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AIMS - Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions.
METHODS AND RESULTS - We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival.
CONCLUSIONS - In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
© 2018 John Wiley & Sons Ltd.
PURPOSE - The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression.
METHODS - We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources.
RESULTS - Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS.
CONCLUSIONS - We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.
BACKGROUND - High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors.
METHODS - We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression.
RESULTS - Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53).
CONCLUSIONS - These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing or substantially reduced the amount of intracellular glutamate through decreased expression of and , respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both and contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, expression positively correlated with that of and , as well as that of and Although high expression of predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
OBJECTIVE - To evaluate the relationship between genetic ancestry and uterine fibroid characteristics.
DESIGN - Cross-sectional study.
SETTING - Not applicable.
PATIENT(S) - A total of 609 African American participants with image- or surgery-confirmed fibroids in a biorepository at Vanderbilt University electronic health record biorepository and the Coronary Artery Risk Development in Young Adults studies were included.
INTERVENTION(S) - None.
MAIN OUTCOME MEASURE(S) - Outcome measures include fibroid number (single vs. multiple), volume of largest fibroid, and largest fibroid dimension of all fibroid measurements.
RESULT(S) - Global ancestry meta-analyses revealed a significant inverse association between percentage of European ancestry and risk of multiple fibroids (odds ratio: 0.78; 95% confidence interval 0.66, 0.93; P=6.05 × 10). Local ancestry meta-analyses revealed five suggestive (P<4.80 × 10) admixture mapping peaks in 2q14.3-2q21.1, 3p14.2-3p14.1, 7q32.2-7q33, 10q21.1, 14q24.2-14q24.3, for number of fibroids and one suggestive admixture mapping peak (P<1.97 × 10) in 10q24.1-10q24.32 for volume of largest fibroid. Single variant association meta-analyses of the strongest associated region from admixture mapping of fibroid number (10q21.1) revealed a strong association at single nucleotide polymorphism variant rs12219990 (odds ratio: 0.41; 95% confidence interval 0.28, 0.60; P=3.82 × 10) that was significant after correction for multiple testing.
CONCLUSION(S) - Increasing African ancestry is associated with multiple fibroids but not with fibroid size. Local ancestry analyses identified several novel genomic regions not previously associated with fibroid number and increasing volume. Future studies are needed to explore the genetic impact that ancestry plays into the development of fibroid characteristics.
Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
There is a paucity of data on risk factors for lung cancer among never smokers. Here, we have carried out the first large study of circulating inflammation markers and lung cancer risk among female never smokers in Shanghai. A study of 248 lung cancer cases in female never smokers and 263 controls was nested within the Shanghai Women's Health Study (n = 75221), matched by dates of birth and blood collection (mean follow-up time = 7.5 years). Prediagnostic plasma levels of 65 inflammation markers were measured using a Luminex bead-based assay. Odds ratios (ORs) were estimated with multivariable logistic regression. Nine of 61 evaluable markers were statistically significantly associated with lung cancer risk among never smoking Chinese women (P-trend across categories <0.05). Soluble interleukin-6 receptor [sIL-6R; highest versus lowest category OR = 2.37; 95% confidence interval (CI) 1.40-4.02) and chemokine (C-C motif) ligand 2/monocyte chemotactic protein 1; (OR = 1.62; 95% CI 0.94-2.80) were associated with an increased risk of lung cancer, whereas interleukin (IL)-21 (OR = 0.53; 95%CI 0.31-0.93), chemokine (C-X3-C motif) ligand 1/fractalkine (OR = 0.54; 95% CI 0.30-0.96), soluble vascular endothelial growth factor receptor 2 (sVEGFR2, OR = 0.45; 95% CI 0.26-0.76), sVEGFR3 (OR = 0.53; 95% CI 0.32-0.90), soluble tumor necrosis factor receptor I (OR = 0.49; 95% CI 0.29-0.83), IL-10 (OR = 0.60; 95% CI 0.34-1.05) and C-reactive protein (OR = 0.63; 95% CI 0.37-1.06) were associated with a decreased risk. sIL-6R remained significantly associated with lung cancer risk >7.5 years prior to diagnosis. Markers involved in various aspects of the immune response were associated with subsequent lung cancer risk, implicating inflammation in the etiology of lung cancer among female never smokers.
Published by Oxford University Press 2017.
BACKGROUND - Molecular biomarkers have the potential to improve the current state of early lung cancer detection. The goal of this project was to develop a policy statement that provides guidance about the level of evidence required to determine that a molecular biomarker, used to support early lung cancer detection, is appropriate for clinical use.
METHODS - An ad hoc project steering committee was formed, to include individuals with expertise in the early detection of lung cancer and molecular biomarker development, from inside and outside of the Assembly on Thoracic Oncology. Key questions, generated from the results of a survey of the project steering committee, were discussed at an in-person meeting. Results of the discussion were summarized in a policy statement that was circulated to the steering committee and revised multiple times to achieve consensus.
RESULTS - With a focus on the clinical applications of lung cancer screening and lung nodule evaluation, the policy statement outlines categories of results that should be reported in the early phases of molecular biomarker development, discusses the level of evidence that would support study of the clinical utility, describes the outcomes that should be proven to consider a molecular biomarker clinically useful, and suggests study designs capable of assessing these outcomes.
CONCLUSIONS - The application of molecular biomarkers to assist with the early detection of lung cancer has the potential to substantially improve our ability to select patients for lung cancer screening, and to assist with the characterization of indeterminate lung nodules. We have described relevant considerations and have suggested standards to apply when determining whether a molecular biomarker for the early detection of lung cancer is ready for clinical use.
INTRODUCTION - Patients with SCLC have a poor prognosis and limited treatment options. Because access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden.
METHODS - We developed a liquid biopsy assay that quantifies somatic variants in cfDNA. The assay detects single nucleotide variants, copy number alterations, and insertions or deletions in 14 genes that are frequently mutated in SCLC, including tumor protein p53 gene (TP53), retinoblastoma 1 gene (RB1), BRAF, KIT proto-oncogene receptor tyrosine kinase gene (KIT), notch 1 gene (NOTCH1), notch 2 gene (NOTCH2), notch 3 gene (NOTCH3), notch 4 gene (NOTCH4), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), phosphatase and tensin homolog gene (PTEN), fibroblast growth factor receptor 1 gene (FGFR1), v-myc avian myelocytomatosis viral oncogene homolog gene (MYC), v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog gene (MYCL1), and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog gene (MYCN).
RESULTS - Over the course of 26 months of peripheral blood collection, we examined 140 plasma samples from 27 patients. We detected disease-associated mutations in 85% of patient samples with mutant allele frequencies ranging from 0.1% to 87%. In our cohort, 59% of the patients had extensive-stage disease, and the most common mutations occurred in TP53 (70%) and RB1 (52%). In addition to mutations in TP53 and RB1, we detected alterations in 10 additional genes in our patient population (PTEN, NOTCH1, NOTCH2, NOTCH3, NOTCH4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed allele frequencies and copy number alterations tracked closely with treatment responses. Notably, in several cases analysis of cfDNA provided evidence of disease relapse before conventional imaging.
CONCLUSIONS - These results suggest that liquid biopsies are readily applicable in patients with SCLC and can potentially provide improved monitoring of disease burden, depth of response to treatment, and timely warning of disease relapse in patients with this disease.
Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
BACKGROUND AND OBJECTIVES - The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease.
METHODS - We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15.
RESULTS - We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs.
CONCLUSION - Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.
© 2017 Wiley Periodicals, Inc.