Prognostic Significance of Aberrant Claudin-6 Expression in Endometrial Cancer

Background: Among the claudin (CLDN) family, CLDN6 exhibits aberrant expression in various cancers, but its biological relevance has not yet been established. We generated a monoclonal antibody (mAb) against human CLDN6 and verified its specificity. By immunohistochemical staining and semi-quantification, we evaluated the relationship between CLDN6 expression and clinicopathological parameters in tissues from 173 cases of endometrial cancer. Results: The established mAb selectively recognized CLDN6 protein. Ten of the 173 cases (5.8%) showed high CLDN6 expression (score 3+), whereas 19 (11.0%), 18 (10.4%) and 126 (72.4%) cases revealed low CLDN6 expression (score 2+, 1+ and 0, respectively). In addition, intratumor heterogeneity of CLDN6 expression was observed even in the cases with high CLDN6 expression. The 5-year survival rates in the high and low CLDN6 groups was approximately 30% and 90%, respectively. Among the clinicopathological factors, the high CLDN6 expression was significantly associated with surgical stage III/IV, histological type, histological grade 3, lymphovascular space involvement, lymph node metastasis and distant metastasis. Furthermore, the high CLDN6 expression was an independent prognostic marker for overall survival of endometrial cancer patients (hazard ratio 3.50, p = 0.014). Conclusions: It can be concluded that aberrant CLDN6 expression is useful to predict poor outcome for endometrial cancer and might be a promising therapeutic target.

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Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer: Overtreatment Is the Main Issue

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000937 ◽

2017 ◽

Vol 27 (4) ◽

pp. 748-753 ◽

Cited By ~ 8

Author(s):

Alper Karalok ◽

Taner Turan ◽

Derman Basaran ◽

Osman Turkmen ◽

Gunsu Comert Kimyon ◽

...

Keyword(s):

Endometrial Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Histological Grade ◽

Myometrial Invasion ◽

Lymph Node Involvement ◽

Node Metastasis ◽

Deep Myometrial Invasion ◽

Endometrioid Endometrial Cancer ◽

Grade 3

ObjectiveThe aim of this study was to evaluate the effectiveness of histological grade, depth of myometrial invasion, and tumor size to identify lymph node metastasis (LNM) in patients with endometrioid endometrial cancer (EC).MethodsA retrospective computerized database search was performed to identify patients who underwent comprehensive surgical staging for EC between January 1993 and December 2015. The inclusion criterion was endometrioid type EC limited to the uterine corpus. The associations between LNM and surgicopathological factors were evaluated by univariate and multivariate analyses.ResultsIn total, 368 patients were included. Fifty-five patients (14.9%) had LNM. Median tumor sizes were 4.5 cm (range, 0.7–13 cm) and 3.5 cm (range, 0.4–33.5 cm) in patients with and without LNM, respectively (P = 0.005). No LMN was detected in patients without myometrial invasion, whereas nodal spread was observed in 7.7% of patients with superficial myometrial invasion and in 22.6% of patients with deep myometrial invasion (P < 0.0001). Lymph node metastasis tended to be more frequent in patients with grade 3 disease compared with those with grade 1 or 2 disease (P = 0.131).ConclusionsThe risk of lymph node involvement was 30%, even in patients with the highest-risk uterine factors, that is, those who had tumors of greater than 2 cm, deep myometrial invasion, and grade 3 disease, indicating that 70% of these patients underwent unnecessary lymphatic dissection. A precise balance must be achieved between the desire to prevent unnecessary lymphadenectomy and the ability to diagnose LNM.

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Tumor-associated macrophage is correlated with survival and SOCS protein expression in canine mammary carcinoma

Pesquisa Veterinária Brasileira ◽

10.1590/1678-5150-pvb-5638 ◽

2018 ◽

Vol 38 (10) ◽

pp. 1972-1980

Author(s):

Carlos H.C. Vieira-Filho ◽

Stella M. Barrouin-Melo ◽

Karine A. Damasceno ◽

Márcio S.S. Araújo ◽

Natalie F. Borges ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Mammary Carcinoma ◽

Inflammatory Infiltrate ◽

Histological Grade ◽

Survival Rates ◽

Clinical Staging ◽

Clinicopathological Parameters ◽

Node Metastasis ◽

Socs3 Expression

ABSTRACT: The inflammatory infiltrate in the tumor microenvironment, particularly in mammary tumors, has aroused great interest in oncology, to play different roles in the progression or tumor regression dependent on the types and cell subsets involved. The present study aimed to evaluate (1) the occurrence and intensity of macrophage infiltration in the mammary carcinoma microenvironment, (2) the expression of SOCS1 and SOCS3 proteins in tumor associated macrophages, (3) any association between these parameters and tumor development, as well as survival rates in female dogs. Twenty-two female dogs diagnosed as carcinoma arising in a mixed tumor (CMT) by histopathology were divided into two groups following mastectomy: dogs without metastasis (CMT(-)=11) and those with metastasis (CMT(+)=11). The following parameters were analyzed: tumor size, lymph node metastasis, clinical stage, histological grade, distribution and intensity of inflammatory infiltrate, tumor macrophage quantification by immunohistochemical analysis of SOCS1 and SOCS3 expression, and immunophenotyping of peripheral blood leukocytes by flow cytometry. Dogs with the higher proportions of macrophages in the inflammatory infiltrate (≥400/tumor) also had higher survival rates in comparison with dogs with less macrophages. Immunostaining revealed higher proportions of SOCS3-positive macrophages in dogs without lymph node metastasis, while SOCS1-positive macrophages were predominant in dogs with metastasis (p<0.05). Multivariate analysis found associations between survival rate and clinical staging (p=0.025), histological grade (p=0.007), and the expression of MHC-CI in circulating monocytes (p=0.018). Higher SOCS3 expression in activated macrophages within the inflammatory infiltrate were considered indicative of an antitumor immune response, improved clinicopathological parameters and longer survival, whereas SOCS1-related activation was associated with tumor progression, metastasis development and reduced survival in female dogs with mammary carcinomas.

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A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5523 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5523-5523

Author(s):

Dana M Roque ◽

Stefania Bellone ◽

Eric R. Siegel ◽

Natalia Buza ◽

Elena Bonazzoli ◽

...

Keyword(s):

Endometrial Cancer ◽

Microsatellite Instability ◽

Phase Ii ◽

Antigen Processing ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Prognostic Significance ◽

Evaluation Criteria ◽

Tumor Mutational Burden ◽

Grade 3

5523 Background: Microsatellite instability (MSI-H) is a biomarker for response to immune-checkpoint inhibitors (ICIs); however, these neoplasms are heterogenous including Lynch (germline), Lynch-like (somatic) and sporadic ( MLH1-methylated) tumors. Whether mechanisms underlying MSI alter responses to ICIs is unclear. We report data from a phase II pilot study (NCT02899793) of pembrolizumab in recurrent MSI-H endometrial cancer (EC) patients and potential mechanisms of primary/secondary ICI resistance. Methods: Patients with measurable, MSI-H EC confirmed by immunohistochemistry and polymerase chain reaction were evaluated by next-generation sequencing and received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Twenty-five patients (24 evaluable) were treated. Six (25%) patients harbored Lynch/Lynch-like tumors while 18 (75%) had sporadic EC. Tumor mutational burden (TMB) was higher in Lynch-like (median 2939, IQR:867-5108) versus sporadic tumors (median 604, IQR:411-798) ( P= 0.0076). Median follow-up was 25.8 months with an ORR of 58% (95% CI, 36.6-77.9%). ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients ( P= 0.024). The 3-year progression-free (PFS) and overall survival (OS) proportions were 100% versus 30% ( P= 0.017) and 100% versus 43% ( P= 0.043), respectively. Grade 3/4 treatment-related adverse events (6.8%) occurred in 12 patients. Defective antigen processing/presentation and deranged induction in interferon responses served as mechanisms of resistance in sporadic MSI-H EC. Conclusions: Our study demonstrated prognostic significance of Lynch-like versus sporadic MSI-H EC on ORR, PFS and OS when treated with pembrolizumab. Clinical studies evaluating separate subtypes of MSI-H EC treated with ICIs are warranted. Clinical trial information: NCT02899793.

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Stage-Stratified Analysis of Prognostic Significance of Bax-Interacting Factor-1 Expression in Resected Colorectal Cancer

BioMed Research International ◽

10.1155/2013/329839 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Yoon Ho Ko ◽

Young-Seok Cho ◽

Hye Sung Won ◽

Ho Jung An ◽

Der Sheng Sun ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Expression ◽

Early Stage ◽

Survival Rates ◽

Prognostic Significance ◽

Clinicopathological Parameters ◽

Kaplan Meier ◽

Low Levels ◽

Stratified Analysis ◽

Independent Indicator

Background/Aim.Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC).Methods.We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray.Results.Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (P=0.034). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285–0.739;P=0.001).Conclusion.Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC.

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NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer

Tumor Biology ◽

10.1177/1010428319830002 ◽

2019 ◽

Vol 41 (2) ◽

pp. 101042831983000 ◽

Cited By ~ 2

Author(s):

Christine Degasper ◽

Andrea Brunner ◽

Natalie Sampson ◽

Irina Tsibulak ◽

Verena Wieser ◽

...

Keyword(s):

Body Mass Index ◽

Endometrial Cancer ◽

Body Mass ◽

Prognostic Significance ◽

Clinicopathological Parameters ◽

Diabetic Patients ◽

Type I ◽

Prognostic Impact ◽

Normal Endometrium ◽

Nadph Oxidase 4

The aim of this study was to explore the role of NOX4 in the biology of the normal endometrium and endometrial cancer. NOX4 plays a key role in other adenocarcinomas and has been implicated in the pathogenesis of diabetes and obesity, which are important risk factors for endometrial cancer. NOX4 expression was assessed in 239 endometrial cancer and 25 normal endometrium samples by quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry. DNA methylation of the NOX4 promoter was determined by means of MethyLight PCR. Data were correlated with clinicopathological parameters and analyzed in the context of diabetes and body mass index. In the normal endometrium, NOX4 microRNA expression was significantly higher in the secretory transformed compared with proliferative endometrium ( p = 0.008). In endometrial cancer specimens, NOX4 expression did not differ between diabetic and non-diabetic patients, but was the highest in patients with a body mass index ≤ 26 ( p = 0.037). The lowest NOX4 expression was found in carcinosarcomas ( p = 0.007). High NOX4 expression predicted poorer clinical outcome with regard to overall survival, especially in non-diabetic patients and those with a body mass index > 20. Independent prognostic significance of NOX4 transcripts was retained in type I endometrial cancer and was the most meaningful in patients with a body mass index > 20. No prognostic impact was shown for NOX4 promoter methylation in endometrial cancer. For the first time, we demonstrate that NOX4 plays a considerable role in the cycle-dependent changes in the normal endometrium and in the biology of endometrial cancer.

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Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000681 ◽

2016 ◽

Vol 26 (5) ◽

pp. 933-938 ◽

Cited By ~ 22

Author(s):

Caroline C. Billingsley ◽

David E. Cohn ◽

David G. Mutch ◽

Erinn M. Hade ◽

Paul J. Goodfellow

Keyword(s):

Endometrial Cancer ◽

Confidence Interval ◽

Prognostic Significance ◽

Hazard Ratio ◽

High Grade ◽

Clinicopathologic Features ◽

Mutation Status ◽

Risk Of Recurrence ◽

Endometrioid Endometrial Cancer ◽

Grade 3

ObjectivePOLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed.MethodsPolymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models.ResultsPOLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09–1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03–1.42).ConclusionsPOLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate.

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Cytokeratin 7-Negative and GATA Binding Protein 3-Negative Breast Cancers: Clinicopathological Features and Prognostic Significance

10.21203/rs.2.11923/v1 ◽

2019 ◽

Author(s):

Shaolei Lu ◽

Evgeny Yakirevich ◽

Li Juan Wang ◽

Murray B Resnick ◽

Yihong Wang

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Molecular Subtype ◽

Binding Protein ◽

Prognostic Significance ◽

Clinicopathological Parameters ◽

Breast Cancers ◽

Cytokeratin 7 ◽

Gata3 Expression ◽

Grade 3

Abstract Background: Cytokeratin 7 (CK7) and GATA binding protein 3 (GATA3) are considered as immunohistochemical hallmarks of breast cancers; however, there are breast tumors lacking these markers. Clinicopathological characterization of CK7 negative breast cancer has not been addressed previously and similar studies on GATA3 negative tumors are limited. Methods: This study included 196 consecutive cases of Nottingham Grade 3 breast cancers with 159 cases of Grade 1 and Grade 2 tumors for comparison. CK7 and GATA3 expression was correlated with patient’s age, histological type, pathological grade and stage, hormone receptor status, molecular subtype and overall survival. Results: CK7 negativity was seen in 13% of Grade 3, 9% of Grade 2, and 2% of Grade 1 cases (P=0.0457). Similarly, 28% of Grade 3, 5% of Grade 2 and 2 % of Grade 1 cases were GATA3 negative (P<0.0001). CK7 negative tumors did not show association with other clinicopathological parameters. GATA3 negative tumors were enriched in the basal-like molecular subgroup and were associated with negative estrogen receptor (ER) and negative progesterone receptor (PR) statuses. Both CK7 and GATA3 expression showed no association with overall survival in patients with Grade 3 tumor. Conclusions: More CK7 negative and GATA3 negative tumors were seen in breast cancer of high histologic grade. GATA3 expression was associated with ER status. Lack of CK7 and GATA3 expression in Grade 3 breast cancer was not associated with patient outcome.

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Cytokeratin 7-Negative and GATA Binding Protein 3-Negative Breast Cancers: Clinicopathological Features and Prognostic Significance

10.21203/rs.2.11923/v3 ◽

2019 ◽

Author(s):

Shaolei Lu ◽

Evgeny Yakirevich ◽

Li Juan Wang ◽

Murray B Resnick ◽

Yihong Wang

Keyword(s):

Overall Survival ◽

Molecular Subtype ◽

Binding Protein ◽

Prognostic Significance ◽

Breast Tumors ◽

Clinicopathological Parameters ◽

Breast Cancers ◽

Cytokeratin 7 ◽

Gata3 Expression ◽

Grade 3

Abstract Background: Cytokeratin 7 (CK7) and GATA binding protein 3 (GATA3) are considered as immunohistochemical hallmarks of breast cancers; however, there are breast tumors lacking these markers. Clinicopathological characterization of CK7 negative breast cancer has not been addressed previously and similar studies on GATA3 negative tumors are limited. Methods: This study included 196 consecutive cases of Nottingham Grade 3 breast cancers with 159 cases of Grade 1 and Grade 2 tumors for comparison. CK7 and GATA3 expression was correlated with patient’s age, histological type, pathological grade and stage, hormone receptor status, molecular subtype and overall survival. Results: CK7 negativity was seen in 13% of Grade 3, 9% of Grade 2, and 2% of Grade 1 cases (P=0.0457). Similarly, 28% of Grade 3, 5% of Grade 2 and 2 % of Grade 1 cases were GATA3 negative (P<0.0001). CK7 negative tumors did not show association with other clinicopathological parameters. GATA3 negative tumors were enriched in the basal-like molecular subgroup and were associated with negative estrogen receptor (ER) and negative progesterone receptor (PR) statuses. Both CK7 and GATA3 expression showed no association with overall survival in patients with Grade 3 tumor. Conclusions: This is the first study to characterize CK7 negative breast tumors in the context of clinicopathology. Profiling the CK7 negative and GATA3 negative breast cancers helps to understand the biology of these specific tumor subgroups and may aid in their diagnosis.

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Evaluation of Clinical Significance of Lymphovascular Space Invasion in Stage IA Endometrial Cancer

Oncology ◽

10.1159/000521382 ◽

2021 ◽

Author(s):

Kaoru Okugawa ◽

Hideaki Yahata ◽

Kazuhisa Hachisuga ◽

Hiroshi Tomonobe ◽

Nobuko Yasutake ◽

...

Keyword(s):

Endometrial Cancer ◽

Clinical Significance ◽

Survival Rates ◽

Prognostic Significance ◽

Low Grade ◽

Recurrence Free Survival ◽

Cancer Specific Survival ◽

Free Survival ◽

Stage Ia ◽

Lymphovascular Space Invasion

Introduction: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. Methods: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. Results: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and four patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and -negative groups (P=0.07 and P=0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (P=0.11 and P=0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (P=0.92 and P=0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. Conclusion: LVSI was not a prognostic factor of not only stage IA endometrial cancer, but also stage IA low-grade cancer.

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PD-L1 Expression Is an Independent Marker for Lymph Node Metastasis in Middle Eastern Endometrial Cancer

Diagnostics ◽

10.3390/diagnostics11030394 ◽

2021 ◽

Vol 11 (3) ◽

pp. 394

Author(s):

Abdul K. Siraj ◽

Sandeep Kumar Parvathareddy ◽

Padmanaban Annaiyappanaidu ◽

Nabil Siraj ◽

Maha Al-Rasheed ◽

...

Keyword(s):

Endometrial Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Tumor Cells ◽

Middle Eastern ◽

Prognostic Significance ◽

Independent Prognostic Marker ◽

Node Metastasis ◽

Protein Status ◽

Impact On Survival

Programmed death ligand 1 (PD-L1) expression in endometrial cancer (EC) tumor cells have been reported in several studies with inconsistent results. Furthermore, there is scarcity of data on the prevalence and prognostic significance of PD-L1 expression in EC from Middle Eastern ethnicity. We aimed to assess PD-L1 expression in a large cohort of Middle Eastern EC and to correlate this with clinico-pathological factors, as well as mismatch repair (MMR) protein status and patients’ outcome. PD-L1 expression was investigated using immunohistochemistry on tissue microarray in an unselected cohort of 440 EC. Kaplan–Meier and logistic regression analysis were used to compare the outcome and prognostic factors. PD-L1 expression in tumor tissue was detected in 18.9% (83/440) EC cases with no impact on survival. When stratified for MMR protein status, PD-L1 expression was similar for both MMR deficient and MMR proficient ECs. However, the expression of PD-L1 in tumor cells was significantly associated with type II (non-endometrioid) histology (p = 0.0005) and lymph node metastasis (p = 0.0172). Multivariate analysis showed PD-L1 expression to be an independent risk factor for lymph node metastasis (odds ratio: 2.94; 95% CI: 1.26–6.84; p = 0.0123). In conclusion, PD-L1 was strongly associated with non-endometrioid EC and was an independent prognostic marker of lymph node metastasis.

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