Gene Summary

Gene:TNFSF13; TNF superfamily member 13
Aliases: APRIL, CD256, TALL2, ZTNF2, TALL-2, TNLG7B, TRDL-1, UNQ383/PRO715
Summary:The protein encoded by this gene is a member of the tumor necrosis factor (TNF) ligand family. This protein is a ligand for TNFRSF17/BCMA, a member of the TNF receptor family. This protein and its receptor are both found to be important for B cell development. In vitro experiments suggested that this protein may be able to induce apoptosis through its interaction with other TNF receptor family proteins such as TNFRSF6/FAS and TNFRSF14/HVEM. Alternative splicing results in multiple transcript variants. Some transcripts that skip the last exon of the upstream gene (TNFSF12) and continue into the second exon of this gene have been identified; such read-through transcripts are contained in GeneID 407977, TNFSF12-TNFSF13. [provided by RefSeq, Oct 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor ligand superfamily member 13
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (17)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Xenograft Models
  • Case-Control Studies
  • Young Adult
  • Cervical Cancer
  • Cell Proliferation
  • TNF
  • Western Blotting
  • RT-PCR
  • Promoter Regions
  • Single Nucleotide Polymorphism
  • NF-kappa B
  • Mice, Inbred BALB C
  • B-Cell Maturation Antigen
  • Biomarkers, Tumor
  • Colorectal Cancer
  • Signal Transduction
  • B-Cell Activating Factor
  • Gene Expression Profiling
  • Receptors, Tumor Necrosis Factor
  • Cancer Gene Expression Regulation
  • Tumor Necrosis Factors
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Base Sequence
  • Chromosome 17
  • bcl-X Protein
  • Membrane Proteins
  • Messenger RNA
  • Cancer RNA
  • Lung Cancer
  • Validation Studies as Topic
  • Chronic Lymphocytic Leukemia
  • B-Lymphocytes
  • Immunohistochemistry
  • X-Linked Inhibitor of Apoptosis Protein
  • Transmembrane Activator and CAML Interactor Protein
  • Apoptosis
  • Transfection
  • RNA Interference
  • Multiple Myeloma
  • Ligands
  • siRNA
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TNFSF13 (cancer-related)

Zheng L, Qi YX, Liu S, et al.
miR-129b suppresses cell proliferation in the human lung cancer cell lines A549 and H1299.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Lung cancer is one of the most prevalent malignant tumors, and is one of the primary causes of cancer-associated deaths. In 2002, an estimated 1.18 million lung cancer-associated deaths were recorded, accounting for 18% of cancer-related deaths and 2% of total mortality. Despite the great progress that has been made in lung cancer therapies, the mechanisms underlying lung cancer formation and development remain largely unknown. Meanwhile, the microRNA miR-129 has been shown to be involved in the formation of many types of cancer. Therefore, this study aims to investigate whether miR129b could suppress proliferation of lung cancer cell lines. NSCLC tissue samples were collected from the Department of Respiratory Medicine between April 2013 and December 2015. Ten normal health individuals were recruited as controls. Lung cancer cell lines A549 and H1299 were used to examine the suppressive effects of miR129b. Quantitative real-time PCR was used to detect miR129b expression. The MTT assay was used to analyze cell proliferation. Results indicated that miR-129b is down-regulated in lung cancer cell lines and NSCLC tissues. Furthermore, overexpression of miR-129b inhibited proliferation of lung cancer cells. In conclusion, miR-129b suppresses lung cancer cell proliferation, and can be a potential therapeutic target for treatment of lung cancers.

Zhang LH, Hao BB, Zhang CY, et al.
Contributions of polymorphisms in miR146a, miR196a, and miR499 to the development of hepatocellular carcinoma.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Hepatocellular carcinoma is one of the most common malignant tumors worldwide; it is estimated that there were 782,000 new cases in 2012. MicroRNAs (miRNAs) play an important role in carcinogenesis by regulating oncogenes and tumor suppressors. We investigated the role of miR-146a, miR-196a2, and miR-499 polymorphisms in the risk of hepatocellular carcinoma in a Chinese population. Hepatocellular carcinoma patients (175) and healthy controls (302) were recruited between April 2013 and March 2015. Genotype analysis of miR-146a, miR-196a2, and miR-499 polymorphisms was carried out by polymerase chain reaction-restriction fragment length polymorphism. There was a significant difference between the genotype distribution of miR-196a2 in hepatocellular carcinoma patients and controls (X(2) = 17.23, P < 0.001). CG and GG miR-146a genotypes significantly elevated the risk of hepatocellular carcinoma compared with the CC genotype, with adjusted ORs (95%CI) of 3.05 (1.07-8.70) and 4.96 (1.64-14.97), respectively. In the recessive model, the CG + GG genotype had a 3.75-fold risk of hepatocellular carcinoma compared with the CC genotype, with an adjusted OR (95%CI) of 3.75 (1.39-10.11). However, no significant association was observed between miR-196a2 and miR-499 variants and risk of hepatocellular carcinoma in the co-dominant, dominant, and recessive models. The miR-146a polymorphism is a G to C substitution that causes a mismatch in the stem-loop of miRNA, which influences how the expression and transcriptional regulation of miRNA affects its target genes. Our study revealed that the GG and CG genotypes of miR-146a increased the risk of hepatocellular carcinoma in the Chinese population.

Feng R, Zhang HX, Zhang HG, Zhang CF
Role of ABCB1 C1236T, G2677T, and C3435T genetic polymorphisms in the development of acute leukemia in a Chinese population.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
We carried out a case-control study to examine the relationship between the ATP-binding cassette subfamily B member 1 (ABCB1) gene polymorphisms C1236T, G2677T, and C3435T and risk of acute leukemia in a Chinese population. Between May 2013 and April 2015, we recruited 164 acute leukemia patients and 285 healthy controls, and determined polymorphism genotypes by polymerase chain reaction-restriction fragment length polymorphism. Using unconditional logistic regression analysis, we observed that in comparison to the wild-type sequence, the TT genotype [odds ratio (OR) = 2.15, 95% confidence interval (CI) = 1.12-4.10; P = 0.01] and the T allele (OR = 1.39, 95%CI = 1.05-1.86; P = 0.02) of ABCB1 G2677T were associated with acute leukemia susceptibility. The TT genotype (OR = 2.03, 95%CI = 1.11- 3.69; P = 0.01) and the T allele (OR = 1.39, 95%CI = 1.05-1.85; P = 0.02) of the C3435T polymorphism also increased acute leukemia risk compared to the wild-type form. However, no significant relationship was established between the ABCB1 C1236T variant and this disease. Our results suggest that the ABCB1 G2677T and C3435T sequence variations may affect susceptibility to acute leukemia.

Chen T, Yang P, He ZY
Long non-coding RNA H19 can predict a poor prognosis and lymph node metastasis: a meta-analysis in human cancer.
Minerva Med. 2016; 107(4):251-8 [PubMed] Related Publications
INTRODUCTION: A long non-coding RNA (lncRNA) H19 has been reported to be aberrantly regulated in a wide range of cancers. This meta-analysis was performed to explore the potential value of H19 as a biomarker for cancer prognosis.
EVIDENCE ACQUISTION: We searched the electronic databases PubMed and Web of Science (up to April 30, 2016) in attention to collect all relevant researches to identify the association of lncRNA H19 with overall survival (OS), disease free survival (DFS) and lymph node metastasis (LNM).
EVIDENCE SYNTHESIS: Our findings revealed that high levels of H19 expression could predict poor OS (pooled HR: 1.19, 95% CI: 1.08-1.32, P=0.001) and LNM (pooled OR: 1.810, 95% CI: 1.27-2.59, P=0.001) in multiple cancers.
CONCLUSIONS: This meta-analysis showed that overexpression of H19 might potentially serve as a reliable biomarker for poor prognosis in different types of cancers.

Ma SH, Ling FH, Sun YX, et al.
Investigation on the role of XPG gene polymorphisms in breast cancer risk in a Chinese population.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
We conducted a case-control study to investigate the role of XPG gene polymorphisms (rs2094258, rs751402, and rs17655) in the development of breast cancer. Patients with breast cancer (320) and control subjects (294) were consecutively selected from the Zhongshan Hospital between April 2013 and January 2015. The genotyping of XPG rs2094258, rs751402, and rs17655 was performed using polymerase chain reaction-restriction fragment length polymorphism. Using the chi-square test, we did not find any significant differences in the genotype distributions of XPG rs2094258 (χ(2) = 1.48, P = 0.48), rs751402 (χ(2) = 0.65, P = 0.72), and rs17655 (χ(2) = 0.01, P = 0.92) genes between breast cancer patients and control subjects. The genotype distributions of XPG rs2094258, rs751402, and rs17655 did not deviate from the Hardy-Weinberg equilibrium in control subjects, and the P values were 0.58, 0.97, and 0.26, respectively. Using unconditional logistic regression analysis, we found that XPG rs2094258, rs751402 and rs17655 gene polymorphisms are not associated with the development of breast cancer after adjusting for potential confounding factors. In conclusion, we found that XPG rs2094258, rs751402, and rs17655 do not influence the development of breast cancer in a Chinese population.

Lenormand C, Couteau J, Nouhaud FX, et al.
Predictive Value of NRAMP1 and HGPX1 Gene Polymorphism for Maintenance BCG Response in Non-muscle-invasive Bladder Cancer.
Anticancer Res. 2016; 36(4):1737-43 [PubMed] Related Publications
AIM: To assess the potential predictive value of natural resistance-associated macrophage protein 1 (NRAMP1) and human glutathione peroxidase 1 (hGPX1) polymorphism in non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG) instillation, we conducted an original ancillary multicenter study.
PATIENTS AND METHODS: We evaluated patients included in the multicenter URO-BCG 4 trial, who received three weekly instillations of one-third dose BCG every 6 months (group I) or two weekly instillations every 3 months (group II) for 3 years. For clinical evaluation we also evaluated tumor recurrence and muscle progression. NRAMP1 and hGPX1 polymorphism analyses were performed on blood DNA. NRAMP1 exon 15 and hGPX1 exon 1c were amplified using Type-it Microsatellite PCR Kit® for multiplex polymerase chain reaction.
RESULTS: From June 2004 to April 2010, 146 randomized patients were included in this retrospective study. Blood samples were obtained from 107 patients. With 36 months of follow-up, 13.6% of patients had a tumor recurrence and muscle-invasive progression was observed in 4.3% of patients. Concerning NRAMP1 D543N polymorphism, patients with allele A had no tumor recurrence or muscle-invasive progression. No significant difference was observed in gene polymorphism distribution between groups I and II. Moreover, we did not observe any significant association of gene polymorphisms, tumor recurrence or muscle-invasive progression, event time and disease-free survival.
CONCLUSION: Our results suggest that no significant difference was found for NRAMP1 and hGPX1 gene polymorphisms associated with recurrence time, muscle invasion frequency and disease-free survival, nevertheless, we observed that the NRAMP1 D543N GG genotype group had a shorter time to tumor recurrence.

Pang CH, Du W, Long J, Song LJ
Mechanism of SEMA3B gene silencing and clinical significance in glioma.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
The aim of the current study was to explore mechanisms of SEMA3B gene expression and its clinical significance in glioma, and provide a theoretical foundation for investigating individualized treatment in glioma. Paraffin-embedded tissues from 43 patients with a confirmed clinical diagnosis of glioma following neurosurgery at the First Affiliated Hospital of Zhengzhou University from December 2013 to April 2014 were selected randomly. An additional three normal brain tissues were obtained following encephalic decompression excision due to acute craniocerebral injury in the same period, which were used as the control group. Immunohistochemical staining for vascular endothelial growth factor was performed on the glioma tissues from the 43 patients. Genomic DNA was extracted for bisulfate conversion and sequencing. SEMA3B was fully expressed in the three normal brain tissues, and incompletely expressed in the 43 glioma tissues, with a lack of expression in 48.8% (21/43) of samples. Moreover, 58% of high-grade gliomas (grade III and IV) lacked SEMA3B expression, which was significantly more than those that lacked expression (20%) in low-grade gliomas (grade I and II), indicating that, as the clinical pathological grade increased, SEMA3B expression decreased. The occurrence and development of malignant tumors is a product of multiple genes and other factors. Here, we provide theoretical basis for glioma development and prognosis involving DNA-methylation driven silencing of SEMA3B, and thus, SEMA3B is a potential target for directed treatments against glioma.

Xiong J, Altaf K, Ke N, et al.
dCK Expression and Gene Polymorphism With Gemcitabine Chemosensitivity in Patients With Pancreatic Ductal Adenocarcinoma: A Strobe-Compliant Observational Study.
Medicine (Baltimore). 2016; 95(10):e2936 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to investigate the relationship of deoxycytidine kinase (dCK) protein expression and gene single-nucleotide polymorphisms to gemcitabine chemosensitivity in patients with pancreatic ductal adenocarcinoma (PDAC).In total, 54 patients with resectable PDAC, who received postoperative gemcitabine-based therapy, were enrolled in this study, from January 2011 to April 2013. The dCK protein expression was measured retrospectively by immunohistochemistry. Furthermore, 5 single-nucleotide polymorphisms (C1205T, A9846G, A70G, C356G, and C364T) of the dCK gene were detected in PDAC cells by PCR amplification and sequencing.The dCK protein expression was found to be negatively correlated with age (P = 0.006), but correlated positively with overall survival (OS) (P = 0.000) and disease-free survival (DFS) (P = 0.003). The A9846G AA genotype in the dCK gene was significantly associated with reduced mortality compared with AG and GG genotypes. The OS and DFS were longer in patients with the A9846G AA genotype than the AG and GG genotypes. In univariate and multivariate analyses, we found that the dCK protein expression and A9846G genotype were significant predictors of both OS and DFS.Our study suggests that the dCK protein expression and A9846G genotype may act as prognostic biomarkers in identifying patients who are likely to benefit from postoperative gemcitabine therapy in PDAC.

Colović N, Bogdanović A, Virijević M, et al.
Acute Myocardial Infarction during Induction Chemotherapy for Acute MLL t(4;11) Leukemia with Lineage Switch and Extreme Leukocytosis.
Srp Arh Celok Lek. 2015 Nov-Dec; 143(11-12):734-8 [PubMed] Related Publications
INTRODUCTION: In patients with acute leukemias hemorrhage is the most frequent problem. Vein thrombotic events may appear rarely but arterial thromboses are exceptionally rare. We present a patient with acute leukemia and bilateral deep leg vein thrombosis who developed an acute myocardial infarction (AMI) during induction chemotherapy. The etiology and treatment of AMI in patients with acute leukemia, which is a rare occurrence, is discussed.
CASE OUTLINE: In April of 2012 a 37-year-old male presented with bilateral deep leg vein thrombosis and malaise. Laboratory data were as follows: Hb 118 g/L, WBC 354 x 10(9)/L (with 91% blasts in differential leukocyte count), platelets 60x109/L. Bone marrow aspirate and immunophenotype revealed the presence of acute lymphoblastic leukemia. Cytogenetic analysis was as follows: 46,XY,t(4;11)(q21:q23) [2]/62-82,XYt(4;11)[18]. Molecular analysis showed MLL-AF4 rearrangement. The patient was on low molecular weight heparin and combined chemotherapy according to protocol HyperCVAD. On day 10 after chemotherapy he got chest pain. Three days later AMI was diagnosed (creatine kinase 66 U/L, CK-MB 13U/L, troponin 1.19 µg/L). Electrocardiogram showed the ST elevation in leads D1, D2, aVL, V5 and V6 and "micro q" in D1. On echocardiography, hypokinesia of the left ventricle and ejection fraction of 39% was found. After recovering from AMI and restoring left ventricle ejection fraction to 59%, second course of HyperCVAD was given. The control bone marrow aspirate showed 88% of blasts but with monoblastic appearance. Flow cytometry confirmed a lineage switch from lymphoblasts to monoblasts. In further course of the disease he was treated with a variety of chemotherapeutic combinations without achieving remission. Eventually, palliative chemotherapy was administered to reduce the bulk of blasts. He died five months after the initial diagnosis.
CONCLUSION: AMI in young adults with acute leukemia is a very rare complication which may occur in patients with very high white blood cell count in addition with presence of a CD56 adhesion molecule and other concomitant thrombophilic factors. The treatment of AMI in patients with acute leukemias should include antiplatelet and anticoagulant therapy, even with more aggressive methods depending on patient's age and clinical risk assessment.

Kava S, Rajaram S, Arora VK, et al.
Conventional cytology, visual tests and evaluation of P16(INK4A) as a biomarker in cervical intraepithelial neoplasia.
Indian J Cancer. 2015 Jul-Sep; 52(3):270-5 [PubMed] Related Publications
OBJECTIVES: (1) To detect cervical intraepithelial neoplasia (CIN) using Papanicolaou test (PAP test), visual tests (visual inspection after the application of acetic acid [VIA], visual inspection after the application of Lugol's iodine [VILI]), colposcopy, and biopsy. (2) To study the biomarker p16(INK4A) expression by immunostaining.
MATERIALS AND METHODS: Experimental study was conducted from November 2009 to April 2011. 1500 women were screened for cancer cervix using conventional PAP test, VIA, and VILI. Sensitivity, specificity, positive, and negative predictive values of these tests were calculated individually, sequentially, and in parallel. Women having positive results underwent colposcopy and biopsy if required. p16(INK4A) expression in biopsy samples was studied using immunohistochemistry.
RESULTS: All test positive cases (n = 235) underwent colposcopy. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PAP with atypical squamous cells of undetermined significance (ASCUS) as cut-off was 40%, 99.25%, 35.25%, and 99.39%; VIA was 60%, 93.06%, 8.03%, and 99.56% and VILI was 80%, 86.06%, 5.4%, and 99.76%, respectively. When PAP, VIA, and VILI were used in parallel sensitivity, specificity, PPV, and NPV improved to 100%, 85.18%, 6.38%, and 100%, respectively. Colposcopic abnormalities were detected in 83 and biopsy proven CIN in 15. p(16INK4A) expression was seen in eight of 15 CIN cases.
CONCLUSIONS: (1) PAP test and visual techniques are complementary. (2) p(16INK4A) expression was seen in majority of CIN 2 lesions suggesting a higher grade lesion.

Asao T, Fujiwara Y, Sunami K, et al.
Medical treatment involving investigational drugs and genetic profile of thymic carcinoma.
Lung Cancer. 2016; 93:77-81 [PubMed] Related Publications
BACKGROUND: Thymic carcinoma is a rare neoplasm of the thymus, and information regarding its genetic profile and optimal medical treatment is limited. We sought to characterize the genetic profile of thymic carcinoma and to evaluate the efficacy of various medical treatments, including treatment with tyrosine kinase inhibitors (TKIs), cytotoxic agents, and immune checkpoint inhibitors.
METHODS: We retrospectively reviewed medical records of 64 consecutive patients with thymic carcinoma at the National Cancer Center Hospital between April 1973 and March 2014. We analyzed treatment course of patients who underwent medical treatment involving investigational drugs. For patients with available tissue samples, targeted sequencing of 50 cancer-related genes using next-generation sequencing was performed.
RESULTS: Thirty-six patients had received chemotherapy. Median progression-free survival in patients receiving first-line chemotherapy was 7.07 months (95% confidence interval, 5.67-8.93). Median survival time was 32.6 months (95% confidence interval, 23.2-43.4). As second- or later-line chemotherapy, a total of 13 patients were treated with 24 investigational drugs, including 8 multi-targeted TKIs, 5 cytotoxic agents, and 2 immune checkpoint inhibitors. Six (24%) of the patients treated with investigational drugs maintained disease control for at least 6 months. Tissue samples of 52 patients (81.3%) were available for targeted sequencing, consisting of 52 formalin-fixed, paraffin-embedded (FFPE) and 16 fresh frozen tissue samples. The genetic alterations of TP53, KRAS, FBXW7, and NRAS were detected in 7 patients (13.5%), and no KIT mutations were noted.
CONCLUSIONS: Multi-targeted TKIs exhibited potential clinical efficacy for previously-treated thymic carcinoma. The frequency of genetic alterations in this study was low, with no apparent relationship with the efficacy of chemotherapy.

Horiike A, Takeuchi K, Uenami T, et al.
Sorafenib treatment for patients with RET fusion-positive non-small cell lung cancer.
Lung Cancer. 2016; 93:43-6 [PubMed] Related Publications
BACKGROUND: RET fusions were recently identified in non-small cell lung cancer (NSCLC) and are considered as a potential therapeutic target of NSCLC. Sorafenib, a multi-kinase inhibitor, has potent anti-RET activity. We conducted a study to evaluate the efficacy of sorafenib in a small number of patients with RET fusion-positive NSCLC.
MATERIALS AND METHODS: Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an Eastern Cooperative Oncology Group performance status 0-2, had adequate organ function, and provided informed consent. The presence of the RET fusion gene was confirmed by a split FISH assay. The patients were treated twice daily with 400mg of sorafenib taken orally. The treatment was continued until either disease progression or unacceptable toxicity.
RESULTS: From March 2012 to April 2013, three patients were enrolled. The responses to sorafenib included one patient with stable disease (SD) and two patients with progressive disease (PD). One patient took sorafenib for twelve months. The most common toxicities were palmar-plantar erythrodysesthesia syndrome, hypertension, and diarrhea.
CONCLUSION: Since sorafenib did not show dramatic responses, we suggest testing other RET inhibitors for the treatment of RET fusion-positive NSCLC. This study was registered at UMIN as trial number 000007515.

Putman RK, Hatabu H, Araki T, et al.
Association Between Interstitial Lung Abnormalities and All-Cause Mortality.
JAMA. 2016; 315(7):672-81 [PubMed] Free Access to Full Article Related Publications
IMPORTANCE: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.
OBJECTIVE: To investigate whether interstitial lung abnormalities are associated with increased mortality.
DESIGN, SETTING, AND POPULATION: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).
EXPOSURES: Interstitial lung abnormality status as determined by chest CT evaluation.
MAIN OUTCOMES AND MEASURES: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.
RESULTS: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.
CONCLUSIONS AND RELEVANCE: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

Barlesi F, Mazieres J, Merlio JP, et al.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
Lancet. 2016; 387(10026):1415-26 [PubMed] Related Publications
BACKGROUND: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute.
METHODS: This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with, number NCT01700582.
FINDINGS: 18,679 molecular analyses of 17,664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18-98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7-16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17,706 analyses for which data were available, HER2 mutations in 98 (1%) of 11,723, KRAS mutations in 4894 (29%) of 17,001, BRAF mutations in 262 (2%) of 13,906, and PIK3CA mutations in 252 (2%) of 10,678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8-25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7-38·2] for presence of a genetic alteration vs 33% [29·5-35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0-18·8] vs 9% [6·7-11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2-10·7] vs 7·1 months [6·1-7·9]; p<0·0001) and overall survival (16·5 months [15·0-18·3] vs 11·8 months [10·1-13·5]; p<0·0001) compared with absence of a genetic alteration.
INTERPRETATION: Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit.
FUNDING: French National Cancer Institute (INCa).

Ally MS, Ransohoff K, Sarin K, et al.
Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma.
JAMA Dermatol. 2016; 152(4):452-6 [PubMed] Free Access to Full Article Related Publications
IMPORTANCE: Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.
OBJECTIVE: To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.
DESIGN, SETTING, AND PARTICIPANTS: Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.
MAIN OUTCOMES AND MEASURES: The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.
RESULTS: Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.
CONCLUSIONS AND RELEVANCE: Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

de Groot S, Charehbili A, van Laarhoven HW, et al.
Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).
Breast Cancer Res. 2016; 18(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid.
METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis.
RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032).
CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC.
TRIAL REGISTRATION: NCT01099436 . Registered April 6, 2010.

Qiao N, Wang L, Wang T, Li H
Inflammatory CXCL12-CXCR4/CXCR7 axis mediates G-protein signaling pathway to influence the invasion and migration of nasopharyngeal carcinoma cells.
Tumour Biol. 2016; 37(6):8169-79 [PubMed] Related Publications
This study explored whether the migration, invasion, and apoptosis of nasopharyngeal carcinoma (NPC) cells were affected by the CXCR4/CXCR7-CXCL12 axis and if this mechanism was related to G-protein signaling pathway. A total of 72 NPC patients admitted in our hospital between April 2013 and February 2015 were incorporated in this study. Immunohistochemistry was performed to compare the expression levels of CXCR4, CXCR7, and CXCL12 between NPC tissues and adjacent normal tissues. Then, the correlation analysis was implemented to assess the association among CXCR4, CXCR7, and CXCL12 expressions. Jellyfish glow protein experiment was carried out after the cultivation of CNE-2Z cell lines in order to observe the intracellular calcium mobilization resulted from G-protein activation contributed by CXCR4/CXCR7-CXCL12 axis. The impact of CXCR4/CXCR7-CXCL12 axis on the migration and invasion of NPC cells was explored using transwell experiments. Finally, the anti-apoptosis effects of CXCR4/CXCR7-CXCL12 axis on NPC cells were investigated by the splicing of poly ADP-ribose polymerase (PARP). Compared to NPC patients with low-grade (stage I-II) tumor node metastasis (TNM) and those without lymph node metastasis, the expression of CXCR4, CXCR7, and CXCL12 were significantly higher in NPC patients with high-grade (stage III-IV) TNM and those with lymph node metastasis (P < 0.05). Moreover, there was significant positive correlation between the expression level of CXCL12 and CXCR7 (r s = 0.484, P < 0.001) as well as the expression level of CXCL12 and CXCR4 (r s = 0.414, P < 0.001). As suggested by cellular experiments using CNE-2Z, the calcium mobilization degree induced by CXCR4-CXCL12 axis in activating G proteins seemed to be slightly more effective than that induced by CXCR4/CXCR7-CXCL12 axis, while the CXCR7-CXCL12 axis could hardly activate calcium mobilization. Furthermore, the transwell experiment showed that CXCR4/CXCR7-CXCL12 axis could exacerbate the migration and invasion of NPC cells (P < 0.05). The transwell experiment also suggested that the CXCR4/CXCR7-CXCL12 axis was associated with the expression of matrix metallo proteinase 9 (MMP9) which is a substance in the downstream of G-protein pathways (P < 0.05). Results from PARP shear zone also indicated that the CXCR4/CXCR7-CXCL12 axis could suppress NPC cell apoptosis (P < 0.05). The expressional levels of CXCR4, CXCR7, and CXCL12 significantly varied with clinical stages and status of lymph node metastasis of NPC patients. This revealed potential indicators which can be used for NPC prognosis. Additionally, the CXCR4/CXCR7-CXCL12 axis may regulate the expression of downstream proteins (e.g., MMP-9) through the activation of G-protein signaling pathways. These conclusions may provide key evidence for NPC aetiology which can be further investigated to develop novel molecular targets for NPC treatments.

Shridhar K, Walia GK, Aggarwal A, et al.
DNA methylation markers for oral pre-cancer progression: A critical review.
Oral Oncol. 2016; 53:1-9 [PubMed] Free Access to Full Article Related Publications
Although oral cancers are generally preceded by a well-established pre-cancerous stage, there is a lack of well-defined clinical and morphological criteria to detect and signal progression from pre-cancer to malignant tumours. We conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as a potential diagnostic biomarker predicting progression. We identified all relevant human studies published in English prior to 30th April 2015 that examined DNA methylation (%) in oral pre-cancer by searching PubMed, Web-of-Science and Embase databases using combined key-searches. Twenty-one studies (18-cross-sectional; 3-longitudinal) were eligible for inclusion in the review, with sample sizes ranging from 4 to 156 affected cases. Eligible studies examined promoter region hyper-methylation of tumour suppressor genes in pathways including cell-cycle-control (n=15), DNA-repair (n=7), cell-cycle-signalling (n=4) and apoptosis (n=3). Hyper-methylated loci reported in three or more studies included p16, p14, MGMT and DAPK. Two longitudinal studies reported greater p16 hyper-methylation in pre-cancerous lesions transformed to malignancy compared to lesions that regressed (57-63.6% versus 8-32.1%; p<0.01). The one study that explored epigenome-wide methylation patterns reported three novel hyper-methylated loci (TRHDE; ZNF454; KCNAB3). The majority of reviewed studies were small, cross-sectional studies with poorly defined control groups and lacking validation. Whilst limitations in sample size and study design preclude definitive conclusions, current evidence suggests a potential utility of DNA methylation patterns as a diagnostic biomarker for oral pre-cancer progression. Robust studies such as large epigenome-wide methylation explorations of oral pre-cancer with longitudinal tracking are needed to validate the currently reported signals and identify new risk-loci and the biological pathways of disease progression.

Chen J, Xia Q, Jiang B, et al.
Prognostic Value of Cancer Stem Cell Marker ALDH1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis.
PLoS One. 2015; 10(12):e0145164 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Many studies have indicated the prognostic and clinicopathological value of aldehyde dehydrogenase 1 (ALDH1) in colorectal cancer (CRC) patients still remains controversial. Thus we performed this study to clarify the relationship between high ALDH1 expression in CRC and its impact on survival and clinicopathological features.
METHODS: Publications for relevant studies in Pubmed, the Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) through April 2015 were identified. Only articles describing ALDH1 antigen with immunohistochemistry in CRC were included. The software RevMan 5.1 was used to analyze the outcomes, including 5-year overall survival (OS), disease-free survival (DFS) and clinicopathological features.
RESULTS: 9 studies with 1203 patients satisfying the criteria were included. The overall rate of high ALDH1 expression was 46.5% by immunohistochemical staining. High ALDH1 expression as an independent prognostic factor was significantly associated with the 5-year OS and DFS (OR = 0.42, 95%CI: 0.26-0.68, P = 0.0004; OR = 0.38, 95%CI: 0.24-0.59, P < 0.0001, respectively). High ALDH1 expression was highly correlated with the tumor (T) stage (T3 + T4 vs. T1 + T2; OR = 2.16, 95%CI: 1.09-4.28, P = 0.03), lymph node (N) stage (N1 + N2 vs. N0; OR = 1.8; 95%CI: 1.17-2.79, P = 0.008), and tumor differentiation (G3 vs. G1 + G2; OR = 1.88; 95%CI: 1.07-3.30, P = 0.03). However, high ALDH1 expression was not significantly correlated with the patient age (>60 years old vs. <60 years old; OR = 1.11, 95%CI: 0.63-1.94, P = 0.72).
CONCLUSIONS: High ALDH1 expression indicates a poor prognosis in CRC patients. Moreover, high ALDH1 expression correlates with the T stage, N stage, and tumor differentiation, but not with age.

Younis SG, Khedr RA, El-Shorbagy SH
Immunohistochemical analysis of O6-methylguanine-DNA methyltransferase (MGMT) protein expression as prognostic marker in glioblastoma patients treated with radiation therapy with concomitant and adjuvant Temozolomide.
J Egypt Natl Canc Inst. 2016; 28(1):23-30 [PubMed] Related Publications
BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) protein expression using immunohistochemical analysis was proposed as a prognostic marker for patients with newly diagnosed glioblastoma (GBM) treated with radiation therapy with concurrent and adjuvant Temozolomide (TMZ).
METHODS: From April 2012 to October 2014, 73 patients with newly diagnosed GBM, MGMT protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens. Patients received the radiation therapy plus concomitant and adjuvant TMZ chemotherapy.
RESULTS: For the whole cohort, the median overall survival (OS) was 15 months, and the progression-free survival was 10 months. Patients who had low MGMT protein expression (⩽15%) had a significantly improved OS and PFS compared with patients who had high MGMT expression (17.0 months vs 14 months; P value .006) and (15.0 months vs 10 months; P value .016) respectively. The age and extent of tumor resection were the strongest clinical predictors of outcome. In multivariate Cox models MGMT protein expression, extent of tumor resection and age were identified as independent prognostic factors.
CONCLUSIONS: MGMT expression was identified as positive prognostic factor in patients with newly diagnosed glioblastoma who underwent surgical resection followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol).

Ihara K, Yamaguchi S, Ueno N, et al.
Expression of DNA double-strand break repair proteins predicts the response and prognosis of colorectal cancer patients undergoing oxaliplatin-based chemotherapy.
Oncol Rep. 2016; 35(3):1349-55 [PubMed] Related Publications
DNA intrastrand cross-linking agents such as oxaliplatin induce DNA double-strand breaks (DSBs) during DNA repair and replication. In the present study, we hypothesized that DNA intrastrand cross-linking agents may significantly benefit colorectal cancer patients with deficiencies in DSB repair. Seventy-eight patients with metastatic or recurrent colorectal cancer who had measurable target lesions and who underwent resection for primary colorectal cancer in our institution between April 2007 and March 2013 were included in the present study. The median age was 64.5 years, and the cohort consisted of 49 males and 29 females. The median progression-free survival (PFS) was 10.9 months. The expression of DSB repair proteins such as RAD51 and MRE11 was investigated by immunohistochemistry, and associations between RAD51 and MRE11 expression and clinicopathological factors or chemotherapeutic effect were assessed. MRE11-negative cases and RAD51-negative cases achieved significantly better tumor reduction compared with cases with positive expression. Cases with negative expression of both proteins or negative expression of either protein had significantly longer PFS than cases with positive expression for both proteins. In conclusion, DSB repair protein expression-negative colorectal cancer cases may be more highly sensitive to chemotherapy, and thus DSB repair protein expression may be a useful prognostic indicator for colorectal cancer patients.

Niu JX, Meng XK, Ren JJ
Studied microRNA gene expression in human hepatocellular carcinoma by microRNA microarray techniques.
World J Gastroenterol. 2015; 21(44):12605-11 [PubMed] Free Access to Full Article Related Publications
AIM: To achieve a better understanding of the molecular mechanisms of microRNA expression changes involved in hepatocellular carcinoma.
METHODS: In this research process, patients were not treated with antivirals, immunosuppressants or immunomodulators for at least 6 mo before collecting serum. The study population was composed of 35 outpatient hepatitis B virus (HBV) cases and 12 healthy control cases from the Affiliated Hospital of Inner Mongolia Medical University (Inner Mongolia, China) from July 2013 to April 2014. The 35 HBV cases were divided into two groups: a hepatocirrhosis group with 20 cases and a liver cancer group with 15 cases. All 35 cases carried HBsAg. The diagnostic criteria followed the European Association for the Study of the Liver 2012 (EASL2012) standards. MicroRNA (miRNA) was extracted from a control group of patients, a group with hepatocirrhosis and a group with liver cancer and its quality was analyzed using the human V2 microRNA expression beadchip. Cluster analysis and a radar chart were then applied to the miRNA changes.
RESULTS: The miRNA-qualified rate of human serum samples was 93%. The concentration of a single sample was > 200 ng/μL and the volume was > 5 μL. All miRNA serum samples were uncontaminated by the genome. The Mann-Whitney test showed significant differences in miRNA between each group, with a detection P-value of < 0.05. Illumina software was set up with Diff Score set to ± 13, meaning that P = 0.001.There were significant changes in miRNA expression between the three groups. miRNA-183 was the most up-regulated, followed by miRNA-373. miRNA-129 and miRNA-188 were both strongly down-regulated and miRNA-378 was down-regulated a small amount. The liver cancer group had greater changes, which indicated that changes in miRNA expression levels were caused by hepatocirrhosis. The liver cancer disease course then further increased these changes. In the pentagon created by these five miRNAs, three groups showed significant deviation. The liver cancer group had a bigger deviation trend. The chart indicated that miRNA expression changes occurred in the hepatocirrhosis group, which increased in the liver cancer disease course and were irreversible.
CONCLUSION: There was a significant relationship between the irreversible up-regulation of miRNA-183/373 and down-regulation of miRNA-129/188/378 and incidences of hepatocirrhosis and liver cancer.

Hasegawa Y, Tanino H, Horiguchi J, et al.
Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study).
PLoS One. 2015; 10(12):e0143643 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT).
METHODS: Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.
RESULTS: This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted.
TRIAL REGISTRATION: University Hospital Medical Information Network. UMIN000003261.

Schweiger T, Starkl V, Glueck O, et al.
Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases.
Eur J Cardiothorac Surg. 2016; 49(4):1103-11; discussion 1111 [PubMed] Related Publications
OBJECTIVES: The c-MET tyrosine kinase is known to play a key role in tumour promotion in a variety of cancers. The prognostic significance of c-MET pathway alterations has previously been described in primary colorectal cancer (CRC). However, data on the expression and genetic mutational status of c-MET in CRC pulmonary metastases (PM) are lacking. We aimed to assess the clinical implications of alterations in the c-MET pathway in patients undergoing pulmonary metastasectomy.
METHODS: From April 2009 to November 2013, all patients with complete CRC lung metastasectomy were included in this study and prospectively followed up. Tissue samples of 51 PM and 33 paired primary CRCs were stained immunohistochemically for c-MET and phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Genetic alterations of MET were detected using an exome panel on a next generation sequencing (NGS) platform. Serum hepatocyte growth factor (HGF) levels were measured in a patient subset (n = 10) before and after metastasectomy.
RESULTS: c-MET expression was significantly higher at the invasive front of metastases compared with central tumour areas (P = 0.020) and was associated with nuclear pSTAT3 expression (P = 0.042). pSTAT3 but not c-MET overexpression in PM was associated with time to tumour recurrence after metastasectomy (P = 0.036). Expression levels of neither c-MET nor pSTAT3 had an impact on time to lung-specific recurrence. However, patients with c-MET or pSTAT3 overexpression in PM had a significantly worse overall survival after metastasectomy (P = 0.023 and 0.008, respectively). Mutations in the MET gene were identified in 20 patients of our cohort by NGS, which failed to be of prognostic relevance. Serum HGF did not significantly differ between patients with PM and healthy controls.
CONCLUSIONS: To the best of our knowledge, this is the first structured evaluation of the c-MET axis in the context of pulmonary metastasectomy for CRC. Our results suggest that overexpression of c-MET/pSTAT3 is associated with an impaired prognosis following complete resection. Moreover, this work suggests that the value of c-MET tyrosine kinase inhibitors in the treatment of patients with CRC lung metastases should be assessed in clinical trials.

Trimboli P, Guidobaldi L, Bongiovanni M, et al.
Use of fine-needle aspirate calcitonin to detect medullary thyroid carcinoma: A systematic review.
Diagn Cytopathol. 2016; 44(1):45-51 [PubMed] Related Publications
BACKGROUND: The measurement of calcitonin in washout fluids of thyroid nodule aspirate (FNA-calcitonin) has been reported as accurate to detect medullary thyroid carcinoma (MTC). The results from these studies have been promising and the most updated version of ATA guidelines quoted for the first time that "FNA findings that are inconclusive or suggestive of MTC should have calcitonin measured in the FNA washout fluid." Here we aimed to systematically review published data on this topic to provide more robust estimates.
RESEARCH DESIGN AND METHODS: A comprehensive computer literature search of the medical databases was conducted by searching for the terms "calcitonin" AND "washout." The search was updated until April 2015.
RESULTS: Twelve relevant studies, published between 2007 and 2014, were found. Overall, 413 thyroid nodules or neck lymph nodes underwent FNA-calcitonin, 95 were MTC lesions and 93 (97.9%) of these were correctly detected by this measurement regardless of their cytologic report.
CONCLUSIONS: The present study shows that the above ATA recommendation is well supported. Almost all MTC lesions are correctly detected by FNA-calcitonin and this technique should be used to avoid false negative or inconclusive results from cytology. The routine determination of serum calcitonin in patients undergoing FNA should improve the selection of patients at risk for MTC, guiding the use of FNA-calcitonin in the same FNA sample and providing useful information to the cytopathologist for the morphological assessment and the application of tailored ancillary tests.

Kim SI, Lim MC, Lee DO, et al.
Uptake of risk-reducing salpingo-oophorectomy among female BRCA mutation carriers: experience at the National Cancer Center of Korea.
J Cancer Res Clin Oncol. 2016; 142(1):333-40 [PubMed] Related Publications
PURPOSE: The aim of this study was to identify the uptake rate of risk-reducing salpingo-oophorectomy (RRSO) and the factors affecting this rate among female BRCA1 or BRCA2 mutation carriers at the National Cancer Center of Korea.
METHODS: Between April 2007 and December 2014, 450 women underwent BRCA gene testing, and 97 women were found to have BRCA1/2 mutations. Through the review of medical records, 42 candidates for RRSO were identified. Of these, 22 underwent RRSO. Demographic, clinical, and consultation-related factors were compared between the RRSO and non-RRSO groups.
RESULTS: The uptake rate of RRSO was 52.4 %. The mean time interval between genetic testing and surgery in the RRSO group was 7.3 months (range 0.6-33.9). The prevalence of amenorrhea was greater in the RRSO group than in the non-RRSO group (59.1 % vs. 20.0 %; P = 0.010). More women in the RRSO group were consulted with gynecologic oncologists (95.5 % vs. 60.0 %; P = 0.008). In multivariate analyses, amenorrhea at the time of genetic counseling (OR 16.44; 95 % CI 1.16-232.82; P = 0.038) and consultation with gynecologic oncologists (OR 30.78; 95 % CI 1.34-707.21; P = 0.032) were identified as factors affecting the carrier's decision to undergo RRSO. One patient in the non-RRSO group (5.0 %) developed primary peritoneal carcinoma, which was diagnosed 4.6 years after genetic testing.
CONCLUSIONS: The uptake rate of RRSO among BRCA1/2 mutation carriers was affected by the presence of amenorrhea and consultation with gynecologic oncologists. Gynecologic oncologists with clinical experience with ovarian cancer should play a major role in aiding carriers' decision-making concerning RRSO.

Gasparri R, Rezende GC, Fazio N, et al.
Fluorodeoxyglucose positron emission tomography in pulmonary carcinoid tumors.
Q J Nucl Med Mol Imaging. 2015; 59(4):446-54 [PubMed] Related Publications
AIM: The role of fluorodeoxyglucose positron emission tomography (FDG-PET) as an additional investigation to computer tomography for pulmonary carcinoid tumors remains controversial. The aim of this study was to assess the role of FDG-PET for the diagnosis and staging of pulmonary carcinoid tumors.
METHODS: We performed a retrospective mono-institutional analysis of data from 97 patients with pathologically confirmed pulmonary carcinoid tumor who had been operated on between July 1998 and April 2009 and had had a preoperative FDG-PET scan performed.
RESULTS: Sixty-five (67%) of the 97 tumors were typical (TC) and 32 (33%) atypical (AC) carcinoid tumors. Overall FDG-PET sensitivity was 67% being lower for TC (60%) than for AC (81%) (P=0.04). FDG-PET negative tumors were smaller than FDG-PET positive tumors, with a respective median size of 15 and 17 mm (P=0.02). Median SUVmax for FDG-PET-positive tumors was 4.0 (2.8-5.1) with no difference between TC and AC tumors. Median Ki-67 expression was respectively 4.7% and 3.1% for FDG-PET positive and FDG-PET negative tumors (P=0.05). During a median follow-up of 49 months (interquartile range 30-63 months), 9 patients (4TC, 5AC) developed recurrent disease. Neither SUVmax nor Ki-67 expression resulted associated with disease-free survival.
CONCLUSION: With an overall sensitivity of 67%, FDG-PET has shown to be useful in the preoperative work-up of patients with suspect lung carcinoid tumors. In particular it could have a role in larger tumors. These results warrant a prospective evaluation of FDG-PET in the staging of lung carcinoid tumor.

Patrono MG, Iniesta MD, Malpica A, et al.
Clinical outcomes in patients with isolated serous tubal intraepithelial carcinoma (STIC): A comprehensive review.
Gynecol Oncol. 2015; 139(3):568-72 [PubMed] Related Publications
OBJECTIVE. Serous tubal intraepithelial carcinoma (STIC) is currently considered the precursor lesion of pelvic (i.e., ovarian or peritoneal) high-grade serous carcinoma. The incidence of STIC has been reported to range from 0.6% to 7% in BRCA mutations carriers. However, the clinical outcome of patients with 'isolated' STIC remains elusive. The aim of this study is to review the published literature on isolated STIC to determine outcomes of these ients and present a summary of management strategies. METHODS. A systematic English-language literature search was conducted in PubMed, MEDLINE-Ovid, Scopus, EBSCO host, Cochrane Library of articles published from February 2006 to April 2015. Study inclusion criteria for review were the following: risk-reducing salpingo-oophorectomy (RRSO), BRCA mutation carriers, non-BRCA mutation carriers, and benign surgical indication. Exclusion criteria were as follows: the presence of synchronous gynecological cancers, concurrent non-gynecological malignancies, the presence of ovarian intraepithelial lesions, and articles that did not include any clinical information and were restricted to pathology information only. RESULTS. A total of 78 patients with isolated STIC were included in our analysis. The median age for all patients was 53.7 years (range; 37-83). Surgical indication was RRSO in 67 patients with BRCA mutations or high-risk personal or family history. In the other 11 patients, an incidental STIC was detected after surgery for non-cancerous indications. Eleven (16.4%) patients received chemotherapy after the diagnosis of STIC. The follow-up time ranged from 2 to 150 months. Three (4.5%) patients with BRCA mutations were diagnosed with primary peritoneal carcinoma (PPC) during the follow-up at 43, 48 and 72 months after RRSO. CONCLUSIONS. The rate of primary peritoneal carcinoma in patients with BRCA mutations and isolated STIC is 4.5%. The role of adjuvant therapy remains elusive and routine surveillance with tumor markers and imaging is not warranted.

Zhu QL, Faquin WC, Samir AE
Relationship Between Sonographic Characteristics and Afirma Gene Expression Classifier Results in Thyroid Nodules With Indeterminate Fine-Needle Aspiration Cytopathology.
AJR Am J Roentgenol. 2015; 205(4):861-5 [PubMed] Related Publications
OBJECTIVE: The purpose of this article is to investigate whether specific clinical and sonographic characteristics are predictive of a benign Afirma test result.
MATERIALS AND METHODS: We conducted a retrospective study of Afirma gene expression classifier analysis performed in 44 patients with 45 indeterminate thyroid fine-needle aspiration (FNA) cytologic results between March 2013 and April 2014. Of these, 33 of 45 nodules (73.3%) were repeat atypia of undetermined significance (AUS) and follicular lesions of undetermined significance (FLUS), or follicular neoplasm (FN) and suspicious for a follicular neoplasm (SFN) before Afirma testing.
RESULTS: Of the 45 nodules, 21 (46.7%) were cytologically diagnosed as FLUS, 16 (35.6%) were diagnosed as AUS, and eight (17.8%) were diagnosed as FN or SFN. By Afirma testing, 23 of the 45 nodules (51.1%) were benign, 21 (46.7%) were suspicious, and one (2.2%) had nondiagnostic results. The mean (± SD) nodule size was smaller in the Afirma-benign group than in the Afirma-suspicious group (1.8 ± 0.8 cm [95% CI, 1.4-2.1] vs 2.2 ± 0.8 cm [95% CI, 1.8-2.6]; p < 0.035). No sonographic feature was statistically significantly different between the Afirma-benign and -suspicious groups, including nodule solidity (p = 0.225), echogenicity (p = 0.543), calcification (p = 0.542), and hypervascularity (p = 0.976). All nodules were ovoid shaped and had circumscribed margins in both Afirma groups.
CONCLUSION: Smaller nodule size was the only characteristic associated with a benign diagnosis on Afirma testing. Sonographic characteristics are not helpful in cases that had a repeat indeterminate FNA finding before Afirma testing.

Wang R, Guo Y, Ma H, et al.
Tumor necrosis factor superfamily member 13 is a novel biomarker for diagnosis and prognosis and promotes cancer cell proliferation in laryngeal squamous cell carcinoma.
Tumour Biol. 2016; 37(2):2635-45 [PubMed] Related Publications
Tumor necrosis factor superfamily member 13 (TNFSF13) modulates cell proliferation and apoptosis and participates in the pathogenesis of solid tumors, but its role in laryngeal cancer development is not clearly defined. In order to investigate whether TNFSF13 can be used as a biomarker for diagnosis and prognosis in laryngeal squamous cell carcinoma (LSCC) and the role of TNFSF13 in laryngeal cancer carcinogenesis, we conducted immunohistochemistry and ELISA assays to evaluate the expression level of TNFSF13 in laryngeal cancer patients and the contrast. We also conducted experiments on the functional study of TNFSF13 in vitro. We found that the expression levels of TNFSF13, ki-67, and NF-κB p65 in LSCC tumor tissues were higher than those in vocal polyp and para-carcinoma tissues. The Spearman rank correlation analysis showed that the expression of TNFSF13 had a positive correlation with the expression of ki-67 and NF-κB p65. Cox regression analysis and Kaplan-Meier plots confirmed the expression level of TNFSF13 was a prognostic factor for LSCC. Moreover, the serum TNFSF13 level was significantly higher in LSCC patients than in the controls, and the serum expression level of TNFSF13 can distinguish LSCC from healthy people, precancerosis, or laryngeal benign tumor. In addition, functional study of TNFSF13 in vitro revealed that knockdown of TNFSF13 inhibited cell proliferation by inducing G1 phase cell cycle arrest in Hep-2 cells. In conclusion, TNFSF13 may be a potential novel molecular target for diagnosis and prognosis in human LSCC, and therapies that target TNFSF13 may have clinical significance for the treatment of LSCC.

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