ongoing discussions among parents, school teachers and scientists. An intriguing question is how much academic load (books!) can be carried safely by children. Yamato et al ( see page 1241 ) show that there is no convincing evidence …
Discontinuation of first-line chemotherapy (CT) after 6 weeks of CT in patients (pts) with metastatic squamous-cell esophageal cancer (MSEC): A randomized phase II trial.
Authors: Antoine Adenis, Jaafar Bennouna, Pierre-Luc Etienne, Emilie Bogart, Eric Francois, Marie-Pierre Galais, Meher Ben Abdelghani, Nuria Kotecki, Pierre Michel, Jean-Philippe Metges, Laetitia Dahan, Guillaume Piessen, Thierry Conroy, Francois Ghiringhelli, Laurent Bedenne, Farid El Hajbi, Emmanuelle Samalin, Stephanie Clisant Delaine, Nicolas Penel, Christophe Mariette
Journal: Journal of Clinical Oncology (2016)

4002 Background: Even though there is no evidence to support the use of CT in MSEC, many physicians treat pts with good ECOG performance status (PS) with fluorouracil (5FU)/platinum-based CT. Therefore, in order to estimate overall survival (OS) in MSEC, we designed a discontinuation phase 2 trial in pts free from progression (PD) after 6 weeks (wks) of CT. Methods: PS<3 MESC pts were treated with 1st-line 5FU/platinum-based CT, and underwent tumor assessment at 6 wks. Pts free from PD after 6 wks of CT were randomized (1:1) to receive CT continuation (arm A) or CT discontinuation plus BSC (arm B). In arm B, pts were allowed to restart CT in case of PD. Primary endpoint was ITT 9-month OS rate (calculated from randomization date). The sample size has been calculated to provide an estimate of ITT 9-month OS rate ± 12.5% in arm A. Arm B served as an internal control, without formal comparison intent.With an anticipated 58% dropout rate at 1st tumor assessment, 106 pts were needed to randomize 62 pts. Secondary objectives were tolerance, PFS, quality of life, and medical costs. Results: 105 pts were included, and 101 received CT (FOLFOX: 76/101; LV5FU2-CDDPq2w: 18/101; TPF: 4/101, FU-CDDPq3w: 3/101). 67/101 pts free from PD at 6 wks were randomized. Baseline pts characteristics were as follows: median age: 64; male gender: 54/67; PS ≤1/2: 61/6; number of metastatic sites 1/≥2: 31/36; BMI<18.5kg/m²: 6/67; prior exposure to CT (combined to radiation therapy and/or surgery): 37/67. 64/67 pts were eligible and treated (arm A 31, arm B 33). CTs were LV5FU2-CDDPq2w 7/31, FOLFOX 24/31. ITT 9-months OS rate was 50% (85%-CI: 37-62) for arm A and 44% (85%-CI: 31-56) for arm B. PFS after randomization was 2.8 mo (95% CI: 1.7-5) for arm A, and 1.4 mo (95% CI: 1.4-2.7) for arm B. Tolerance was good, as expected with the CT we used. Conclusions: Inpts with MESC free from PD after 6 wks of 5FU/platinum-based CT who were randomized to the CT-continuation arm, 9-month OS rate in arm A was 50%. Despite a trend in OS and PFS favoring arm A, it does not appear that CT continuation provides much clinical benefit over CT discontinuation plus BSC, in such pts. Results of quality of life and medical costs are awaited. Clinical trial information: NCT01248299.
Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis
Authors: Prakash Thapa, Du Hyung Choi, Min Soo Kim, Seong Hoon Jeong
Journal: Asian Journal of Pharmaceutical Sciences (2018)

The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables (impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.
Differences in the molecular landscape of cancer between African American (AA) and Caucasian (CC) cancer patients.
Authors: Elisabeth I. Heath, Filipa Lynce, Joanne Xiu, Sandeep K. Reddy, Ryan Bender, Elias Obeid, Stephen V. Liu, Aliccia Bollig-Fischer, Ari VanderWalde
Journal: Journal of Clinical Oncology (2016)

6558 Background: The racial and ethnic differences in the molecular pathology of cancer have yet to be fully characterized. Here we report on the mutational landscape of tumors classified by race. Methods: DNA from formalin-fixed paraffin-embedded samples was sequenced using the Illumina NextSeq (Agilent SureSelect XT, 592 gene) and MiSeq (TruSeq, 47 gene). Immunohistochemistry (IHC) evaluated protein expression. The exome aggregation consortium database was evaluated for known ethnicity associations. Results: Tumors from 363 AA and 888 CC patients were included. In both groups, the most prevalent cancer types were NSCLC (AA:25.1%, C:19.9%), CRC ( 25.1%; 18.7%) and breast cancer (BC; 14.6%, 11%). When only pathogenic or presumed pathogenic mutations (determined according to ACMG guidelines) were considered, in CRC, AA had fewer BRAF mutations than CC (2.5% vs. 10.3%, p = 0.035), including the V600E variant (1.24% AA vs 8.2% CC, p = 0.02). AA had lower ATM mutations vs. CC (0 vs. 7.1%, p = 0.014) but higher MEK1 (3.7% (D67N and K57N) vs. 0, p = 0.04) and PIK3CA mutations (23% vs. 11%, p = 0.01, no difference in distribution of exon 9 /20), KRAS was similar. In BC, AA had more NF1 mutations [7.7% (frameshift mutations) vs. 0, p = 0.044] than CC . No significant differences were seen in NSCLC. When all variants are considered, previously unreported variants in KAT6B (most frequent variants: E1097del and E1359_E1360insEEE) were seen more frequently in AA. A mean of 45 variants/tumor was seen in AA vs. 36 in CC, p = 9E-7; experiments to determine the origin of key variants and multivariate analyses are ongoing. In CRC, IHC analysis revealed that AA had higher TOPO1 (61% vs. 46%, p = 0.03) expression than CC. In BC, AA had higher RRM1 (52% vs. 23%, p = 0.009), lower TLE3 (64% vs. 82%, p = 0.02) and lower TS (46% vs. 25%, p = 0.016) expression. Conclusions: Different molecular landscapes of the most common cancers between AA and CC patients were seen. Observations such as higher BRAF V600E mutation rates in CC CRC may have clinical implications. Further investigation is warranted to explore these differences.
Consensus molecular subtypes (CMS), markers of systemic inflammation (SI) and clinicopathological parameters in colorectal cancer (CRC).
Authors: Michael Lam, Allan Andresson Lima Pereira, Preeti Kanikarla Marie, Jennifer S Davis, Ruo Xi Yu, Jeffrey Morris, Ganiraju C. Manyam, Bradley McIntosh Broom, Dipen M. Maru, Riham Katkhuda, David Menter, Scott Kopetz
Journal: Journal of Clinical Oncology (2018)

e15600 Background: The CMS provide a representation of CRC heterogeneity. Upregulated immune pathways are suggested in CMS1 through lymphocyte (lymph) reactivity and CMS4 with an inflammatory response. Markers of SI such as neutrophil (neut) to lymph ratio (NLR), neut to platelet (plt) score (NPS) and lymph to monocyte ratio (LMR) provide gross measures of the SI state. We investigated whether there were any associations between the SI state and CMS of the tumor. Methods: Patients consented to an approved translational research tissue banking protocol were previously annotated for CMS using the CRC consortium classifier reported in 2015. Complete blood count (CBC) parameters were collected before resection of the primary tumor. Cut offs for NLR (5), NPS (1 point given for plt > 400 or neut > 7.5) and LMR (2.13) were taken from published literature. Measures of association were tested with chi-squared, Fisher’s exact test, ANOVA or Kruskal-Wallis as appropriate. Results: A total of 261 patients had transcriptomics analysis and CBCs available. CMS distribution was similar to previously reported distributions (17%, 32%, 8%, 17%) for CMS1-4, respectively. CMS was significantly associated with primary sidedness (p < 0.001), pathological differentiation (p < 0.001), mucinous histology (p < 0.001), perforation (p = 0.001) and MSI (p < 0.001). CMS1 had higher proportions of right sided, poorly differentiated tumors, mucinous histology and MSI-high (MSI-H). NPS was the only SI measure associated with CMS (p < 0.001) with higher scores having increased proportions of CMS1. Higher NPS was also associated with higher pathological T stage, poorer differentiation and MSI-H status. Individually, elevated plt and neut counts showed a trend towards CMS1. Raw plt counts were associated with CMS classes while trends with seen with neuts and monocytes. The absolute differences were still within normal reference limits. Conclusions: A high NPS score was associated with CMS1 in addition to other CMS1 features including poorer differentiation and MSI-H. This potentially links CMS1 tumors with a platelet and neutrophil response in the circulation warranting further investigation.