Genetic Activation of the MET Pathway and Prognosis of Patients With High-Risk, Radically Resected Gastric Cancer

2011 ◽  
Vol 29 (36) ◽  
pp. 4789-4795 ◽  
Author(s):  
Francesco Graziano ◽  
Nadia Galluccio ◽  
Paola Lorenzini ◽  
Annamaria Ruzzo ◽  
Emanuele Canestrari ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
High Risk ◽  
Quantitative Polymerase Chain Reaction ◽  
Disease Free Survival ◽  
Copy Number Gain ◽  
Free Survival ◽  
Prognostic Effect ◽  
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Purpose To investigate whether prognosis of patients with high-risk gastric cancer may depend on MET copy number gain (CNG) or an activating truncation within a deoxyadenosine tract element (DATE) in the promoter region of the MET ligand HGF. Patients and Methods A single-institution cohort of 230 patients with stage II/III gastric cancer was studied. Formalin-fixed paraffin-embedded tumor specimens were used for DNA extraction. Quantitative polymerase chain reaction (qPCR) for MET CNG and sequencing for HGF DATE truncation (< 25 deoxyadenosines instead of 30) were used. Results were analyzed for association with disease-free survival (DFS) and overall survival (OS). To assess the reliability of the qPCR measurement, a random sample of cases was reanalyzed using an alternative assay (fluorescent in situ hybridization [FISH]) with calculation of the intracorrelation coefficient (ICC). Results In 216 assessable patients, MET CNG five or more copies and homozygous HGF-truncated DATE occurred in 21 patients (10%) and 30 patients (13%), respectively. Patients with MET CNG five or more copies (MET-positive) showed significantly worse prognosis with multivariate hazard ratio (HR) of 3.02 (95% CI, 1.71 to 5.33; P < .001) for DFS and multivariate HR of 2.91 (95% CI, 1.65 to 5.11; P < .001) for OS. The agreement between qPCR and FISH was high, with ICC = 0.9% (95% CI, 0.81% to 0.95%; the closer the ICC is to 1, the greater is the agreement). HGF-truncated DATE did not show relevant prognostic effect. Conclusion In this study, qPCR revealed approximately 10% of white patients with gastric cancer harboring MET CNG of five or more copies. This marker was significantly associated with unfavorable prognosis. This information is relevant to the current clinical development of anti-MET compounds.

Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II and III included in the MOSIAC study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3524-3524 ◽  
Author(s):  
Jean-François Flejou ◽  
Thierry André ◽  
Benoist Chibaudel ◽  
Aurelie Scriva ◽  
Tamas Hickish ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Stage Ii ◽  
Stage Iii ◽  
Free Survival ◽  
Translational Study ◽  
Hazard Ratios ◽  
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Three Samples ◽  
Evaluable Population ◽  
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3524 Background: The MOSAIC study (André T, N Engl J Med, 2004) demonstrated that adding oxaliplatin to adjuvant 5FU and LV improved three-year disease-free survival (DFS) in stage II and III resected CC. Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study (Zaanan A, Ann Oncol 2010). Methods: Of the 2,246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1,019 pts were obtained. Thirty-three samples with insufficient tumor tissue were excluded from this translational study. MMR status was determined by immunohistochemistry (IHC) analysis of the protein products of MLH1, MSH2, PMS2, and MSH6 genes. Results: A total of 986 pts (44%) were evaluable for MMR status and MMR status was not evaluable for 1,260 pts (56%). Relapse-free survival (RFS), DFS and overall survival (OS) were similar in both, MMR and MMR not evaluable population. Ninety (9.1%) and 896 (90.9%) pts had dMMR and proficient MMR (pMMR) CC, respectively. Of the patients with 90 dMMR CC, 45 pts had stage II and 45 stage III. Hazard Ratios (HRs) for stage II and III dMMR are 0.52 (0.21–1.28) for RFS, 0.52 (0.24–1.14) for DFS, and 0.45 (0.19–1.05) for OS, respectively. HR for stage III dMMR are 0.56 (0.19–1.61) for RFS, 0.51 (0.18–1.41) for DFS, and 0.44 (0.15–1.34) for OS, respectively. HR for stage II dMMR are 0.64 (0.11–3.70) for RFS, 0.60 (0.17–2.09) for DFS, and 0.52 (0.13–2.10) for OS, respectively. Conclusions: Analyses ofcolon cancerMMR status in pts included in the MOSAIC study support the use of FOLFOX4 in pts with dMMR stage III cancer. Clinical trial information: NCT00275210. [Table: see text]

Single-nucleotide polymorphisms (SNPs) associated with outcomes in patients with localized and metastatic renal cell carcinoma (RCC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 437-437
Author(s):  
Carmen Garrigos ◽  
Marta Espinosa ◽  
Ignacio Osman ◽  
Rainiero Ávila ◽  
Rafael Medina ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Predictive Biomarkers ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Snp Data ◽  
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Vegf Isoforms

437 Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in patients (pts) with both localized and advanced RCC treated at Hospital Universitario Virgen del Rocío. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). 64 SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview, and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS), and response to treatment (RR). SPSS v16 was utilized for statistical analyses. Results: In pts with localized RCC, 6 SNPs in 3 genes involved in angiogenesis predicted for worse DFS (VEGFR2: rs10013228, rs2071559; PDGFRA: rs2228230) and shorter OS (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p<0.05). In the advanced setting, 7 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics determined inferior OS (IL8: rs2227543, NR1l2: rs3814055, NR1l3: rs2307424, PDGFA: rs9800958, PDGFRB: rs2302273) and worse RR (VEGFA: rs699947, rs3025010 p<0.01)). Additionally 3 SNPs in PDGFR-B and VEGF isoforms predicted for better RR (PDGFRB: rs17708574 (p=0.08), VEGFB: rs594942 (p=0.03), VEGFC: rs2016110 (p=0.07). Conclusions: Genetic analysis of RCC patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics seem to determine post-surgical outcomes and treatment response in our series. These results are promising. Validation of the results is ongoing.

A 2-Protein Signature Predicting Clinical Outcome in High-Grade Serous Ovarian Cancer

2018 ◽  
Vol 28 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Chengjuan Jin ◽  
Yingfeng Xue ◽  
Yingwei Li ◽  
Hualei Bu ◽  
Hongfeng Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Subtypes ◽  
Disease Free Survival ◽  
Tissue Microarrays ◽  
Multivariate Regression Analysis ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Free Survival ◽  
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ObjectiveHigh-grade serous ovarian cancer (HGSOC) accounts for approximately 70% deaths in ovarian cancer. The overall survival (OS) of HGSOC is poor and still remains a clinical challenge. High-grade serous ovarian cancer can be divided into 4 molecular subtypes. The prognosis of different molecular subtypes is still unclear. We aimed to investigate the prognostic values of immunohistochemistry-based different molecular subtypes in patients with HGSOC.MethodsWe analyzed the protein expression of representative biomarkers (CXCL11, HMGA2, and MUC16) of 3 different molecular subtypes in 110 formalin-fixed, paraffin-embedded HGSOC by tissue microarrays.ResultsHigh CXCL11 expression predicted worse OS, not disease-free survival (DFS; P = 0.028 for OS, P = 0.191 for DFS). High HMGA2 expression predicted worse OS and DFS (P = 0.037 for OS, P = 0.021 for DFS). MUC16 expression was not associated with OS or DFS (P = 0.919 for OS, P = 0.517 for DFS). Multivariate regression analysis showed that CXCL11 combined with HMGA2 signature was an independent predictor for OS and DFS in patients with HGSOC.ConclusionsCXCL11 combined with HMGA2 signature was a clinically applicable prognostic model that could precisely predict an HGSOC patient's OS and tumor recurrence. This model could serve as an important tool for risk assessment of HGSOC prognosis.

scholarly journals Hydroxysteroid 11-Beta Dehydrogenase 1 Overexpression with Copy-Number Gain and Missense Mutations in Primary Gastrointestinal Stromal Tumors

2018 ◽  
Vol 7 (11) ◽  
pp. 408 ◽  
Author(s):  
Chien-Feng Li ◽  
Ting-Ting Liu ◽  
Jui-Chu Wang ◽  
Shih-Chen Yu ◽  
Yen-Yang Chen ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
High Risk ◽  
Copy Number ◽  
Gastrointestinal Stromal Tumors ◽  
Disease Free Survival ◽  
Copy Number Gain ◽  
Missense Mutations ◽  
Stromal Tumors

The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of HSD11B1, the informative results of Sanger sequencing (n = 58), mRNA quantification by branched-chain DNA in situ hybridization assay (n = 70), copy number assay by fluorescent in situ hybridization (n = 350), and immunohistochemistry (n = 350) were correlated with clincopathological variables, KIT/PDGFRA/BRAF genotypes, and disease-free survival (DFS). HSD11B1 was stably silenced to explore its oncogenic function. HSD11B1 mRNA varied between high-risk and non-high-risk groups (p = 0.009) and positively correlated with HSD11B1 immunoexpression (r = 0.783, p < 0.001). HSD11B1 copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression (p < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense HSD11B1 mutations (17.2%) were related to high risk (p = 0.044), age ≥70 years (p = 0.007), and shorter DFS among relapsed cases (p = 0.033). CNG was related to unfavorable KIT/PDGFRA/BRAF genotypes (p = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases (p < 0.001). Both abnormalities strongly associated with risk levels (both p < 0.001) and shorter univariate DFS (both p < 0.0001), and HSD11B1 CNG remained prognostically independent (p < 0.001) with a 3-fold increased hazard ratio. In vitro, HSD11B1 knockdown significantly inhibited proliferation and caused G2/M arrest. In conclusion, HSD11B1 overexpression may occur owing to CNG, confer a pro-proliferative function, and predict a worse prognosis in GISTs.

scholarly journals Polioencephalomyelitis in Domestic Swine Associated With Porcine Astrovirus Type 3

2019 ◽  
Vol 57 (1) ◽  
pp. 82-89 ◽  
Author(s):  
Franco S. Matias Ferreyra ◽  
Laura K. Bradner ◽  
Eric R. Burrough ◽  
Vickie L. Cooper ◽  
Rachel J. Derscheid ◽  
...  
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Neurologic Disease ◽  
Viral Encephalomyelitis ◽  
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Porcine Astrovirus ◽  
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Type 3 ◽  
Domestic Swine ◽  
Formalin Fixed

In the past decade, different members of the genus Mamastrovirus have been associated with outbreaks of neurologic disease in humans, cattle, sheep, mink, and, most recently, porcine astrovirus 3 (PoAstV3) in swine. We performed a retrospective analysis of 50 cases of porcine neurologic disease of undetermined cause but with microscopic lesions compatible with a viral encephalomyelitis to better understand the role and pathogenesis of PoAstV3 infection. Nucleic acid was extracted from formalin-fixed paraffin-embedded (FFPE) tissue for reverse transcription quantitative polymerase chain reaction (RT-qPCR) testing for PoAstV3. In addition, 3 cases with confirmed PoAstV3-associated disease were assayed by RT-qPCR to investigate PoAstV3 tissue distribution. PoAstV3 was detected in central nervous system (CNS) tissue via RT-qPCR and in situ hybridization in 13 of 50 (26%) FFPE cases assayed. PoAstV3 was rarely detected in any tissues outside the CNS. Positive cases from the retrospective study included pigs in various production categories beginning in 2010, the earliest year samples were available. Based on these results, PoAstV3 appears to be a recurring putative cause of viral encephalomyelitis in swine that is rarely detected outside of the CNS at the time of clinical neurologic disease, unlike other common viral causes of neurologic disease in swine.

scholarly journals Outcomes of Radiotherapy for Mesenchymal and Non-Mesenchymal Subtypes of Gastric Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 943 ◽  
Author(s):  
Jeong Il Yu ◽  
Hee Chul Park ◽  
Jeeyun Lee ◽  
Changhoon Choi ◽  
Won Ki Kang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Adjuvant Chemoradiotherapy ◽  
Recurrence Free Survival ◽  
Curative Surgery ◽  
Free Survival ◽  
Rna Analysis ◽  
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Independent Variable ◽  
Formalin Fixed

Background: The purpose of this study was to evaluate the clinical outcomes following postoperative chemotherapy (XP) versus chemoradiotherapy (XP-RT) according to mesenchymal subtype based on RNA sequencing in gastric cancer (GC) in a cohort of the Adjuvant chemoRadioTherapy In Stomach Tumor (ARTIST) trial. Methods: Of the 458 patients enrolled in the ARTIST trial, formalin-fixed, paraffin-embedded (FFPE) specimens were available from 106 (23.1%) patients for RNA analysis. The mesenchymal subtype was classified according to a previously reported 71-gene MSS/EMT signature using the NanoString assay. Results: Of the 106 patients analyzed (50 in XP arm, 56 in XP-RT arm), 36 (34.0%) patients were categorized as mesenchymal subtype by NanoString assay. Recurrence-free survival (RFS, p = 0.009, hazard ratio (HR) = 2.11, 95% confidence interval (CI): 1.21–3.70) and overall survival (OS, p = 0.003, HR = 2.28, 95% CI: 1.31–3.96) were significantly lower in the mesenchymal subtype than in the non-mesenchymal subtype. In terms of post-operative radiotherapy (RT), mesenchymal subtype was not an independent variable to predict RFS or OS regardless to the assigned arm (XP with or without RT) in this patient cohort. However, there was a trend in the adjuvant XP arm, which showed higher OS than the XP-RT arm for the mesenchymal subtype and lower OS than the XP-RT arm for the non-mesenchymal subtype. Conclusions: We could not determine any significant differences between the mesenchymal and non-mesenchymal subtypes with respect to the effects of adjuvant XP with or without RT in gastric cancer following curative surgery.

Use of class III beta tubulin to predict efficacy from paclitaxel- or docetaxel-based chemotherapy in patients with advanced gastric cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 52-52
Author(s):  
J. Ahn ◽  
M. Jung ◽  
H. Chang ◽  
X. Zhang ◽  
H. Jeung ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
High Expression ◽  
Class Iii ◽  
Beta Tubulin ◽  
Free Survival ◽  
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Formalin Fixed Paraffin Embedded

52 Background: To predict clinical outcome in patients with advanced gastric cancer (AGC) received paclitaxel or docetaxel based chemotherapy, we evaluated expression of class III beta tubulin (bTubIII). Methods: Expression of bTubIII was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumors from the primary gastric cancer. Tumors were classified as bTubIII “low” and “high” according to median of IHC score [intensity (0-3) × portion (0-100)]. The expression of bTubIII was investigated for their association with clinical outcomes of efficacy and toxicity. Results: One hundred twenty-four AGC pts who were treated with paclitaxel or docetaxel combined with an infusional 5-fluorouracil and low-dose leucovorin as first and second-line palliative chemotherapy were enrolled. Thirty-three patients (26.7%) were confirmed to have high expression of bTubIII. The patients with high expression of bTubIII showed higher disease control rate (DCR) and longer progression-free survival (PFS) than those with low expression in patients treated with paclitaxel (79.3 % vs. 57.3 %, p = 0.039, and 3.0 months vs. 1.5 months, p = 0.073). By contrast, there was no difference of DCR and PFS according to expression of bTubIII in patients treated with docetaxel. The expression of bTubIII was not associated with toxicity in both patients treated with paclitaxel or docetaxel. Conclusions: The expression of bTubIII may be a predictive marker in AGC patients received paclitaxel based chemotherapy, but not docetaxel. No significant financial relationships to disclose.

High number of PD-1 positive tumoral lymphocytes as a potent biomarker for adopting cytokine-induced killer cells in hepatocellular carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15680-e15680
Author(s):  
Boyang Chang ◽  
Peihong Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Therapy ◽  
Univariate Analysis ◽  
Killer Cell ◽  
Disease Free Survival ◽  
Free Survival ◽  
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Cik Cell ◽  
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e15680 Background: Adjuvant cytokine-induced killer cell (CIK) treatment has shown potential in reducing recurrence rate and prolong survival of patients with hepatocellular carcinoma (HCC). We aim to evaluate the PD-1/PD-L1 expression in tumor cells and tumor infiltrative lymphocytes in HCC patients and their correlation with survival benefit from cytokine-induced killer cell therapy. Methods: Between 2004 and 2011, 290 HCC patients received curative section were retrospectively enrolled by one-to-one propensity score matching, including 145 cases received adjuvant CIK cell transfusion after surgery (Surgery-CIK group), and 145 cases underwent surgery only (Surgery only group). Immunohistochemistry (IHC) was used to measure the PD-1 and PD-L1 expression in formalin fixed paraffin embedded tissue of all subjects; IHC of CD4, CD8 and Foxp3 were also conducted in the surgery-CIK group to explore their correlation with PD1/PD-L1 expression and survival of HCC patients. Results: The surgery-CIK group had significantly improved overall survival (OS; HR 0.55, 95% CI 0.33-0.92) and disease-free survival (DFS; HR 0.59, 95% CI 0.42-0.83) as compared to the surgery-only group. In the surgery-CIK group, univariate analysis showed both high PD-L1 expression and a high number of PD-1+ TILs were significantly associated with improved OS, while only the high number of PD-1+ TILs was associated with improved DFS. Multivariate analyses showed a high number of PD-1+ TILs was the only independent factor predicting favorable OS (HR 0.19, 95% CI 0.08-0.45) and DFS (HR 0.40, 95% CI 0.24-0.66) in the surgery-CIK group. By contrast, in the surgery-only group, no significant associations between PD-1/PD-L1 expression and survival of patients were identified. Conclusions: A high number of PD-1+ TILs can serve as a potent biomarker to adopt CIK cell therapy in HCC patients after curative resection.

scholarly journals Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiwei Feng ◽  
Nan Jia ◽  
Haining Jiao ◽  
Jun Chen ◽  
Yan Chen ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
High Risk ◽  
Tumor Recurrence ◽  
Disease Free Survival ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Free Survival ◽  
Tumor Relapse ◽  
Disease Free ◽  
Tumor Dna

Abstract Background Currently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC. Methods Tumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival. Results Somatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616–188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4. Conclusions Personalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.

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