Negative Expression of DSG1 and DSG2, as Prognostic Biomarkers, Impacts on the Overall Survival in Patients with Extrahepatic Cholangiocarcinoma

Aims. To evaluate the expression of DSG1 and DSG2 and investigate their clinicopathological significance in EHCC. Method. The protein expression of DSG1 and DSG2 was measured by EnVision immunohistochemistry in 15 normal biliary tract tissues, 10 biliary tract adenoma tissues, 30 peritumoral tissues, and 100 EHCC tumour tissues. Result. The expression of the DSG1 and DSG2 proteins was significantly lower in EHCC tumour tissues than in normal biliary tract tissues, biliary tract adenoma, and peritumoral tissues (P<0.05). Adenoma and peritumoral tissues with negative DSG1 and/or DSG2 protein expression exhibited atypical hyperplasia. DSG1 expression was positively correlated with DSG2 expression in EHCC (P<0.01). In patients with good differentiation, no invasion, no lymph metastasis, TNM I + II stage, and radical surgery, the positive expression of DSG1 and DSG2 proteins was higher (P<0.05). In comparison to patients with negative DSG1 and/or DSG2 expression, the average overall survival time of those with positive expression was significantly longer (P=0.000). Cox multivariate analysis revealed that negative DSG1 and DSG2 expressions were independent of poor prognosis factors in EHCC patients. The AUC calculated for DSG1 was 0.681 (95% confidence interval: 0.594–0.768) and that for DSG2 was 0.645 (95% confidence interval: 0.555–0.734), while that for DSG1 and DSG2 was 0.772 (95% confidence interval: 0.609-0.936). Conclusions. Negative protein expression of DSG1 and DSG2 is closely related to the pathogenesis, severe clinicopathological characteristics, aggressive biological behaviours, and dismal prognosis in EHCC.

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Comparison of ADAM19 and CUEDC2 expression in EHCC and their clinicopathological significance

Biomarkers in Medicine ◽

10.2217/bmm-2020-0321 ◽

2020 ◽

Vol 14 (16) ◽

pp. 1573-1584

Author(s):

Shu Xu ◽

Shengfu Huang ◽

Daiqiang Li ◽

Qiong Zou ◽

Yuan Yuan ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Survival Time ◽

Biliary Tract ◽

Extrahepatic Cholangiocarcinoma ◽

Positive Correlation ◽

Overall Survival Time ◽

Positive Expression ◽

Dismal Prognosis ◽

Clinicopathological Significance

Background: To evaluate the expression and clinicopathological significance of a disintegrin and metalloproteinases 19 (ADAM19) CUE domain containing protein 2 (CUEDC2) in extrahepatic cholangiocarcinoma (EHCC). Materials & methods: Immunostaining of ADAM19 and CUEDC2 was performed by EnVision immunohistochemistry in benign and malignant biliary tract tissues. Result: The expression of ADAM19 and CUEDC2 were significantly higher in EHCC (p < 0.05). ADAM19 expression was positive correlated with CUEDC2 expression in EHCC (p < 0.05). The overall survival time of those with positive expression of ADAM19 and CUEDC2 was lower (p < 0.001). Both positive expression of ADAM19 and CUEDC2 were independent prognostic factors in EHCC. Conclusion: ADAM19 and CUEDC2 have a positive correlation to the pathogenesis and dismal prognosis in EHCC.

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MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.334 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 334-334 ◽

Cited By ~ 1

Author(s):

Kanwal Pratap Singh Raghav ◽

Wenting Wang ◽

Michael J. Overman ◽

Scott Kopetz

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Overall Survival ◽

Protein Expression ◽

Survival Data ◽

Fold Increase ◽

Clinicopathological Characteristics ◽

Fisher Exact Test ◽

Mesenchymal Transition ◽

Emt Markers

334 Background: Dysregulation of the proto-oncogene MET (mesenchymal-epithelial transition factor gene) has been implicated in tumorigenesis and correlates with worse survival and chemo/radio-resistance in colorectal cancer (CRC). EMT has been identified as a dominant molecular characteristic of a subset of CRC tumors and represents a key feature in the developing colorectal taxonomy. The purpose of this study was to compare protein expression of MET with protein/gene expression of EMT markers and other clinicopathological characteristics, and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 590 CRC samples using data from The Cancer Genome Atlas. Fisher-exact test and Pearson’s method was used to determine the relationship between MET protein expression, clinicopathological characteristics and EMT marker protein expression by reverse-phase protein array (RPPA) and EMT-associated gene expression by RNA-sequencing. Regression tree method was applied to find the best cutoff point for MET using patients with available survival data. Overall survival (OS) was estimated non-parametrically using Kaplan-Meier curve and log-rank test was used to evaluate hazard ratio. Results: MET expression by RPPA did not correlate with traditional clinicopathologic characteristics. MET was overexpressed in 17% of CRC tumors and was significantly associated with OS (HR 2.92; 95% CI: 1.45 - 5.92). Correlation analysis of MET levels with gene expression of EMT markers AXL, CDH1, FGFR1, SNAIL, TWIST1/2, VIM, SLUG, ZEB1/2, FN1 demonstrated that the highest quartile of MET protein expression was associated with a 1.5 fold increase in ZEB1 (p = 0.002), a 1.4 fold increase in AXL (p = 0.005) and ZEB2 (p = 0.008), and a 1.3 fold increase in VIM (p = 0.02). MET expression also correlated strongly with protein expressions of SNAIL (transcription factor for EMT) (r = 0.96) and ERCC1 (r = 0.83) (a marker for oxaliplatin chemo-resistance). Conclusions: Increased MET protein expression is seen in 17% of CRC tumors and strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be a surrogate biomarker for this unique subset of CRC.

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ERCC1 mRNA levels as a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.239 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 239-239

Author(s):

Shuichiro Uemura ◽

Hidekazu Kuramochi ◽

Go Nakajima ◽

Yasuto Sato ◽

Ryota Higuchi ◽

...

Keyword(s):

Overall Survival ◽

Survival Rate ◽

Mrna Expression ◽

Biliary Tract ◽

Prognostic Biomarker ◽

Biliary Tract Carcinoma ◽

R0 Resection ◽

Cancer Type ◽

Mrna Levels ◽

Extrahepatic Cholangiocarcinoma

239 Background: To date, no prognostic biomarker for biliary tract carcinoma has been identified. In previous studies of biliary tract carcinoma, no reliable data was found due to the varying composition of the cancer type (gallbladder, cholangiocarcinoma, and ampullary carcinoma), differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. Methods: Fifty extrahepatic cholangiocarcinoma patients who underwent a pancreatoduodenectomy with R0 resection at the Tokyo Women’s Medical University Hospital were examined. All patients were pathologically diagnosed as having papillary or tubular adenocarcinoma. T-RNA was extracted from FFPE samples, and mRNA expression levels were measured by real-time RT-PCR. Results: In the preliminary analysis, 10 patients who have survived more than 5 years (LS group) and 10 patients who had a relapse within 2 years (SS group) were selected. EGFR, AREG, EREG, MMP-9, CDH-1, PARP1, and ERCC1 mRNA expression were examined; only the ERCC1 mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7, p=0.0073). The median survival time (MST) of the patients with high ERCC1 levels was significantly higher than that in patients with a low ERCC1 level (MST: not reached vs. 16M). Then, 30 more patients with the same backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. The patients with high ERCC1 mRNA levels had a significantly greater overall survival rate compared with those with low ERCC1 levels (MST: not reached vs. 12.5M, 5-year survival rate: 92% vs 51%; p=0.04). In multivariate analysis, no lymph node metastases or high ERCC1 expression were significantly associated with better overall survival. Conclusions: ERCC1 mRNA expression seemed to be a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.

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Microsatellite Instability Analysis and Its Prognostic Value in Invasive Nonampullary Duodenal Adenocarcinoma

10.21203/rs.3.rs-784037/v1 ◽

2021 ◽

Author(s):

Guang Yang ◽

Takehiro Tanaka ◽

Hideaki Kinugasa ◽

Hiromitsu Kanzaki ◽

Xi Meng Chen ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Confidence Interval ◽

Microsatellite Instability ◽

Tumor Stage ◽

Duodenal Adenocarcinoma ◽

Positive Expression ◽

Stage Disease ◽

Early Tumor ◽

Instability Phenotype

Abstract Purpose: Nonampullary duodenal adenocarcinoma is a rare disease. Although several prognostic factors have been reported for this disease, they remain controversial due to their rarity. In this study, we retrospectively analyzed 54 cases of invasive nonampullary duodenal adenocarcinoma, focusing on the microsatellite instability phenotype, PD-L1 expression, and prognostic factors. Methods: Expression of the PD-L1 protein and cell differentiation markers in tumors was detected by immunohistochemistry. Microsatellite markers (NR-21, NR-22, NR-24, BAT-25 and BAT-26) were amplified for MSI assessment by PCR.Results: The incidence of microsatellite instability in invasive nonampullary duodenal adenocarcinoma was 35.2%. No significant correlation between the microsatellite instability phenotype and clinicopathological factors was observed. Positive expression of PD-L1 by immune cells was common in advanced-stage disease (P=0.054), and positive expression of PD-L1 in cancer cells correlated significantly with the histologically undifferentiated type (P=0.016). Kaplan-Meier survival analysis demonstrated a significantly better overall survival in patients with microsatellite instability (P=0.013) and at early-stage disease (P=0.000) than in those with microsatellite stability or at late tumor stages. Univariate and multivariate analyses showed that microsatellite instability (hazard ratio [HR]: 0.282, 95% confidence interval [CI]: 0.106-0.751, p=0.011) and early tumor stage (stage Ⅰ-Ⅱ) (hazard ratio [HR]: 8.81, 95% confidence interval [CI]: 2.545-30.500, p=0.001) were independent better prognostic factors of overall survival. Conclusions: Microsatellite instability and early tumor stage (stage Ⅰ-Ⅱ) were independent better prognostic factors of overall survival. A high proportion of microsatellite instability phenotypes and positive PD-L1 expression may be helpful for identifying immune checkpoint inhibitors as a novel therapeutic strategy.

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Impact of c-erbB-2 Protein on 5-year Survival Rate of Gastric Cancer Patients after Surgery: A Cohort Study and Meta-analysis

Tumori Journal ◽

10.5301/tj.5000444 ◽

2015 ◽

Vol 103 (3) ◽

pp. 249-254 ◽

Cited By ~ 4

Author(s):

Hao Wu ◽

Zhenzhai Cai ◽

Guangrong Lu ◽

Shuguang Cao ◽

He Huang ◽

...

Keyword(s):

Gastric Cancer ◽

Lymph Node ◽

Survival Rate ◽

Lymph Node Metastasis ◽

Protein Expression ◽

Meta Analysis ◽

Clinicopathological Characteristics ◽

Node Metastasis ◽

Positive Expression ◽

Significant Difference

Objective To explore the association of c-erbB-2 protein expression with clinicopathological characteristics and prognosis of gastric cancer (GC) after surgery. Methods A total of 133 patients undergoing surgical resection for GC between March 2006 and January 2009 in the Second Affiliated Hospital of Wenzhou Medical University were included in this study. c-erbB-2 protein expression was determined by immunohistochemistry. Afterwards, a meta-analysis was performed to further confirm the association between c-erbB-2 protein expression and GC by employing stringent inclusion and exclusion criteria. All data analyses were conducted with STATA 12.0 and SPSS 19.0. Results There was no significant difference in c-erbB-2 expression among patients with various parameters including age, gender and histological types (all p>0.05). Among 133 GC patients, 32 patients presented c-erbB-2-positive expression and 101 presented c-erbB-2-negative expression (24.1% vs. 75.9%). The c-erbB-2-positive expression rate was significantly higher in GC tissues of patients with lymph node metastasis than those without. Similarly, a significant increase in c-erbB-2 expression was observed in well/moderately differentiated GC tissues compared with poorly differentiated GC. Patients with negative c-erbB-2 expression had a higher 5-year survival rate than those with positive c-erbB-2 expression, which was consistent with the results of the meta-analysis (OR = 0.54, 95% CI 0.37-0.80, p = 0.002). Conclusions Our study demonstrated that high expression of c-erbB-2 protein was strongly associated with lymph node metastasis, histological differentiation and 5-year survival rate in GC patients after surgery.

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Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC)

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-019-02989-x ◽

2019 ◽

Vol 145 (9) ◽

pp. 2285-2292 ◽

Cited By ~ 1

Author(s):

Jenny Hötzel ◽

Nathaniel Melling ◽

Julia Müller ◽

Adam Polonski ◽

Gerrit Wolters-Eisfeld ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Protein Expression ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Close Homologue

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The Prognostic Role of LRIG Proteins in Endometrial Cancer

Cancers ◽

10.3390/cancers13061361 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1361

Author(s):

Zoia Razumova ◽

Husam Oda ◽

Igor Govorov ◽

Eva Lundin ◽

Ellinor Östensson ◽

...

Keyword(s):

Overall Survival ◽

Endometrial Cancer ◽

Prognostic Factor ◽

Confidence Interval ◽

Initial Study ◽

Surface Proteins ◽

University Hospital ◽

Study Cohort ◽

Risk Of Death

Endometrial cancer (EC) is the most common gynecologic malignancy in Sweden and it has various prognostic factors. The LRIG family is a group of three integral surface proteins with a similar domain organization. The study aimed to explore LRIG family as prognostic factor proteins in EC. The initial study cohort included 100 women with EC who were treated at the Department of Women’s and Children’s Health, Karolinska University Hospital Solna, between 2007 and 2012. We assessed the associations between LRIG protein expression and type, grade, and stage of EC, as well as progression-free and overall survival. Immunohistochemistry results revealed that most women in the analytical sample had >50% LRIG1-, LRIG2- and LRIG3-positive cells. A statistically significant association was observed between having a high number of LRIG3-positive cells and superior overall survival (incidence rate ratio = 0.977; 95% confidence interval: 0.958–0.996, p = 0.019). Moreover, positive LRIG3 staining of the cell membrane was associated with reducing in the risk of death (hazard ratio = 0.23; 95% confidence interval: 0.09–0.57). Our results show that LRIG3 expression might be a prognostic factor in EC. The role of LRIG1 and LRIG2 expression remains to be further investigated.

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P14.21 Tehila Kaisman-Elbaz MD/PhD

Neuro-Oncology ◽

10.1093/neuonc/noz126.256 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii71-iii71

Author(s):

T Kaisman-Elbaz ◽

Y Elbaz ◽

V Merkin ◽

L Dym ◽

A Noy ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

False Discovery Rate ◽

Medical Center ◽

Tumor Resection ◽

Multiple Hypothesis Testing ◽

Hemoglobin Level ◽

Distribution Width ◽

False Discovery ◽

Dismal Prognosis

Abstract BACKGROUND Glioblastoma is known for its dismal prognosis though its dependency on patients’ readily available RBCs parameters defining the patient’s anemic status such as hemoglobin level and Red blood cells distribution Width (RDW) is not fully established. Several works demonstrated a connection between low hemoglobin level or high RDW values to overall glioblastoma patient’s survival, but in other works, a clear connection was not found. This study addresses this unclarity. MATERIAL AND METHODS In this work, 170 glioblastoma patients, diagnosed and treated in Soroka University Medical Center (SUMC) in the last 12 years were retrospectively inspected for their survival dependency on pre-operative RBCs parameters using multivariate analysis followed by false discovery rate procedure due to the multiple hypothesis testing. A survival stratification tree and Kaplan-Meier survival curves that indicate the patient’s prognosis according to these parameters were prepared. RESULTS Beside KPS>70 and tumor resection supplemented by oncological treatment, age<70 (HR=0.4, 95% CI 0.24–0.65), low hemoglobin level (HR=1.79, 95% CI 1.06–2.99) and RDW<14% (HR=0.57, 95% CI 0.37–0.88) were found to be prognostic to patients’ overall survival in multivariate analysis, accounting for false discovery rate of less than 5%. CONCLUSION A survival stratification highlighted a non-anemic subgroup of nearly 30% of the cohort’s patients whose median overall survival was 21.1 months (95% CI 16.2–27.2) - higher than the average Stupp protocol overall median survival of about 15 months. A discussion on the beneficial or detrimental effect of RBCs parameters on glioblastoma prognosis and its possible causes is given.

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Mortality due to cancer treatment delay: systematic review and meta-analysis

BMJ ◽

10.1136/bmj.m4087 ◽

2020 ◽

pp. m4087 ◽

Cited By ~ 5

Author(s):

Timothy P Hanna ◽

Will D King ◽

Stephane Thibodeau ◽

Matthew Jalink ◽

Gregory A Paulin ◽

...

Keyword(s):

Systematic Review ◽

Overall Survival ◽

Confidence Interval ◽

Cancer Treatment ◽

Head And Neck ◽

Adjuvant Radiotherapy ◽

Systemic Treatment ◽

Meta Analysis ◽

Treatment Delay ◽

Hazard Ratio

Abstract Objective To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways. Design Systematic review and meta-analysis. Data sources Published studies in Medline from 1 January 2000 to 10 April 2020. Eligibility criteria for selecting studies Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models. Results The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings. Conclusions Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

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Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Blood ◽

10.1182/blood.v87.1.265.265 ◽

1996 ◽

Vol 87 (1) ◽

pp. 265-272 ◽

Cited By ~ 332

Author(s):

O Hermine ◽

C Haioun ◽

E Lepage ◽

MF d'Agay ◽

J Briere ◽

...

Keyword(s):

Overall Survival ◽

Protein Expression ◽

B Cell ◽

Hodgkin’S Lymphoma ◽

Prognostic Significance ◽

Hodgkin's Lymphoma ◽

Independent Effect ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Large B Cell

Abstract Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T- cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.

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