Morikazu Miyamoto

Significance of mesothelin and CA125 expression in endometrial carcinoma: a retrospective analysis

Abstract Background This study aimed to investigate the association between clinicopathologic factors, mesothelin, and cancer antigen (CA) 125 in endometrial carcinoma. Methods Between 1989 and 2017, patients with endometrial carcinoma who underwent total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either or both immunochemical expression of mesothelin and CA125 and clinicopathological features were retrospectively examined. Results Among 485 patients, 171 were positive for mesothelin, 368 were positive for CA125, and 167 were positive for mesothelin and CA125. The expression of mesothelin and CA125 was positively correlated (p < 0.01). More patients with mesothelin expression showed myometrial invasion of more than 50% (p = 0.028) and positive lymphovascular invasion (p = 0.027). Similarly, more patients with co-expression of mesothelin and CA125 had myometrial invasion of more than 50% (p = 0.016) and positive lymphovascular invasion (p = 0.02). Patients with mesothelin expression and co-expression of mesothelin and CA125 demonstrated worse progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, mesothelin expression and co-expression were poor prognostic factors for PFS (mesothelin expression: hazard ratio [HR] = 2.14, p < 0.01; co-expression: HR = 2.19, p < 0.01) and OS (mesothelin expression: HR = 2.18, p < 0.01; co-expression: HR = 2.22, p < 0.01). Conclusions Mesothelin expression and co-expression might be associated with tumor aggressiveness and poor prognosis in patients with endometrial carcinoma. Persons with mesothelin-expressing endometrial cancers present a particularly high medical unmet need.

Co-Expression of Mesothelin and CA125 Is Associated with the Poor Prognosis of Endometrial Serous Carcinoma and Mixed Carcinomas Including Serous Carcinoma

The aim of this study was to investigate the association between the clinicopathologic factors and either expression or co-expression of mesothelin and cancer antigen (CA) 125 in endometrial serous carcinoma and mixed carcinomas including serous carcinoma. Between 1990 and 2017, patients with endometrial serous carcinoma and mixed carcinoma including serous carcinoma treated by total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either expression or co-expression of mesothelin and CA125 was evaluated by immunochemical analysis and the clinico-pathological features were retrospectively examined. Among the 40 patients included, 19, 31, and 18 patients exhibited single positive mesothelin, single positive CA125, and positive co-expression, respectively. The expression of mesothelin and CA125 was observed to be positively associated (p = 0.021). There was no significant association of age and FIGO stage with individual mesothelin or CA125 expression or their co-expression. Overall survival (OS), but not progression-free survivals (PFS), of only mesothelin-positive patients was worse (p = 0.024). Hence, OS and PFS of patients with positive co-expression were worse (PFS: p = 0.043, OS: p = 0.012). In multivariate analysis, single mesothelin expression and single CA125 expression did not lead to worse prognosis. However, positive co-expression was the worst prognostic factor for OS (hazard ratio: 3.32, p = 0.039). Co-expression of mesothelin and CA125 may accurately predict OS in endometrial serous carcinoma and mixed carcinomas including serous carcinoma. Further studies should examine this relationship.

The Haphazard Pattern in Grade-3 Endometrioid Carcinoma Is Associated with Poor Prognosis and Tumor Lymphocyte Infiltration

The aim of this study was to examine the associations among the haphazard invasive patterns, defined as directionless infiltration into the myometrium; expression of key proteins; tumor infiltrative lymphocytes (TILs); and the prognosis of gade-3 endometrioid carcinoma (G3EC). Between 1990 and 2013, patients with G3EC who underwent surgery at our hospital were identified. Invasive patterns were classified into either haphazard, infiltrative, or expansile patterns. The estrogen, progesterone, androgen receptor, cytokeratin 5/6, epidermal growth factor receptor, E-cadherin, snail-2, vimentin, ZEB1, chromogranin A, synaptophysin, MLH1, MSH2, MSH6, and PMS2 levels were evaluated by immunochemical analysis. The degree of strong or weak lymphocyte infiltration (LI) were evaluated using zone formation of LI at the invasive front. Haphazard, infiltrative, and expansile patterns were discovered in 8 (18%), 6 (13%), and 31 (69%) cases, respectively. Cases with the haphazard patterns were diagnosed at a more advanced stage (p < 0.01) and recurred more frequently (p < 0.01). There were statistical differences in progression-free survival (PFS) and overall survival (OS) between the three groups (PFS; p < 0.01: OS; p < 0.01). In multivariate analysis, only the haphazard pattern was found to be an independent, worse prognostic factor of PFS (Hazard ratio (HR) =10.8, p < 0.01) and OS (HR = 23.3, p < 0.01). Furthermore, the haphazard invasive pattern was related with weak LI (p < 0.01) but not with the expression of all proteins analyzed. The haphazard pattern was found to be a worse prognostic factor and was associated with weak LI in G3EC. The aggressive feature of G3EC might be associated with LI but not tumor biology.

Rapid decrease in serum VEGF-A levels may be a worse prognostic biomarker for patients with platinum-resistant recurrent ovarian cancer treated with bevacizumab and gemcitabine

The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with  10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.

Prognostic similarity between ovarian mucinous carcinoma with expansile invasion and ovarian mucinous borderline tumor

Abstract There is a similarity of histological features and survival between ovarian mucinous carcinoma (MC) with expansile invasion and ovarian mucinous borderline tumor (MBT). The aim of this study was to compare the clinical outcomes of MC with expansile invasion with those of MBT based on the 2020 World Health Organization (WHO) criteria. A pathological review was performed on patients with MC, ovarian MBT, and seromucinous borderline tumors that underwent surgery at our hospital between 1984 and 2019. Clinicopathological features were compared retrospectively between MC with expansile invasion and MBT. Among 83 cases of MC, 85 cases of MBT, and 12 cases of seromucinous borderline tumor, 25 MC cases with expansile invasion and 98 MBT cases were included through review. MC cases with expansile invasion were diagnosed with advanced International Federation of Gynecology and Obstetrics (FIGO) stages more frequently (P = .02) than that of MBT cases. In addition, patients with MC with expansile invasion received adjuvant chemotherapy more often (P &lt; .01) than that of patients with MBT. There were no statistically significant differences in recurrence rate (P = .10) between MC with expansile invasion and MBT. Progression-free survival (PFS) was worse in MC cases with expansile invasion than that in MBT cases (P = .01). However, a multivariate analysis for PFS showed that histological subtype, FIGO stage, and adjuvant chemotherapy were not an independent prognostic factor. The prognostic outcome of MC with expansile invasion might mimic those of MBT. These results showed ovarian borderline tumor treatment could be applied to MC treatment.

Diagnostic efficacy of ascites cell block for ovarian clear cell carcinoma

AbstractBackgroundAscites cytology is important for determining the stage and treatment methods for ovarian clear cell carcinoma (CCC) as defined by the 2014 International Federation of Obstetrics and Gynecology classification.MethodsPatients with CCC who underwent surgery at our hospital between January 2012 and December 2019 and who received cytodiagnosis of their ascites using Papanicolaou (Pap) and May–Grünwald–Giemsa (MGG) staining, and cell block methods were identified. The cell block technique was performed using hematoxylin‐eosin (H&amp;E) staining and immunohistochemical staining for hepatocyte nuclear factor‐1β (HNF‐1β), estrogen receptor (ER), progesterone receptor (PR), and Wilms tumor‐1 (WT‐1). Cancer cells of CCC were defined as tumor cells that were positive for HNF‐1β and negative for ER, PR, and WT‐1. The diagnostic accuracy of ascites cytology using Pap and MGG staining and cell block methods was examined.ResultsBased on cytological data, our study included 17 patients: seven (41.1%) with malignant (MAL) ascites, eight (47.1%) with negative for malignancy (NFM), and two (11.8%) with atypia of undetermined significance (AUS) because of a few atypical cells based on Pap and MGG staining. Malignant cells diagnosed by cell blocks were detected in 7/7 patients with MAL ascites based on PAP and MGG staining, 2/8 (25.0%) patients with NFM, and 1/2 (50%) patients with AUS.ConclusionThese findings show that the cell block method combined with the immunohistochemical investigation may be useful for increasing the diagnostic accuracy of malignant cells in CCC.

The worsening impact of programmed cell death ligand 1 in ovarian clear cell carcinomas

To investigate the clinical significance of programmed cell death ligand 1 (PD-L1) expression in ovarian clear cell carcinoma (CCC). Patients with CCC who underwent primary surgery at our hospital between 1984 and 2014 were enrolled in this study. PD-L1 and mismatch repair (MMR) protein expression in tumor cells, tumor-infiltrating lymphocytes (TILs), including cluster of differentiation (CD) 8, CD4, forkhead box P3 (FOXP3), programmed cell death 1 (PD-1), and BAF250a, were evaluated using immunohistochemistry. The association between PD-L1 expression, clinicopathological features, prognosis, and expression of several proteins was investigated. Of the 125 patients with CCC, 17 had negative PD-L1 and 108 had positive PD-L1. Patients with positive PD-L1 expression showed a lower response to chemotherapy (p = 0.01). In addition, patients with positive PD-L1 showed worse progression-free survival (PFS, p = 0.01) and overall survival (OS, p = 0.01) than that in patients with negative PD-L1 expression. Multivariate analyses for PFS and OS showed that PD-L1 expression was an independent prognostic factor for PFS (hazard ratio [HR] 7.81, p < 0.01) and OS (HR 12.90, p < 0.01). PD-L1 expression was not associated with the expression of several TILs or proteins. The expression of PD-L1 was related to a lower response to chemotherapy and worse prognosis in CCC. These results may be useful for the development of new treatments.

Potential efficacy of weekly low-dose administration of bevacizumab as a combination therapy for platinum-resistant ovarian carcinoma: a retrospective analysis

Abstract Background Bevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients. Methods Patients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared. Results Among the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease (p = 0.03) and a lower dose of Bev at the first time during the first cycle administration (p &lt; 0.01) than in group B. Progression-free survival (PFS) was better in group A than in group B (p &lt; 0.01). Multivariate analysis revealed that group A was a better prognostic factor for PFS (hazard ratio 0.53, p = 0.03). Stable duration was longer in group A than in group B (p &lt; 0.01). The incidences of adverse effects, including hematological toxicities such as neutropenia (p = 0.01) and nonhematological toxicities such as hypertension (p &lt; 0.01), intestinal obstruction (p &lt; 0.01), and thromboembolic events (p &lt; 0.01), were lower in group A than in group B. Conclusions Weekly low-dose administration of Bev might improve prognosis and decrease the frequency of adverse effects associated with this drug although the prospective study was needed to get corroboration.

Clinical significance of CD8‐positive lymphocytes on tumor cell clusters of ascites cell block in ovarian high‐grade serous carcinoma

AbstractBackgroundThe clinical significance of CD8‐positive (CD8+) lymphocytes on tumor cell clusters of ascites cell blocks in patients with ovarian high‐grade serous carcinoma (HGSC) was investigated.MethodsAmong HGSC patients who underwent surgery from January 2014 to December 2019, 38 patients with ascites cell block were selected. Using these cell blocks and primary ovarian tumor tissue, the presence of CD8+ lymphocytes and the expression of PD‐L1 were examined immunohistochemically. Tumor cell clusters were defined as cell clumps consisting of more than 10 malignant cells in cell block. Cases with at least one CD8+ lymphocyte in tumor cell cluster were defined as positive CD8+ lymphocytes (Group A); others were defined as negative CD8+ lymphocytes (Group B). The tumor tissue CD8+ lymphocytes were counted mechanically. Clinicopathological features were retrospectively compared between the two groups.ResultsIn total, 38 cases were identified: 25 (65.8%) in Group A and 13 (34.2%) in Group B. More cases in Group A were positive for CD4 (p &lt; 0.01), PD‐L1 (p = 0.02), FoxP3 (p = 0.02) and had a higher number of CD8+ lymphocytes in the tissue (p = 0.03). Patients in Group A had better progression‐free survival (p &lt; 0.01) and overall survival (p = 0.04). In multivariate analysis, Group A was an independent prognostic factor for both progression‐free survival (hazard ratio, 0.24; p &lt; 0.01) and overall survival (hazard ratio, 0.21; p = 0.03).ConclusionThe presence of CD8+ lymphocytes in tumor cell clusters of ascites was associated with the status of immune reaction in the tissue and prognosis in patients with HGSC and might be useful information of the immune‐associated therapy.

Establishment of a Model to Predict the Prognosis of Endometrial Carcinoma Using Tumor‐Infiltrating Lymphocytes Evaluated With Artificial Intelligence: A Retrospective Analysis

ABSTRACT Background The objective of this study was to establish a new model for predicting the prognosis of endometrial carcinoma (EC) using tumor‐infiltrating lymphocytes (TILs) based on artificial intelligence (AI). Methods Patients with EC who were treated between 1989 and 2022 were included in this study. For each patient, one hematoxylin and eosin‐stained slide containing the most invasive frontline of the tumor was selected and digitized. The area within a 500 μm width span, extending 250 μm toward the stroma and tumor from the manually annotated invasive frontline, was automatically annotated. The average number of lymphocytes per area (μm 2 ) in the annotated area was calculated using AI. Patients were classified into the High‐TIL and Low‐TIL groups, and survival analysis was conducted. Four mismatch repair (MMR)‐related proteins were evaluated using immunohistochemical staining. Results A total of 659 patients were included: 346 (52.5%) in the High‐TIL group and 313 (47.5%) in the Low‐TIL group. MMR deficiency was observed more frequently in the High‐TIL group than in the Low‐TIL group ( p  &lt; 0.01). Progression‐free survival (PFS) and overall survival (OS) were better in the High‐TIL group than in the Low‐TIL group (both p  &lt; 0.01). Multivariate analysis revealed that TIL status was a prognostic factor for PFS (hazard ratio [HR] (95% confidence interval [CI]) 0.61 (0.43–0.87); p  &lt; 0.01) and OS (HR (95% CI) 0.54 (0.33–0.86); p  = 0.01). Conclusion TILs evaluated using AI could accurately and significantly predict the prognosis of EC. Further studies are needed to establish new methods for evaluating TILs in ECs.