Tomoyuki Yoshikawa

Clear cell adenocarcinoma associated with clear cell adenofibromatous components: a subgroup of ovarian clear cell adenocarcinoma with distinct clinicopathologic characteristics.

We occasionally encountered clear cell adenofibromatous (CCAF) components coexisting in the ovarian clear cell adenocarcinoma (CCA). To reveal the clinicopathologic significance of CCAF components in CCA, we classified 67 cases of surgically resected CCA into CCA with and without CCAF components [CCAF(+) and (−) groups], and compared clinicopathologic parameters, that is, patient age, clinical stage, the degree of optimal cytoreduction, patient outcome, histologic grade and Ki-67 labeling index of the CCA, and the presence of endometriosis, between these 2 groups. Fourteen cases (21%) and 53 cases were classified as CCAF(+) and CCAF(−) groups, respectively. Of these 14 CCAF(+) cases, the CCAF components with atypia were observed adjacent to the CCAF components without atypia in 10, and adjacent to the obvious CCAs in 13 cases. In comparison with the CCAF(−) group, the CCAF(+) group showed a higher frequency of histologically low-grade tumors [93% (13 of 14) vs. 43% (23 of 53), P=0.0027], a lower Ki-67 labeling index (mean 35.9% vs. 44.0%, P=0.0492), and better patient prognosis (5-year survival 78.8% vs. 49.3%, P=0.0277). Endometriosis was much less frequent in the CCAF(+) group than in the CCAF(−) group [14.7% (2 of 14) vs. 67.9% (36 of 53), P=0.00096]. Multivariate analysis identified only optimal cytoreduction as independent favorable prognostic factor. These results suggest that CCAF besides endometriosis is associated with the development of CCA, and that the CCAF(+) group may be a distinct subgroup of CCA with less aggressive biologic behavior.

Clinical Significance of UDP-Glucuronosyltransferase 1A1*6 for Toxicities of Combination Chemotherapy with Irinotecan and Cisplatin in Gynecologic Cancers

Background: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. Methods: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m2 of irinotecan on days 1, 8 and 15, and 60 mg/m2 of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. Results: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. Conclusion: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

Complete Remission of Metastatic and Relapsed Uterine Cervical Cancers Using Weekly Administration of Bevacizumab and Paclitaxel/Carboplatin

Background: Palliative therapy is usually employed for the treatment of metastatic or relapsed cervical cancer. Many agents including cisplatin have been used for fighting the tumor; however, the gold standard therapy has not yet been confirmed. Case Report: Two cases of recurrent metastatic or refractory cervical cancer successfully treated with weekly administration of bevacizumab (2 mg/kg), paclitaxel (80 mg/m2), and carboplatin (area under the curve (AUC) = 2.0) are presented. 1 course of the therapy consisted of weekly paclitaxel/carboplatin on days 1, 8, and 15 and weekly bevacizumab on days 1, 8, 15, and 21, q28 days. Complete remission was observed after 3–4 courses of the therapy. Hematologic and non-hematologic toxicities higher than grade 3 were not observed during the chemotherapy. In both cases, there was no evidence of disease more than 10 months after the therapy. Conclusions: Weekly administration of bevacizumab and paclitaxel/carboplatin has potential activity in recurrent, metastatic, and refractory cervical carcinomas. These findings warrant further trials in such clinical settings.

Clear cell adenocarcinoma with a component of poorly differentiated histology: a poor prognostic subgroup of ovarian clear cell adenocarcinoma.

In this study, we aimed to determine whether the presence of poorly differentiated histologic components in ovarian clear cell adenocarcinoma (CCA) affects patient prognosis. Pathologic slides from 159 patients with CCA were studied, and the tumors were classified as Por(+) in the event of poorly differentiated histology; that is, if solid masses or cords, or individual infiltrating tumor cells with little or no glandular/papillary differentiation were present in >5% of the tumor area examined. All other tumors were classified as Por(−). The prognostic value and interobserver reproducibility of this assignment were analyzed. The agreement level in the assignment between 2 pathologists was 93.7% (&kgr;=0.86). After a consensus was reached, 53 (33%) and 106 (67%) tumors were classified as Por(+) and Por(−), respectively. Patients with Por(+) tumors showed a significantly worse outcome than those with Por(−) tumors, both in the early stages (stages I/II, 5-year survival rate 53.9% vs. 96.3%, P<0.0001 by log-rank test) and advanced stages (stages III/IV, 5-year survival rate 26.5% vs. 49.2%, P<0.001 by generalized Wilcoxon test). Por(−) tumors showed an effective response to postoperative platinum-based first-line chemotherapy more frequently compared with Por(+) tumors (48% vs. 14%, P=0.042). The Por(+) tumor was found to be an independent prognostic factor for survival irrespective of the clinical stage or presence of residual tumor after the initial surgery. These results suggest that the tumor with a poorly differentiated histology is an adverse prognostic subgroup in ovarian CCA. On the basis of the prognostic impact and interobserver reproducibility, the present binary classification system for CCAs was deemed to be highly superior to the compared conventional histologic grading system.

Histological grading of ovarian clear cell adenocarcinoma: proposal for a simple and reproducible grouping system based on tumor growth architecture.

In this study, we aimed to develop a histological grading system for ovarian clear cell adenocarcinoma (CCA), based on the tumor growth architectures. Cases were defined as Group A if ≥90% of a tumor examined was composed of well-differentiated tubulocystic and/or papillary architectures; Group C if at least 10% of the tumor was composed of very poorly differentiated histology (i.e. solid masses or individual infiltrating tumor cells with no or little glandular/papillary differentiation); and tumors not corresponding to the first 2 descriptions were defined as Group B. The interobserver reproducibility and prognostic value of the assigned groups were analyzed for 159 CCAs from 5 institutions. The level of agreement in assigning the groups between 2 pathologists was 88.7% (=0.82). After consensus was reached, 46 (29%), 79 (50%), and 34 (21%) tumors were classified in Groups A, B, and C, respectively. In early-stage cases [International Federation of Gynecology and Obstetrics (FIGO) stage I–II], Group A tumors had significantly better outcomes (100% 5-yr survival) than Group B tumors (82% 5-yr survival, P=0.024 by log-rank test) or Group C tumors (56% 5-yr survival, P=0.00054 by log-rank test). Moreover, early-stage Group B tumors had significantly better outcomes than Group C tumors (P<0.001 by a generalized Wilcoxon test). In advanced cases (FIGO stage III–IV), Group A tumors had significantly better outcomes than Group C tumors (52% vs. 16% 5-yr survival, respectively, P=0.043). Group A and C tumors defined with our system were identified to have favorable and unfavorable prognostic factors, respectively, independent of the clinical stage of the disease and presence of residual tumors after the initial surgery. The proposed grouping system could divide patients with CCA into 3 subgroups with distinct prognostic indications, providing a 3-tier histological grading system for ovarian CCA.

Is there any predictor for hypersensitivity reactions in gynecologic cancer patients treated with paclitaxel-based therapy?

PurposeRecently, generic drugs of paclitaxel have been commonly used mainly by economic reasons; however, predictive factors for toxicities are not fully determined. Hypersensitivity reaction (HSR) is one of the most important adverse events in the paclitaxel-based therapy, and sometimes leads to lethal condition. The aim of the study was to identify predictors for HSR in patients treated with paclitaxel-based regimens.MethodsAll the patients treated with chemotherapy including paclitaxel at our hospital between 1998 and 2013 were retrospectively evaluated. Clinicopathological factors of the patients that developed HSR and those without HSR were compared, and predictive factors for HSR were identified.ResultsAmong 414 patients enrolled in the study, 26 patients (6.3%) developed HSR. Multivariate analyses showed that younger age (odds ratio 6.31), a history of allergy (odds ratio 3.79), and short-course premedication (odds ratio 14.1) were identified as predictive factors for HSR. There was no significant difference in the incidence of HSR between original paclitaxel and generic drug. The incidence of HSR was higher as the number of these predictors was accumulated.ConclusionsThree factors were identified as predictive factors for HSR: younger age, a history of allergy, and short-course premedication. Accumulation of these factors increased the incidence of HSR; however, the use of generic drug was not associated HSR in gynecologic cancer patients.

JAK2/STAT3 pathway as a therapeutic target in ovarian cancers

The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.

Seromucinous component in endometrioid endometrial carcinoma as a histological predictor of prognosis

Objective In 2014 World Health Organization criteria, seromucinous carcinoma was defined as a new histological subtype in ovarian carcinomas, but “seromucinous carcinoma” was not defined in endometrial carcinomas. The aim of this study was to identify seromucinous carcinoma resembling ovarian seromucinous carcinoma in endometrial carcinomas, and to evaluate the clinical significance for prognoses of the patients. Methods Central pathological review was conducted for patients with endometrioid carcinoma of the endometrium treated by primary surgery at our hospital between 1990 and 2013. Results Among 340 cases included in the study, no case had all tumor cells resembling ovarian seromucinous carcinoma in all specimens, and 31 cases (9.1%) had seromucinous component in combination with endometrioid carcinomas. Immunohistochemical analysis revealed seromucinous component had positive reactivity for cytokeratin (CK) 7, and negative reactivity for CK20 and caudal type homeobox 2 (CDX2) in all cases. Seromucinous component showed lower immunoreactivity of estrogen receptor and progesterone receptor, compared with endometrioid carcinoma component. Progression-free survival of the cases with seromucinous component was better than those without seromucinous component (p=0.049). Conclusion Seromucinous component was identified in approximately 10% of endometrioid carcinoma, and could be a histological predictor for prognosis.

Inhibition of autophagy protein LC3A as a therapeutic target in ovarian clear cell carcinomas.

Objective Ovarian clear cell carcinoma (CCC) is one of histological subtypes showing poor prognosis due to chemoresistance. The association of autophagy-related proteins and clinical implementation in CCC has not been determined. Methods The present study investigated whether expression of autophagy-related protein, light chain 3A (LC3A), was related with prognoses in the patients with CCC using immuno-histochemical stainings, and whether inhibition of autophagy modified the sensitivity to cisplatin in CCC cells in vitro. Results High expression of autophagy-related protein, LC3A, was detected in 78 cases (78%) in all CCC cases. The patients with high LC3A expression showed significantly lower response rate to primary chemotherapy (17% vs. 100%, p<0.010), and had worse progression-free survival (PFS) and overall survival (OS) compared with those with LC3A low expression. Furthermore, multivariate analyses revealed that high expression of LC3A was identified as independent worse prognostic factors for PFS and OS. Inhibition of autophagy protein LC3A using hydroxychloroquine (HCQ) increased sensitivity to cisplatin in CCC cells in vitro. Conclusion High expression of LC3A proteins was associated with lower response to platinum therapy, leading to worse prognoses in CCC. Although further studies are needed to confirm the results, inhibition of autophagy by HCQ was associated with platinum sensitivity. Autophagy protein LC3A could be a promising target for treatment for CCC.

Indispensability of UGT1A1^*6 genotyping in Japanese cancer patients treated with irinotecan

We would like to congratulate Onoue and colleagues [1] for their excellent article on investigation of the relationship between severe neutropenia and UGT1A1 and SLCO1B1 polymorphisms. In the article, they suggested that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients. The significance was observed in not only UGT1A1*6 ?/? patients but also UGT1A1*6 ?/cases. Odds ratios were surprisingly high; 5.19 in UGT1A1*6 ?/cases and 7.63 in UGT1A1*6 ?/? cases. A metaanalysis of nine Euro-American studies revealed that frequency of grades III and IV hematologic toxicities increased in the patients with UGT1A1*28 ?/? genotype at a high doses of irinotecan [2]. At lower doses (B150 mg/m), the risk of hematologic toxicity in patients with UGT1A1*28 ?/? genotype was not statistically significantly different from that among patients with UGT1A1*28 ?/or UGT1A1*28 -/genotype [2]. Taking account of the results, it seems appropriate that genotyping of UGT1A1*28 could be omitted for the patients treated at a low dose of irinotecan in western countries. On the other hand, the significant contribution of UGT1A1*6 ?/to grades III and IV neutropenia and diarrhea was also clearly observed in Japanese prospective multi-institutional analysis for gynecologic patients treated with a low dose of irinotecan (60 mg/m, 3 weeks on and 1 week off) and cisplatin [3]. The UGT1A1*6 ?/genotype was identified as an independent risk factor for grades III and IV neutropenia (hazard ratio = 6.54), and grades III and IV diarrhea (hazard ratio = 7.45). We are so surprised to see almost the same odds ratio for severe neutropenia in heterogeneously treated cohort with irinotecan [1] as in our homogeneously treated cases [3]. It is noteworthy that severe toxicities in UGT1A1*6 ?/cases were observed in two separate studies, even at a low dose of irinotecan. Recently in Japan, genotyping of UGT1A1*28 and *6 has been approved by the Japanese Organization of the Ministry of Health, Labor and Welfare; however, there exists an argument against routine use of UGT1A1 genotype testing for the patients who will be treated with irinotecan. It is true that UGT1A1 genotyping is not a magic tool to certify no toxicities caused by irinotecan, as there are some cases that experience severe toxicities in UGT1A1 wild-type cases. We would emphasize that one half of the cases who experienced grade III–IV neutropenia were treated at a lower dose of irinotecan and increasing doses of irinotecan were not related with increase toxicities in the analysis by Onoue and colleagues [1]. On the contrary, a report on a Japanese population suggested the metabolic ratios were variable according to administrated dose of irinotecan in patients with homozygosity of UGT1A1*6 or heterozygosity of UGT1A1*6 [4]. Thus, dose matters of irinotecan have been unresolved in Japanese patients with different frequency of UGT1A1*28 and *6 from western patients. Together, the utility of M. Takano (&) M. Kato T. Yoshikawa T. Goto K. Furuya Department of Obstetrics and Gynecology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan e-mail: mastkn@ndmc.ac.jp