tbuckley/cabot-search huggingface dataset:
Survivin expression in peripheral blood as a prognostic marker in patients with gastric cancer.
Authors: Masanori Terashima, Yushi Yamakawa, Keiichi Hatakeyama, Yuichiro Miki, Rie Makuuchi, Shinsaku Honda, Taichi Tatsubayashi, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Keiichi Oshima, Toru Mochizuki
Journal: Journal of Clinical Oncology (2014)

4079 Background: Detection of circulating tumor cells (CTC) in peripheral blood is thought to be a promising method to evaluate the extent of minimal residual disease. However, unlike breast or lung cancer, little information is available in gastric cancer. Among them, evaluation of survivin, a member of the inhibitor of apoptosis (IAP) family, mRNA expression in peripheral blood appears to be a promising procedure with relative good performance for predicting recurrence after curative resection. In order to evaluate the clinical significance of surviving expression in peripheral blood, we performed real-time RT-PCR analysis using whole blood obtained from healthy volunteers and patients with gastric cancer. Methods: A total of 22 healthy volunteers and 96 patients with gastric cancer were enrolled in this study. Peripheral blood samples were collected using PAXgene and RNA was isolated using Boom method. After cDNA synthesis, quantitative real-time PCR targeting survivin gene was performed. The relative expression level of survivin mRNA was calculated with actin beta as an internal standard. Correlation between survivin expression and clinicopathologic factors and survival was investigated. Results: Survivin mRNA expression level in peripheral blood was significantly higher in gastric cancer (median: 370, range: 35-1890) than in healthy volunteers (median:117, range: 46 to 538) in healthy volunteers. Tere was no significant correlation between survivin mRNA expression level and clinicopathologic factors. If the cut-off level of survivin was determined at 540 from ROC analysis, survivin was positive in 28 of 96 patients (29%). Disease-free survival was significantly worse in survivin positive patients than in negative patients (p=0.0216). In multivariate analysis, survivin was selected as independent prognostic factor as well as lymph node involvement. Conclusions: Survivin expression in peripheral blood was significantly higher in gastric cancer patients than in healthy volunteers. In addition, survivin was selected as an independent prognostic factor in patients with gastric cancer.
Vitamin D level at diagnosis and its variation during follow-up as prognostic factor of cutaneous melanoma.
Authors: Philippe Saiag, Philippe Aegerter, Dominique Vitoux, Celeste Lebbe, Pierre Wolkenstein, Nicolas Dupin, Vincent Descamps, Selim Aractingi, Nicole Basset-Seguin, Philippe Autier, Mathieu Boniol
Journal: Journal of Clinical Oncology (2014)

9057 Background: Low 25-hydroxyvitamin D3 (25(OH)D3) serum concentration at diagnosis of melanoma might be associated with worse survival. We prospectively studied the prognostic value of 25(OH)D3 at diagnosis and during follow-up. Methods: Melancohort is a cohort of patients recruited in Paris hospitals in 2003-08 within 1-3 months after diagnosis of AJCC stage I-II, III or IV invasive melanoma and followed until 06/2011. Blood 25(OH)D3 was measured by mass spectrometry. 25(OH)D3 levels were standardized on month of blood drawn, age, sex and body mass index (BMI). Role of 25(OH)D3 level at inclusion and change through time on disease-free survival (DFS) were analyzed in a time dependent covariates Cox model adjusting for age, sex, BMI and AJCC stage. Results: 1,171 patients were included, with 411 first relapses during follow-up and 303 deaths. On average 3.25 measures per patient were performed. Median 25(OH)D3 serum concentration at inclusion was 47.2 nmol/L (interquartile range 30.65-63.18). 25(OH)D3 levels at inclusion were inversely correlated with prognostic factors such as AJCC stage (p<0.0001 Kruskal-Wallis), Breslow’s thickness (p<0.0001 spearman correlation), and ulceration (p=0.0004 Kruskal-Wallis), but were not associated with DFS in the Cox model, either as a continuous (p=0.747) or categorical variable. Changes in 25(OH)D3 levels during follow-up were significantly associated with worse DFS: with a third quartile Q3 of average change per year (-0.3;4.6nmol/L/Y) used as reference, HR were for Q1 (<-5.25nmol/L/Y) 1.94 95%CI(1.36-2.76), for Q2 (-5.25;-0.30nmol/L/Y) 1.23 95%CI(0.85-1.78), and for Q4 (>4.60nmol/L/Y) 1.61 95%CI(1.14-2.28). In sensitivity analyses, no changes were observed either by AJCC stage or by number of 25(OH)D3 measures performed. Analyses performed on overall survival yielded similar results. Conclusions: We show that 25(OH)D3 variation during follow-up is an independent melanoma prognostic marker, but not its level at diagnosis. The biological significance of this finding should be investigated. Previously reported association between low 25(OH)D3 level at diagnosis and poor prognosis were probably due to insufficient adjustment for prognostic factors. Clinical trial information: NCT00839410.
Predictive value of primary tumor location (TL) in patients (pts) with pan-<i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) receiving chemotherapy (CTX) ± cetuximab or panitumumab (C/P): An updated meta-analysis.
Authors: Zi-Xian Wang, Ming-ming He, Ying-Nan Wang, Feng Wang, Rui-hua Xu
Journal: Journal of Clinical Oncology (2018)

830 Background: Previous evidence suggests that TL may be predictive of the efficacy of C/P versus bevacizumab. This meta-analysis was aimed to evaluate the efficacy of CTX plus C/P versus CTX only as a first-line (1L) or second-line (2L) treatment for RAS wt right- and left-sided mCRC (R- and L-mCRC) in randomized controlled trials (RCTs). Methods: A systematic literature review was performed of PubMed and oncology congress websites (2000–present). RCTs studying the additional efficacy of C/P to CTX in RAS wt R- and L-mCRC were included. Assessed outcomes included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Random-effects meta-analytic models were used in the presence of significant heterogeneity ( I 2 &gt; 50%). Otherwise, fixed-effects models were performed. Random-effects meta-regression models were used to evaluate the interaction between TL and the efficacy of C/P. Results: A total of three 1L RCTs (CRYSTAL, PRIME, and TAILOR) and one 2L RCT (20050181) were included (325 pts with R-mCRC and 1214 with L-mCRC). Pooled estimates of the efficacy of C/P are summarized in the table. In both R- and L-mCRC pts, the addition of C/P to CTX significantly improved PFS and ORR. A significant OS benefit from C/P was observed in L-mCRC but not R-mCRC pts. No significant interaction was detected between TL and the efficacy of C/P on PFS, OS, and ORR ( P= 0.69, 0.09, and 0.22, respectively). Conclusions: Adding C/P to CTX clearly benefits RAS wt L-mCRC pts in terms of PFS, OS, and ORR. Considering the improvements in PFS and ORR versus CTX only, anti-EGFR agents remain an option for pts with RAS wt R-mCRC. [Table: see text]
Prognostic potential of MDM2 309T>G polymorphism in stage I lung adenocarcinoma.
Authors: Kimihiro Shimizu, Yasuaki Enokida, Jun Atsumi, Seiichi Kakegawa, Yoshiaki Takase, Seshiru Nakazawa, Toshiteru Nagashima, Yoichi Ohtaki, Kazumi Tanaka, Kyoichi Kaira, Izumi Takeyoshi
Journal: Journal of Clinical Oncology (2014)

11055 Background: The MDM2 protein plays an important role in regulating cell proliferation and apoptosis by ubiquitination and proteosome-mediated degradation of p53. c.309 (rs2279744) polymorphism (T>G) in the MDM2 intronic promoter has been reported as a susceptibility and/or prognostic factor in various cancers. The purpose of this study was to investigate the risk factors for worse survival in patients with pathological (p-) stage I lung adenocarcinoma. Methods: We retrospectively reviewed 179 stage I lung adenocarcinoma patients. Clinicopathological and genetic characteristics including MDM2 SNP309, p53 codon72, as well as EGFR, KRAS, and p53 mutation were analyzed. Associations between these factors and survival outcome were analyzed by cox proportional hazards models. We further evaluated the associations of prognostic effects of SNP309 and smoking status or gene mutation status by stratified analyses. Results: A significant association was found between pleural invasion or lymphatic invasion and SNP309 TT genotype (TT vs. TG+GG, p= .027, p= .008, respectively; χ2 test) Overall-survival (OS) of patients with MDM2 TT genotype was significantly shorter than that with TG genotype and GG genotype (p= .048 and p= .009, respectively by log-rank test). A multivariate analysis of OS showed that MDM2 genotype (TT; Hazard Ratio [HR] =3.7, 95% confidential interval [CI] 1.5 to 9.2, p= .005) was an independently significant prognostic factor. Subgroup analysis also showed that TT genotype was especially associated with worse OS among smoker group (HR=6.75, 95%CI 1.90 to 24.0, p= .005), EGFR wild-type group (HR=3.75, 95%CI 1.22 to 11.6, p= .022), p53 wild-type group (HR=7.00, 95%CI 2.30 to 21.3, p= .001), and p53 codon72 RR+RPgroup (HR=5.44, 95%CI 1.91 to 15.5, p= .002). Conclusions: Our findings suggest that MDM2 TT genotype is associated with worse OS among p-stage I lung adenocarcinoma patients, particularly in the smoker group, EGFR wild-type group, p53 wild-type group, and p53 codon72 RR+RP group.
Modeling the risk of progression in smoldering multiple myeloma.
Authors: Adam J Waxman, Rosemarie Mick, Alfred L. Garfall, Adam D. Cohen, Dan T. Vogl, Edward Allen Stadtmauer, Brendan M. Weiss
Journal: Journal of Clinical Oncology (2014)

8607 Background: Smoldering multiple myeloma (SMM) is a precursor state to multiple myeloma (MM) with a highly variable risk of progression to active MM. Identifying patients at risk of imminent progression to MM is critical for redefining MM requiring therapy and for designing clinical trials of early intervention. Existing biomarkers and risk models have not been validated. We sought to validate the Mayo Clinic risk models and biomarkers and to derive a novel risk model for an ethnically diverse SMM population seen at an urban academic medical center. Methods: We performed a retrospective study of all SMM patients seen within the University of Pennsylvania Health System (2008-2012). Patients were identified by ICD9 codes for MGUS and MM and classified as SMM per IMWG criteria after review of electronic medical records. Using classification and regression tree and Cox regression analyses, we developed a model for risk of progression to active MM. Results: We identified 126 SMM patients, median age 62 years, 55% male, 78% Caucasian, 19% African-American, and 3% other races. Median follow-up was 4 years. We validated the Mayo models and biomarkers (table). The Penn model included 3 factors: bone marrow plasma cells (BMPC) ≥40% (HR 2.72, CI 1.28-5.77, p<0.009), serum free light chain ratio (sFLCR) ≥50 (HR 4.57, CI 1.99-10.5, p <0.001) and albumin ≤ 3.5 gm/dL (HR 3.38, CI 1.57-7.27, p<0.001) [Low-risk = 0 factors, Intermediate risk = 1 factor, high risk ≥ 2 factors]. Adjusting for race did not impact risk of progression in any of the models. All patients with BMPC ≥60% progressed to MM within 2 years. Conclusions: We validated the Mayo risk models and biomarkers. In our population, albumin was a useful biomarker for risk of progression in SMM. N Median TTP (yrs) 2-yr Progression Free Survival + SE HR 95% CI P value Mayo 2003 BMPC ≥ 10 and M-s < 3 98 8.4 80 + 6 1.00 <0.001 BMPC ≥ 10 and M-s ≥ 3 23 1.7 42 + 11 3.05 1.66 – 5.59 Mayo 2008 Low risk 47 NR 83 + 6 1.00 0.003 Intermediate risk 54 5.6 71 + 7 1.98 0.99 – 4.00 High risk 13 0.7 31 + 13 4.59 1.92 – 11.01 Penn Low risk 73 NR 84 + 4 1.00 <0.001 Intermediate risk 24 3.07 56 + 12 3.24 1.55 – 6.75 High risk 14 0.35 19 + 11 11.16 5.03 – 24.78 BMPC < 60 115 6.8 76 + 4 1.00 <0.001 ≥ 60 6 0.1 0 15.42 6.19 – 38.41 sFLCR < 100 107 8.4 73 + 5 1.00 0.009 ≥ 100 11 1.7 47 + 17 2.99 1.32 – 6.78 Abbreviations: NR, not reached.
An unselected non-small cell lung cancer population: Treatment practices and trial eligibility.
Authors: Khalid Salim Al-Baimani, Zuhaib Mir, Tinghua Zhang, Hannah Jonker, Elise Azzi, Paul Wheatley-Price
Journal: Journal of Clinical Oncology (2014)

e19119 Background: NSCLC advances in recent years include multiple lines of systemic therapy, and new molecular targets that may improve survival. These treatments are based on clinical trial data, yet many patients (pts) won’t be trial eligible, or be fit for any systemic therapy. Methods: With ethics approval, we identified all thoracic malignancy pts seen as new consults by one medical oncologist from Sep 2009 to Apr 2013. Data included demographics, presentation, performance status (PS), smoking status, histology, stage, baseline bloodwork, treatment, and date of death or last follow-up. Primary endpoint was overall survival (OS) in stage 4 NSCLC, and factors associated with OS, specifically reporting pts who had no therapy. Results: Of 400 thoracic cancer pts: 50% female; median age 67 (range 36-90); 59% ECOG PS 0-1. NSCLC 81%, SCLC 15%, mesothelioma 3%. Common presentations were incidental (19%), dyspnea (17%), cough (16%), and pain (14%). At diagnosis, 157 pts had stage 4 NSCLC, and 70 pts relapsed after presenting with an earlier stage. Of these 227, 61% received no palliative systemic therapy, 17% received 1 line, 14% 2 lines, 8 % ≥3 lines. Where available (n=157), common reasons for no palliative systemic therapy were poor PS (65%) or patient choice (27%). Median OS of all stage 4 was 6.7 months. By lines of treatment the median OS was 3.4, 8.5, 16.5 and 17.3 months for 0, 1, 2 and ≥3 lines respectively (p<0.01). In univariate analysis; PS, dyspnea, pain, >5% weight loss, constitutional symptoms and hemoptysis were all significantly associated with shorter OS. In multivariate analysis; only PS 3-4 (HR 2.9 95% CI 1.6 -5.4 p<0.01) or the initial presence of respiratory symptoms (cough; dyspnea; hemoptysis; pneumonia) (HR 2.5 95% CI 1.2-5.3, p= 0.02) were associated with shorter OS. From 157 pts with stage 4 at diagnosis, 152 had sufficient data to determine standard clinical trial eligibility (PS 0-1, no CNS disease, creatinine <120mmol/L). Of these, 109 (72%), would have been considered ineligible. Conclusions: Therapy choices in advanced NSCLC are based on clinical trial data. In this unselected series, we demonstrate that most pts would be ineligible for many studies, and indeed >50% receive no palliative systemic therapy at all.
Patients with Immune Thrombocytopenia (ITP) Frequently Experience Severe Fatigue but Is It Under-Recognized By Physicians: Results from the ITP World Impact Survey (I-WISh)
Authors: Caroline Kruse, Alexandra Kruse, Shirley Watson, Mervyn Morgan, Nichola Cooper, Waleed Ghanima, Andrew Provan, Donald M. Arnold, Cristina Santoro, Ming Hou, Yoshiaki Tomiyama, Serge Laborde, Barbara Lovrencic, John Waller, Gavin Taylor-Stokes, Tom Bailey, Miona Stankovic, James B. Bussel
Journal: Blood (2018)
Biologically Inspired and Chemically Derived Methods for Glucose‐Responsive Insulin Therapy
Authors: Michael A. VandenBerg, Matthew J. Webber
Journal: Advanced Healthcare Materials (2019)

Abstract The controlled delivery of therapeutics in a manner responsive to physiological indicators has promise in realizing new therapeutic approaches to combat disease. This approach is especially relevant in the context of diabetes. Natural fluctuations in blood glucose seen in the healthy state, complete with peaks and troughs, are poorly regulated as a result of detrimental production or ineffective signaling of the insulin hormone. While several manifestations of diabetes are treated with regularly administered exogenous insulin, the present standard of care results in suboptimal glycemic management that poorly recreates natural hormone control, leading to long‐term instability and a significantly increased risk for secondary health complications. New synthetic technologies that make insulin available only when needed, and at the exact dose required, have been explored under the broad vision of realizing a “fully synthetic pancreas.” Yet, many challenges remain to realizing a technology that is appropriately responsive, safe, and well integrated into a manageable routine. Herein, many of the approaches explored thus far to sense physiological blood glucose and elicit response through the release of therapeutic insulin are summarized. The approaches point to a new, autonomous approach to managing diabetes with biomimetic therapy.
Obesity-induced alteration in iron metabolism via elevated hepcidin and the risk of postmenopausal breast cancer among Caucasians.
Authors: Puja Agarwal, Carol Braunschweig, Kent Hoskins
Journal: Journal of Clinical Oncology (2014)

1597 Background: Obesity is an established risk factor for postmenopausal breast cancer and also induces iron dysregulation via elevated hepcidin (hepatic peptide hormone). Hepcidin degrades ferroportin (Fp-only known iron exporter) and traps iron that enhances carcinogenesis within the cell. Breast tumors with high hepcidin and low Fp have poor prognosis. The purpose of this study was to determine if systemic hepcidin independently enhances the established obesity and postmenopausal breast cancer risk. Methods: A nested case (n=44)-control (n=44) study was conducted from an ongoing cohort on women seeking breast biopsies enrolled in a study to develop blood-based biomarkers. White postmenopausal women with incident breast cancer were matched for age and BMI to women with a non-proliferative benign lesion. Both cases and controls were stratified by obesity status (50% had a BMI > 30 & 50% < 30). Blood samples, anthropometric and other information were collected prior to biopsy. C-reactive protein, IL-6, leptin, adiponectin, estradiol, soluble transferrin receptor and hepcidin were measured using ELISA and cases and controls were compared with T-test, Wilcoxon Rank test and conditional logistic regression. Results: Hepcidin (p=0.02) along with other obesity related factors for breast cancer (inflammation (CRP, IL-6); leptin and estrogen; (all p values ≤ 0.05)) significantly differed with obesity status among the controls. Among the cases hepcidin levels were similar in obese and non-obese. Hepcidin (β=0.04; p value=0.043) was a significant independent predictor of disease (p value) status when controlled for age, leptin, family history of breast cancer, age of menarche and use of hormone replacement therapy and IL-6 in multivariable conditional logistic regression. Conclusions: Influence of obesity on hepcidin reported in premenopausal women also occurs post menopause. Hepcidin level is associated with breast cancer and may represent a novel mechanism to explain the link between obesity and breast cancer. Further study of this association is warranted.
Gene expression profiles of primary tumors versus circulating tumor cells in metastatic breast cancer.
Authors: Wendy Onstenk, Anieta M. Sieuwerts, Marleen Weekhout, Bianca Mostert, Esther Anneke Reijm, Carolien H. M. Van Deurzen, Jaco Kraan, A. Jager, Caroline Seynaeve, Dieter Peeters, Paul Hamberg, Felix E. de Jongh, Anne M. van Galen, Raquel Ramirez Moreno, Marcel Smid, Luc Dirix, Jan-Willem Gratama, John W. M. Martens, John A. Foekens, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2014)

11017 Background: Before considering circulating tumor cells (CTCs) as a liquid biopsy in metastatic breast cancer (MBC), the degree of molecular discrepancy between primary tumors (PTs) and CTCs has to be established. Methods: In 69 MBC patients with ≥1 CTC before start of first-line systemic treatment, our previously described panel of 55 tumor-associated gene transcripts was measured by quantitative reverse transcription polymerase chain reaction in both formalin fixed paraffin embedded PTs and CellSearch-enriched CTCs. From 11 patients, a lymph node metastasis (LN), obtained at the time of primary tumor resection, was available for comparison with PTs and CTCs. A Compare Batches normalization was used to correct for batch effects. Overall gene expression profiles and the expression of therapeutic targets ESR1/ER and ERBB2/HER2 were compared. Associations with clinical outcome (time-to-treatment switch, start first- to second-line treatment) were exploratory. Results: In 55% of patients, PT and CTC profiles did not cluster. Patients with non-clustering profiles more often had synchronous metastases (42% versus 3%, χ2 P = .001), and ER-positive tumors (68.4% versus 38.7%, χ2 P = .03) compared to patients with clustering profiles. Discrepant expression of ER and HER2 was found in 26% and 25% of patients, respectively. Whereas ER was equally lost and gained in CTCs compared to PTs (12% versus 15%, McNemar P=.82), HER2 was more often lost than gained (21% versus 5%, McNemar P=.02). Patients with concordant ER-positive expression in PTs and CTCs had the best prognosis, those with discordant expression performed worse, and prognosis for concordant ER-negative patients was worst (Log-rank test for trend P < .001). A similar pattern was observed for HER2, although this was not statistically significant (P = .10). In all 11 patients, LN profiles clustered with the PT profiles; in 2 patients CTCs mismatched with both PT and LN. Conclusions: Gene expression profiles of PTs and CTCs at time of MBC differ in a substantial proportion of patients. Expression of ER and HER2 is often discrepant between PTs and CTCs, which had prognostic implications in this patient cohort and may thus be of clinical relevance.
Abstract 19650: Associations of Exercise Ankle-Brachial Index, Pain-Free Walking Distance, and Maximum Walking Distance With Peripheral Artery Questionnaire: Finding From PORTRAIT Registry
Authors: Tarek A Hammad, Kim G. Smolderen, John A. Spertus, Philip G. Jones, Mehdi H. Shishehbor
Journal: Circulation (2017)

Objective: Beyond the use of exercise ankle-brachial index (ABI) to diagnose peripheral artery disease (PAD), an exercise ABI can provide further insight into the functional significance of PAD. While ACC/AHA guidelines recommend exercise ABI only when resting measurement is normal and symptoms are suggestive of PAD, the variability in the use of exercise ABI, patient’s factors associated with its use and its relation to patient’s symptoms as quantified by the Peripheral Artery Questionnaire (PAQ), are unknown. Methods: From the multinational PORTRAIT registry, between 06/2011 and 02/2015, we identified 1,132 consecutive patients with PAD (resting ABI ≤ 0.9). We built a hierarchical logistic regression model, including random effects for site and country, to examine predictors and variation, by the calculation of fully-adjusted median odds ratios (MOR), in ordering exercise ABIs. Lastly, association between exercise ABI (absolute and relative change in ABI with exercise, pain-free walking distance (PFWD),...