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Objective To investigate the clinical characteristics of women with Stage I primary mucinous epithelial ovarian carcinoma (mEOC) and evaluate the impact of uterus-preserving surgery (UPS) in terms of survival prognosis. Methods A regional multi-institutional retrospective study conducted between January 1986 and March 2017 by reviewing records of the Tokai Ovarian Tumor Study Group. Clinical and pathologic data and survival outcomes were assessed for women with Stage I primary mEOC. The baseline imbalance between women with and those without UPS was adjusted by an inverse probability of treatment weighting method using the propensity score (PS) of independent clinical variables. Results Among 4730 women with malignant ovarian tumors, 185 had Stage I primary mEOC and were included in the study. The mean age was 47.6 years (range 12-87 years), and 56 (30.3%) women underwent UPS. After PS-based adjustment, women in the UPS group did not have a poorer prognosis regarding overall survival (P=0.776) or recurrence-free survival (P=0.683). Even after age stratification, there was no statistical difference in survival outcomes between the UPS and non-UPS groups. Conclusion UPS was not associated with decreased survival and may be a treatment option for women with Stage I primary mEOC irrespective of age.

Background Long-term follow-up reports of low-grade endometrial stromal sarcoma (LGESS) including its clinical course and pathological data are rare. We previously reported the case of a Japanese woman diagnosed with LGESS, who was treated with multidisciplinary therapy. She had been suffering from uterine cervical tumor diagnosed as cervical polyps, or fibroid in statu nascendi, since 24 years old. The patient had survived for 25 years with the disease. This report presents her progress and pathological change since the previous report. Case presentation At age 45, the patient experienced a relapse of the remnant LGESS tumor between the right diaphragm and liver. Although chemotherapy was not effective, the tumor was eliminated by proton therapy. At age 46 years, the remnant tumors outside the irradiated field were resected. The disease was originally diagnosed as “neuroendocrine carcinoma (NEC)” using the surgical specimen. Therefore, cisplatin and irinotecan combination chemotherapy were administered to treat the remnant dissemination. After 4 cycles of chemotherapy, the liver metastases had enlarged and were resected surgically. Consequently, no remnant tumor was visible in the abdominal cavity at the end of the surgery. To determine the origin of NEC, we examined the previously resected specimens obtained from her ileum at age 40 years. A boundary between the LGESS and neuroendocrine tumor grade 2 (NET G2)-like lesion was found in the tumor, indicating that the origin of these tumors was LGESS. After less than 2 years of chemotherapy and undergoing surgery, a relapse of the tumor in the liver induced biliary duct obstruction with jaundice, which was treated with endoscopic retrograde biliary drainage. Although pazopanib prolonged her life for 10 months, she died from sepsis at age 49 years, which was caused by the infection that spread to the liver metastatic tumor via the stented biliary ducts. Autopsy revealed adenocarcinoma-like differentiation of the tumor. Conclusion This LGESS patient has survived for a long time owing to multidisciplinary treatment including proton therapy. The LGESS tumor differentiated to NET G2-like tissue and then further to adenocarcinoma-like tissue during the long-term follow-up.

Background The aim of this study was to investigate how much the risks of recurrence and death are increased as a consequence of selecting fertility-sparing surgery (FSS) in young women with epithelial ovarian cancer (EOC). Methods After a central pathological review and search of the medical records from 14 collaborating hospitals, a non-randomized, observational cohort study was conducted between 1987 and 2015, including 1183 women with stage I EOC. Finally, a total of 285 patients with stage I EOC at reproductive age were recruited. Oncologic outcomes were compared between the FSS (N = 101) and radical surgery (RS) group (N = 184) using a propensity score (PS)-matching technique to adjust for relevant risk factors: the age, substage, histological type, grade, CA125 values, ascites cytology, ascites volume, and chemotherapy. Results During 66.0 months (median) of follow-up, 42 patients (14.7%) developed recurrence, and 31 patients (10.9%) died. In the original cohort, there was no significant difference in overall survival (OS) or recurrence-free survival (RFS) between the FSS and RS groups {Log-rank: OS (P = 0.838), RFS (P = 0.377)}. In the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in RFS or OS between the FSS and RS groups {RFS (FSS vs. RS), HR: 1.262 (95% CI: 0.559–2.852), P = 0. 575; OS (FSS vs. RS), HR: 1.206 (95% CI: 0.460–3.163), P = 0.704}. Conclusions After adjustment for clinicopathologic factors, FSS in itself may not worsen the oncologic outcome in young women with early-stage EOC. A large-scale clinical study is necessary to validate the findings.

Fertility-sparing surgery (FSS) has mainly been chosen for young women with ovarian-confined/well-differentiated epithelial ovarian cancer (EOC). In general, FSS consists of at least conservation of contralateral ovary and the uterus with a staging surgery. However, information on the clinical outcome in women who underwent cystectomy as a fertility-preserving option is lacking. After a central pathological review and search of the medical records from multiple institutions between 1987 and 2015, a total of eight early-stage EOC patients treated with cystectomy as FSS were retrospectively evaluated. Diagnosis and staging were based on International Federation of Gynecology and Obstetrics criteria (2014). Surgery consisted of uni- or bilateral cystectomy. The oncologic and reproductive outcomes were assessed. The median age was 29 years (range 26–38 years). The median follow-up time was 103.6 months (range 42.2–218.3 months). The stage was IA in 3, IC1 in 4, and IC3 in one patient. Five patients received adjuvant chemotherapy. After cystectomy, two patients experienced recurrence in the pelvic cavity and bilateral ovaries, respectively. The former patient died of the disease 42 months after cystectomy, and conversely, the latter one was rescued by subsequent radical surgery. Four full-term childbirths were observed in three patients. Although oophorectomy is considered as an appropriate fertility-preserving operation, cystectomy may be an unavoidable option when it is the only surgical procedure available. It is desirable to verify the utility by accumulating larger numbers of patients through a future registry system.

Objective Sex cord-stromal tumours of the ovary are relatively uncommon neoplasms that account for 3 % of all ovarian cancers. Uterine preservation with careful staging is achievable; however, conservative surgery remains controversial. This study examined the prognostic effects of uterine preservation in patients with stage I sex cord-stromal tumours. Study design This retrospective cohort study was undertaken between January 1986 and February 2019, and the clinicopathological data of 4897 women with malignant ovarian tumours were collected. Seventy-seven patients with stage I sex cord-stromal tumours were eligible for inclusion. The characteristics and survival outcomes of these patients were examined. To investigate the prognostic effects of uterine-preserving surgery, baseline imbalances between patients with and without uterine-preserving surgery were adjusted using an inverse probability of treatment weighting with propensity scores composed of independent clinical variables. Results The mean ages of patients in the uterine-preserving surgery and non-uterine-preserving surgery groups were 39.8 and 57.8 years, respectively. After inverse probability of treatment weighting adjustments, no significant differences in overall survival (p = 0.205) or recurrence-free survival (p=0.071) were observed between the uterine-preserving surgery and non-uterine-preserving surgery groups. Estimated 10-year overall survival rates were 98.7 % in the uterine-preserving surgery group and 95.9 % in the non-uterine-preserving surgery group, and 10-year recurrence-free survival rates were 87.2 % in the uterine-preserving surgery group and 78.2 % in the non-uterine-preserving surgery group. Uterine-preserving surgery did not significantly affect the site of tumour recurrence. Conclusion Uterine-preserving surgery may be a feasible surgical option for patients with stage I sex cord-stromal tumours. Further research is needed to guarantee prognostic accuracy and develop effective therapeutic approaches for sex cord-stromal tumours.

Background The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. Methods We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P = 0.696) and recurrence-free survival (P = 0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. Conclusions The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

Endometrial clear-cell carcinoma (ECC) is relatively rare. The expression of diagnostic markers in this disease is similar to that of clear-cell carcinoma, but the molecular carcinogenic events and therapeutic targets are mostly unknown. MET gene amplification has been reported in various cancers, including ovarian clear-cell carcinomas; however, the MET gene status has not previously been examined in ECC. We performed real-time quantitative PCR (QPCR) and fluorescence in situ hybridization (FISH) to analyze the MET gene statuses of 12 ECC cases. We found MET amplifications in two cases (2/12; 16.7%) by both methods. Of the 12 cases, 9 were pure clear-cell carcinomas, and 3 were mixed types that included mixes with endometrioid carcinomas in 2 cases, and the remaining case was a heterologous-type carcinosarcoma that primarily consisted of a clear-cell carcinoma component and a scarce chondrosarcoma component. Both of the MET amplification cases were mixed; one contained endometrioid features, and the other chondrosarcoma features. This is the first report to analyze the statuses of the MET gene in ECCs, and the two mixed cases exhibited amplifications that are shared with ovarian clear-cell carcinomas. Further studies with larger numbers of cases are necessary to reveal the relationship between ECC and MET amplification.

The objective of this study was to estimate the frequency of possible occult metastasis through long-term survival analyses in patients with clear cell carcinoma (CCC) who had undergone complete resection. During the period of 1990-2015, 799 patients with stage I-IV CCC were identified in the TOTSG database. Of these, a total of 528 patients without a residual tumor were enrolled in the study and classified into four groups: Group 1: FIGO stage IA-IB (N=104), Group 2: FIGO stage IC1 (N=170), Group 3: FIGO stage IC2/IC3 (N=98), and Group 4: FIGO stage II-III (no residual tumor: N=156). Cumulative incidences of recurrence (CIR) and death (CID) were examined. The median age was 54, ranging from 29-87. The 5-year CIR / CID of each group were as follows: Group 1 (7.3% / 3.8%), Group 2 (14.3% / 10.2%), Group 3 (37.7% / 18.4%), and Group 4 (46.5% / 33.8%), respectively {P

Occasionally, ovarian tumors are found to have originated from non-ovarian organs as metastatic lesions since the ovary is a common site of metastasis from many cancers. The aim of the current study was to estimate the long-term oncologic outcome of patients with metastatic mucinous ovarian carcinoma (MmOC) in comparison with those with primary mucinous ovarian carcinoma (PmOC) at an advanced stage. The data of one hundred and sixty-seven patients with mucinous ovarian cancer, including 91 patients with MmOC from the digestive organs and 76 patients with stage III–IV PmOC, were retrospectively analyzed. The prognostic significances of clinicopathologic factors were evaluated employing both uni- and multivariable analyses. Pathological slides were evaluated based on centralized pathological review. The median age of patients with PmOC and MmOC was 55 (18–81) and 51 years (30–82), respectively. With follow-up of a total of 167 patients, 145 patients (86.8%) developed recurrence. In addition, 122 patients (73.0%) died of the disease. Regardless of the residual tumor status, patients with PmOC did not a show a significantly poorer OS than those with MmOC. Furthermore, in a Cox multivariable hazard model, after adjustment for various clinicopathologic confounders, a gastric cancer (GC)-originated tumor and larger residual tumor were significant predictors of poorer OS [GC (vs. PmOC): HR (95% CI) 2.205 (1.303–3.654), P = 0.0036]. The oncologic outcome of patients with MmOC was extremely poor; however, it was almost the same as that of those with PmOC. We should recognize MmOC derived from gastric carcinoma as a highly aggressive malignancy.

ObjectiveComplete tumor resection is considered essential in the management of patients with ovarian clear-cell carcinoma. There is a debate regarding whether patients with recurrent ovarian clear-cell carcinoma benefit from secondary cytoreductive surgery.MethodsDetails of patients with clear-cell carcinoma were collected by the Tokai Ovarian Tumor Study Group (Nagoya University Hospital and 13 affiliated institutions) and evaluated between January 1990 and December 2015. Histology was confirmed after central pathological review. The primary endpoint of the study was disease-free survival after secondary cytoreductive surgery. Distributions of events were evaluated using the χ2 test. Survival analysis was based on the Kaplan-Meier method. Survival curves were compared using the log-rank test. A value of pResultsA total of 169 patients who underwent secondary cytoreductive surgery (N=25) or medical management (N=144) for recurrent clear-cell carcinoma were collected. The median age for patients undergoing secondary cytoreductive surgery was 50 years (range 35–66). Overall, 18 patients had complete resection. In patients who underwent secondary cytoreductive surgery, the median disease-free and post-recurrence survival periods were 10.9 months and 21.2 months, respectively. Moreover, among 18 patients who underwent complete resection, seven showed no evidence of disease during the observation periods. The median post-recurrence survival periods of patients with complete or incomplete resection were 30.1 months and 10.4 months, respectively (p=0.002). On stratification by the recurrence site, patients with intraperitoneal recurrence showed poorer post-recurrence survival than those with recurrence at other sites (p=0.016). However, comparison between the secondary cytoreductive surgery group versus the medical management group showed there was no difference in post-recurrence survival, even when considering complete tumor resection (p=0.114).ConclusionPatients with intraperitoneal recurrence or incomplete tumor resection had the worst survival after secondary cytoreductive surgery.

Background The influence of capsule rupture on patients’ oncologic outcome has been controversial in early-stage ovarian carcinoma. The aim of this study was to investigate the significance of the capsule status in early-stage patients with mucinous epithelial ovarian carcinoma (mEOC). Patients and methods During the period of 1990–2015, 351 patients with stage I-IV mEOC were identified in the multicentric database. Of these, a total of 194 mEOC patients with a stage I tumor were in the study. Results The median follow-up of the surviving patients was 67.6 (2.0–248.1) months. The FIGO stage distribution was IA in 85 (43.8%), IB in 2 (1.0%), IC1 in 58 (29.9%), IC2 in 18 (9.3%), and IC3 in 31 (16.0%). The 5-year overall survival (OS) rates in patients with stage IA-B, IC1, and IC2-3 tumors were 95.8, 82.5, and 82.9%, respectively {IA-B vs. IC1: P = 0.0031, IA vs. IC2-3: P = 0.0042}. Similarly, the 5-year recurrence-free survival rates in patients with stage IA-B, IC1, and IC2-3 tumors were 93.5, 73.0, and 79.2%, respectively (Log-rank: P = 0.0034). Among all patients, 104 received adjuvant chemotherapy and 90 did not. There was no significant difference in each substage group between the non-chemotherapy and chemotherapy groups in the 5-year overall survival rate {chemotherapy (yes vs. no): 87.0 vs. 90.3%: P = 0.5389}. Multivariate analysis demonstrated that the capsule status was a significant prognostic factor for OS {IA-B (referent) vs. IC1: HR (95% CI): 3.527 (1.125–12.568), P = 0.0300)}. Conclusion mEOC patients staged greater than IC1 show a marked risk of mortality even after postoperative chemotherapy.

Aims To determine versican-producing cells in normocellular bone marrow and to evaluate chronological alteration in the number of versican-producing macrophages in bone marrow of patients with acute myelogenous leukaemia (AML) after cord blood stem cell transplantation (CBSCT) to gain insight in the significance of versican in recovery of haematopoiesis. Methods We enrolled seven age-matched unrelated patients with normocellular bone marrow for determining versican-producing cells in bone marrow, CBSCT-treated patients with AML, 18 with fine and other four with poor engraftment, for determining chronological alteration of versican-expressing and CD68-expressing cells in transplanted bone marrow in reference to the total cells. Clot samples of patients with AML were collected from the +16 to +55 day after transplantation and separated into four groups. We included an AML case whose specimen was obtained on the +9 day. Cells positive in immunohistochemistry using antibodies to versican and CD68 were counted to obtain the mean±SD in a unit area of the bone marrow, plotted chronologically and compared with the numbers from the age-matched normocellular group. Results We determined by a double immunohistochemistry that the versican-expressing cells in bone marrow are macrophages. The time-course curve demonstrated an inverse relationship between the versican-positive macrophages and the total cells in the transplanted bone marrow for over 55 days. In bone marrow of poor engraftment cases, versican-positive macrophages appeared to be decreased in comparison with age-matched and sampling day-matched patients. Conclusions These results suggest that versican and/or versican-expressing macrophages positively contribute to bone marrow regeneration of patients with AML after CBSCT.

Background: Patients with FIGO stage IV epithelial ovarian carcinoma have a poor but non-uniform prognosis. This study aimed to compare the survival of patients with serous or endometrioid tumours (S/E) and clear cell or mucinous tumours (non-S/E). Methods: Data for 223 patients who underwent surgery between 1987 and 2010 and were diagnosed by centralized pathology review and were retrospectively analysed. The patients included 169 with S/E tumours and 54 with non-S/E tumours. Results: The median overall survivals (OSs) of the S/E and non-S/E groups were 3.1 and 0.9 years, respectively (P

Endometrial clear-cell carcinoma (ECC) is relatively rare. The expression of diagnostic markers in this disease is similar to that of clear-cell carcinoma, but the molecular carcinogenic events and therapeutic targets are mostly unknown. MET gene amplification has been reported in various cancers, including ovarian clear-cell carcinomas; however, the MET gene status has not previously been examined in ECC. We performed real-time quantitative PCR (QPCR) and fluorescence in situ hybridization (FISH) to analyze the MET gene statuses of 12 ECC cases. We found MET amplifications in two cases (2/12; 16.7%) by both methods. Of the 12 cases, 9 were pure clear-cell carcinomas, and 3 were mixed types that included mixes with endometrioid carcinomas in 2 cases, and the remaining case was a heterologous-type carcinosarcoma that primarily consisted of a clear-cell carcinoma component and a scarce chondrosarcoma component. Both of the MET amplification cases were mixed; one contained endometrioid features, and the other chondrosarcoma features. This is the first report to analyze the statuses of the MET gene in ECCs, and the two mixed cases exhibited amplifications that are shared with ovarian clear-cell carcinomas. Further studies with larger numbers of cases are necessary to reveal the relationship between ECC and MET amplification.

Objectives We reviewed the clinical outcomes of patients with early-stage epithelial ovarian cancer (EOC) who had undergone fertility-sparing surgery (FSS) to assess recurrence-free survival (RFS). Study design After central pathological review and scanning of the medical records of multiple institutions, a total of 94 patients with stage I EOC (IA: 43 and IC: 51) treated with FSS were analyzed. IC substages were defined as follows: intraoperative spillage (IC1), preoperative capsule rupture or surface invasion (IC2), and positive cytology results (IC3). Results The median age was 30.5 (13–40) years. The median follow-up time was 66.6 months. Fourteen patients (14.9%) showed carcinoma recurrence. Eleven (11.7%) patients died of the disease. The total 5-year RFS rate including all women who received FSS was 84.3%. There was no significant difference in RFS between patients with IC1 and those with stage IA ( P =0.9411). In contrast, the RFS rate of patients with IC2/3 was significantly poorer than in patients with stage IA (IA vs. IC2/3: P =0.0487, IC1 vs. IC2/3: P =0.0471). In further analyses according to each histological type and grade, the RFS rate of subjects with the mucinous type was the same as that of those with a clear-cell histology ( P =0.3350). There was a significant difference in RFS of patients with grade 1 (G1) and G2–3 ( P =0.0004). To eliminate selection bias from a number of clinicopathologic factors as thoroughly as possible, the age, FIGO stage, histological type, grade, and postoperative adjuvant chemotherapy were entered into multivariate RFS analyses. Cox multivariable analysis showed that the substage group and grade were independent prognostic factors for RFS. Conclusions Confined to young women with intraoperative rupture, FSS may be proposed, if without tumor-associated dense adhesion. However, those with preoperative rupture, surface invasion, and positive cytology showed a greater risk of recurrence, suggesting that they are not recommended candidates. Although patients with G2–3 tumors showed a poorer prognosis than those with G1, the number of these subjects was so small that the current results should be reconfirmed in the next study.

Ovarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell-cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression-free survival rates of the CBX7-positive patients were significantly shorter than those of the CBX7-negative patients (p < 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that cell viability was significantly reduced compared to the control cells (p < 0.001). Expression microarray analysis revealed that apoptosis-related genes, particularly tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p < 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL-induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy.

Objective: To evaluate the expression of antibodies against calretinin, cytokeratin 5/6, desmin, D2-40, HBME-1, mesothelin, thrombomodulin, WT1, Ber-EP4, CEA, EMA and MOC-31 individually and to compare it with a new rapid procedure for fluorescence immunocytochemistry (ICC) using liquid-based cytology (LBC). Study Design: Sixty-four peritoneal cell specimens prepared with the LBC method were stained with these markers to evaluate their usefulness and develop a rapid fluorescence immunostaining method using Ber-EP4 that is applicable to intraoperative cancer cytodiagnosis. Results: The adenocarcinoma markers were positive in 92% of adenocarcinoma cases, 57% of cases with suspicion of adenocarcinoma, and 5% of negative cases (reactive mesothelial cells). On the other hand, the mesothelial cell markers were positive in 8-15% of adenocarcinoma cases, 43-57% of cases with suspicion of adenocarcinoma, and 93-95% of negative cases. The rapid new fluorescence ICC procedure clearly stained only the adenocarcinoma cells within 20 min. Conclusion: Immunocytochemical examination with the LBC method is a powerful ancillary technique for discriminating adenocarcinoma cells from mesothelial cells. This rapid new fluorescence ICC procedure can be used as an ancillary technique for accurate detection of adenocarcinoma cells in the intraoperative cytological examination of peritoneal or pleural washing fluid.

This study was conducted to assess the long-term clinical outcome for patients with recurrent mucinous epithelial ovarian cancer (RmOC) in comparison with recurrent serous epithelial ovarian cancer (RsOC). Three hundred and eighty-four patients with recurrent ovarian cancer, including 340 RsOC and 44 RmOC patients, were analyzed in this study. The pathological slides were evaluated under central pathological review. The prognostic significance of clinicopathological factors was evaluated employing both uni- and multivariable analysis. The 3- and 5-year postrecurrence survival (PRS) rates of patients with RmOC were 17.3, and 6.9 %, respectively. In contrast, those of patients with RsOC were 29.8 and 18.8 %, respectively. The PRS of patients with RmOC was significantly poorer than that of patients with RsOC (PRS: P = 0.0006). Moreover, either in the presence or absence of a residual tumor (RT) at initial surgery, the PRS of patients with RmOC was markedly poorer than that of patients with RsOC [RT (−): P

Background: To examine the difference in the survival of patients with recurrent ovarian cancer who received fertility-sparing surgery (FSS) and those receiving radical surgery. Methods: Clinicopathologic data on a total of 90 patients with stage I recurrent ovarian cancer collected under the central pathological review system were subjected to survival analyses. Patients were divided into 2 groups: 1) FSS (N = 11), 2) Radical (N = 79). Results: Five-year overall survival rates of patients in the two groups were as follows: 40.8% (FSS)/44.2% (Radical), respectively. There was no significant difference in overall survival among the groups (P = 0.887). Additionally, three-year postrecurrence survival rates of patients in the two groups were 24.8% (FSS) and 25.3% (Radical) (P = 0.730). Furthermore, we accumulated 137 patients {FSS (N = 58), Radical group (N = 79)} with stage I recurrent ovarian cancer from the current study and six representative reports in the literature. Patients who experienced recurrence in the remaining ovary alone (FSS) showed a more favorable prognosis than those who had extra-ovarian site recurrence (overall survival: P = 0.021, postrecurrence survival: P = 0.069). Conclusions: Although our retrospective analysis was very preliminary, we could propose the hypothesis that patients with stage I recurrent ovarian cancer who undergo FSS may not show poorer survival rates than patients who receive radical surgery.

Aim: The effect of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced epithelial ovarian cancer (aEOC) who are optimally debulked. Material and Methods: Demographic and clinicopathologic data were obtained from the Tokai Ovarian Tumor Study Group between 1986 and 2009. All patients were divided into two groups. Group A (n = 93): (i) patients did not undergo SRL; and (ii) lymph node exploration or sampling was optional. Group B (n = 87): patients underwent SRL. Survival curves were calculated using the Kaplan–Meier method. Differences in survival rates were analyzed using the log–rank test. Results: All pT3–4 aEOC patients were optimally debulked (residual tumor

Objective We analyzed a large number of stage I clear cell carcinoma of the ovary (CCC) patients to estimate the survival impact of the capsule status in stage I CCC patients, particularly in comparison with non-CCC patients. Methods Clinicopathologic data on 564 patients with stage I epithelial ovarian cancer (EOC) collected under the central pathological review system were subjected to uni- and multivariable analyses to evaluate the disease-free survival (DFS) and overall survival (OS). Results There was no significant difference in both the OS and DFS of CCC patients between IA and IC(ir) (intraoperative capsule rupture) {IA vs. IC(ir); OS: P =0.1402, DFS: P =0.2701}. In contrast, CCC patients at IC(non-ir) {IC excluding for IC(ir), such as preoperative capsule rupture, positive ascites/washing, and surface involvement} showed a poorer OS and DFS than those at IC(ir), or those at the corresponding stage in non-CCC. In multivariable analysis, the capsule status was an independent prognostic factor of a poor OS and DFS {OS: HR, 2.832; 95% CI 1.156–6.938; P =0.023; DFS: HR, 4.327; 95% CI, 1.937–9.667; P =0.0004)} {In contrast, non-CCC: N.S. (OS/DFS)}. Furthermore, in CCC patients, intraperitoneal recurrences were more frequently observed in IC(non-ir) CCC than IA or IC(ir) CCC ( P =0.0083) {In contrast, non-CCC: N.S. }. Conclusion This study suggests that CCC patients other than those with intraoperative capsule rupture show a considerable risk for mortality despite adjuvant chemotherapy.

Background: Clear-cell carcinoma of the ovary (CCC) is often diagnosed at childbearing age, or sometimes during treatment for infertility. Therefore, most young women with early-stage CCC wish to preserve their reproductive and endocrine functions if possible. Methods: Clinicopathologic data collected under the central pathological review system were subjected to survival analyses. We analyzed patients with stage I CCC who underwent fertility-sparing surgery (FSS, n = 16) and compared their long-term survival with those receiving radical surgery (n = 205), or patients with non-CCC undergoing FSS (n = 64). Results: There was no difference in both the overall survival (OS) and disease-free survival (DFS) between patients with CCC who underwent FSS and those who received radical surgery [CCC/FSS (n = 16) versus CCC/radical (n = 205); OS: P= 0.519, DFS: P= 0.265]. Moreover, patients with CCC who underwent FSS did not show a poorer OS and DFS than non-CCC patients who underwent FSS (CCC/FSS versus non-CCC/FSS; OS: P= 0.584, DFS: P= 0.401), or those at the corresponding stage with no CCC. Furthermore, according to the series of patients with CCC in both the current study and four studies in the literature, there was no difference in the recurrence rate between patients with or without CCC who were treated conservatively (CCC/FSS: 13.2% versus non-CCC/FSS: 10.9%, P= 0.614). Conclusions: Although our study did not have sufficient power to yield a definite conclusion, our data suggests that at least patients with stage IA CCC may be treated with FSS.

Objectives: To compare the clinical outcome of patients with stage I epithelial ovarian cancer (EOC) who received with fertility-sparing surgery (FSS) with those who underwent radical surgery (RS). Methods: After a central pathological review and search of the medical records from multiple institutions, a total of 572 patients were retrospectively evaluated. All patients were divided into three groups: group A {FSS (n=74); age, ⩽40} groups B and C [RS; age, 40⩾{(B), n=52} 40

The purpose of this study was to clarify the clinical outcome of patients with stage IA mucinous epithelial ovarian cancer (mEOC) treated with fertility-sparing surgery (FSS).After a central pathological review and search of the medical records from multiple institutions, a total of 148 stage I mEOC patients were retrospectively evaluated in the current study. All mEOC patients were divided into three groups: group A (FSS; age, 40≥); groups B and C {radical surgery; age, 40≥ (B); 40(C)}. Survival analysis was performed among these three groups using Kaplan-Meier methods.The median follow-up time of all mEOC patients was 71.6 (4.8-448.3) months. Among the 41 patients in group A, 27 patients (65.9%) had IA disease, and 14 (34.1%) had IC disease. Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 97.3% (OS)/90.5% (DFS); group B, 94.4% (OS)/94.4% (DFS); group C; 97.3% (OS)/89.3% (DFS). Collectively, there was no significant difference in OS or DFS among these groups even though they were stratified to each substage (IA/IC) (OS, P=0.180; DFS, P=0.445, respectively). Furthermore, in multivariate analyses, the surgical procedure was not an independent prognostic factor for either OS or DFS (OS, HR: 0.340, 95% CI: 0.034-3.775, P=0.352; DFS, HR: 0.660, 95% CI: 0.142-3.070, P=0.596).Patients with stage I mEOC treated with FSS did not necessarily show a poorer prognosis than those receiving radical surgery.

Residual tumor size after primary surgery is the most important prognostic factor in advanced ovarian cancer. We conducted a retrospective study in Japanese women to evaluate the association of various residual disease diameters and histological subtypes with overall survival (OS) in patients with residual disease ≥1 cm. Demographic and clinicopathological data were obtained from the Tokai Ovarian Tumor Study Group; 294 patients with International Federation of Gynecology and Obstetrics stage III and IV epithelial ovarian carcinoma who had undergone primary debulking surgery between 1986 and 2007 and had ≥1 cm residual tumor were identified. A Cox proportional hazards model was used to assess the association of prognostic factors with OS. Non-serous advanced ovarian cancer was associated with a significant increase in the risk of death. For serous ovarian cancer, residual tumor size was not an independent prognostic factor [multivariate hazard ratio (HR) = 1.63, 95% confidence interval (CI) = 0.96–2.79 (2–5 cm); HR = 1.25, 95% CI = 0.72–2.17 (>5 cm); trend P = 0.480], whereas taxane-based chemotherapy was associated with a better prognosis (HR = 0.66, 95% CI = 0.44–0.99, P = 0.046). For non-serous ovarian cancer, in contrast, residual tumor size was associated with an increased risk of death [multivariate HR = 0.87, 95% CI = 0.36–2.14 (2–5 cm); HR = 2.21, 95% CI = 0.96–5.08 (>5 cm); trend P = 0.067], whereas taxane-based chemotherapy was not a prognostic factor [HR = 0.70, 95% CI = 0.29–1.65, P = 0.409 (taxane-based)]. Although primary maximal cytoreduction is essential to improving OS in advanced ovarian cancer, our findings suggest the management of patients with suboptimal residual tumor should take into account differences between histological subtypes.

Objectives: The aim of this study was to estimate the survival impact of adjuvant paclitaxel and carboplatin (TC) compared to cisplatin (CDDP)-based chemotherapies for early-stage ovarian clear-cell carcinoma (CCC). Methods: Clinicopathologic information on 99 stage I–II CCC patients was obtained between 1987 and 2005. All patients underwent complete surgical staging including systemic lymphadenectomy, followed by TC or various CDDP-based regimens. In the present study, only CCC patients with no residual tumor were enrolled. Results: The median age was 53 years and ranged from 30 to 69 years. Fifty-three (53.5%) patients received TC and 46 (46.5%) patients underwent various CDDP-based chemotherapies after initial surgery. Five-year progression-free survival (PFS) rates of TC and various CDDP groups were 66.5 and 75.8%, respectively (n.s., p = 0.933). In addition, 5-year overall survival (OS) rates of TC and various CDDP groups were 82.4 and 82.3%, respectively (n.s., p = 0.583). In multivariate analyses of OS and PFS, the regimen of chemotherapywas not a significant prognostic factor (OS, p = 0.502; PFS, p = 0.977. Conclusions: In our current examination of the long-term survival of early-stage CCC patients, we did not identify a superiority of TC over various CDDP-based regimens as frontline adjuvant chemotherapy.

Objective: To evaluate the usefulness of our original liquid-based cell preparation system AMAPS (aspiration material preparation system) and to compare it with the AutoSmear system in breast aspiration cytology. Study Design: A total of 487 specimens of fine-needle aspiration cytology of the breast were retrieved, of which 250 were processed with AMAPS and 237 with the AutoSmear method (before the introduction of AMAPS). A final histological diagnosis was obtained by an excisional biopsy or a surgical resection in 148 cases. Results: Cell recovery rates were significantly improved with AMAPS (96.8 and 99.1% in Papanicolaou and Diff-Quik, respectively) compared with the AutoSmear method (40.9 and 42.3%, respectively; p < 0.01). Within-run and day-to-day reproducibility of cell recovery was satisfactory, with coefficients of variations of 6.8 and 8.7%, respectively. Following the introduction of AMAPS in breast cytology, the unsatisfactory rate decreased significantly (from 16.0 to 8.8%; p < 0.01), while the diagnostic sensitivity for malignancy did not change (97.8 to 98.1%). Moreover, the diagnostic specificity for benign lesions increased from 75 to 93.8%, thus decreasing the excision rate of fibrocystic disease. Conclusion: AMAPS may serve as an alternative to the conventional technique or commercially available liquid-based cytology systems.

A man, aged 65 years, presented with frequent episodes of hypoglycemia and unconsciousness. Hypoglycemia was accompanied by undetectable serum insulin and C-peptide levels and a high serum insulin-like growth factor (IGF)-II level. He was found to have a retroperitoneal solitary fibrous tumor. He underwent successful resection of the tumor and had no hypoglycemic episodes after the operation. Immunohistochemical analysis revealed positive immunostaining for IGF-II in tumor cells. The presence of the high-molecular-weight form of IGF-II in the patient’s serum was confirmed by immunoblotting, which suggests that his hypoglycemia was due to an increase in the plasma level of IGF-II secreted by the tumor.

Aim To assess the spectrum of findings using multiphase contrast-enhanced computed tomography (CT) in patients with autoimmune pancreatitis (AIP). Materials and methods Fifty patients (four female and 46 male, mean age 65 years) were retrospectively identified from consecutive patients with abnormal CT findings of the pancreas and negative work-up for known causes. These patients had at least one finding supporting the diagnosis of AIP: serological abnormality, histopathological abnormality, or response to steroid. Two radiologists evaluated multiphase contrast-enhanced CT images in consensus. Results The pancreas showed diffuse enlargement (n = 16; 32%), focal enlargement (n = 18; 36%), or no enlargement (n = 16; 32%). Forty-nine (98%) patients showed abnormal contrast enhancement in the affected pancreatic parenchyma, including hypoattenuation during the pancreatic phase (n = 45; 90%) and hyperattenuation during the delayed phase (n = 39; 87%). The following findings were also seen in the pancreas: a capsule-like rim (n = 24; 48%); no visualization of the main pancreatic duct lumen (n = 48; 96%); ductal enhancement (n = 26; 52%); upstream dilatation of the main pancreatic duct (n = 27; 54%); upstream atrophy of the pancreatic parenchyma (n = 27; 54%); calcification (n = 7; 14%); and cysts (n = 5; 10%). Forty-two (84%) patients showed one or more of the following extrapancreatic findings: biliary duct or gallbladder abnormality (n = 40; 80%); peripancreatic (n = 8; 16%) or para-aortic (n = 10; 20%) soft-tissue proliferation; and renal involvement (n = 15; 30%). Conclusion Patients with AIP presented with a variety of CT findings in the pancreas and the extrapancreatic organs. The present study highlights pancreatic ductal enhancement in a subset of patients with AIP.

Objective Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces immune tolerance. The purpose of the present study is to investigate IDO expression and its functional role in ovarian cancer cells in vitro and in vivo . Methods IDO expression was immunohistochemically scored in surgically-resected ovarian cancer tissues ( n =60), and its association with tumor-infiltrating lymphocyte (TIL) count or patient survival was analyzed. Next, IDO cDNA was transfected into the human ovarian carcinoma cell line SKOV3, establishing stable clones of IDO-overexpressing cells (SK-IDO). SK-IDO cells were characterized in vitro as well as in vivo using a nude mouse xenograft model. Results High IDO expression in tumor cells was found in 34 (56.7%) cases and was correlated with a reduced number of CD8+ TIL. Patients with high IDO expression had significantly impaired overall and progression-free survival compared to patients with no or low IDO expression. There were no significant differences in in vitro cell proliferation, migration, invasion, or chemosensitivity to paclitaxel between the SK-IDO and control vector-transfected (SK-pcDNA) cells. However, tumor peritoneal dissemination was significantly increased in SK-IDO-xenografted mice compared to SK-pcDNA-xenografted mice. This tumor-progressive effect in SK-IDO-xenografted mice was abrogated by oral administration of the IDO inhibitor 1-methyl-tryptophan (1-MT). Finally, treatment with weekly i.p. paclitaxel combined with daily administration of 1-MT significantly prolonged the survival of the SK-IDO-xenografted mice compared to treatment with paclitaxel alone. Conclusions These results suggest that IDO is involved in ovarian cancer progression in vivo and may be a promising therapeutic target for advanced ovarian cancer.

The purpose of this study was to investigate a capability of PuraMatrix (PM), which is a self-assembling peptide nanomaterial, as a scaffold for bone regeneration in combination with dog mesenchymal stem cells (dMSCs) and/or platelet-rich plasma (PRP) using tissue engineering and regenerative technology. Initially, teeth were extracted from an adult hybrid dog's mandible region. After 4 weeks, bone defects were prepared on both sides of the mandible with a trephine bar. The following graft materials were implanted into these defects: (1) control (defect only), (2) PM, (3) PM/PRP, (4) PM/dMSCs, and (5) PM/dMSCs/PRP. From scanning electron microscope images, PM had a three-dimensional nanostructure, and dMSCs attached on the surface of PM. At 2, 4, and 8 weeks after implantation, each sample was collected from the graft area with a trephine bar and assessed by histologic and histomorphometric analyses. It was observed that the bone regenerated by PM/dMSCs/PRP was of excellent quality, and mature bone had been formed. Histometrically, at 8 weeks, newly formed bone areas comprised 12.39 +/- 1.29% (control), 25.28 +/- 3.92% (PM), 27.72 +/- 3.15% (PM/PRP), 50.07 +/- 3.97% (PM/dMSCs), and 58.43 +/- 5.06% (PM/dMSCs/PRP). The PM/dMSCs and PM/dMSCs/PRP groups showed a significant increase at all weeks compared with the control, PM, or PM/PRP (P < 0.05 at 2, 4, and 8 weeks, analysis of variance). These results showed that MSCs might keep their own potential and promote new bone regeneration in the three-dimensional structure by PM scaffolds. Taken together, it is suggested that PM might be useful as a scaffold of bone regeneration in cell therapy, and these results might lead to an effective treatment method for bone defects.

We studied the morphologic, immunologic and clinical features of 14 cases of primary non-lymphoblastic non-Hodgkin's lymphomas of the mediastinum. The patients ranged in age from 3 to 76 years, with a median age of 28 years. According to the Ann Arbor classification, 71% of our cases were in an early stage. Three cases were in Stage I, eight in Stage II, one in Stage III and two in Stage IV (one with multiple hepatic lesions and another with bone marrow involvement). The patients were heterogeneous in terms of the disease and were therefore histologically classified into three categories: diffuse large B cell lymphoma with sclerosis (DLS; n = 8); large cell anaplastic lymphoma (LC-Ana; n = 5); and low grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma; n = 1). DLS was the most common group and was characterized as CD5-, CD10-, CD19+, CD20+, CD21- and CD22+. Imprint smears showed azurophilic granules in the cytoplasm of the tumor cells of three of four DLS cases. All of the six cases examined were negative when tested for Epstein-Barr virus (EBV) sequences after hybridization with the EBV internal repeat probe. DLS and MALT lymphoma cases were of a B-lineage lymphoma of the thymus, while most of the LC-Ana cases were of a T-lineage lymphoma. Patients with non-lymphoblastic non-Hodgkin's lymphomas had a relatively favorable prognosis compared with lymphoblastic lymphoma (P0.01 by the generalized Wilcoxon test). There was no significant difference in the survival between non-lymphoblastic non-Hodgkin's lymphoma and Hodgkin's disease (P0.05 by the generalized Wilcoxon test).

This clinical study used injectable tissue-engineered bone, along with bone marrow-derived stromal cells (BMDSCs) and platelet-rich plasma (PRP), to conduct maxillary sinus floor augmentation by the simultaneous placement of bone graft and dental implants and to examine the state of regenerated bone after functional loading in 16 sinus augmentations in 12 patients whose alveolar crestal bone height was 2-10 mm. We used PRP as an autologous scaffold-which provides signal molecules-with in vitro expanded BMDSCs to enhance osteogenesis. All 41 dental implants prepared with the materials were clinically stable after second-stage surgery. The height of mineralized tissue at 2 years showed the mean increases of 8.8 +/- 1.6 mm compared to preoperative values, and no adverse effects and remarkable bone absorption were seen in the 2-6-year follow-up time. Although these results are preliminary, injectable tissue-engineered bone would stably predict the success of bone formation and dental implants, reduce patient burden, and provide minimally invasive cell therapy for patients.

Wnt signaling activates the canonical pathway and induces the accumulation of non-phosphorylated beta-catenin (NPBC) in the nucleus. Although this pathway plays an important role in the maintenance of haematopoietic stem cells as well as in oncogenesis, the significance of nuclear NPBC remains unclear in malignant haematopoiesis. This study examined the expression of nuclear NPBC in bone marrow specimens from 54 and 44 patients with de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), respectively. On immunohistochemistry with an anti-NPBC antibody, the nuclei were positively stained in 22 and 18 of AML and MDS specimens, respectively. Staining of nuclear NPBC was associated with AML subtypes (M6 and M7), low complete remission (CR) rate, and poor prognosis. Nuclear NPBC was also associated with a high score when using the International Prognostic Scoring System (IPSS) for MDS and with -7/-7q and complex karyotypes. These findings suggest that in situ detection of nuclear NPBC by immunohistochemistry could provide new insights into the pathogenesis and prognosis of AML and MDS.

背景 : 後腹膜に発生する後腹膜粘液性嚢胞性腫瘍 (Retroperitoneal mucinous cystic tumor) はまれな腫瘍である. 今回, 術前の穿刺細胞診で診断が困難であった 1 例を経験したので, 術中に得られた嚢胞内溶液の細胞像を示し, 考察を加え報告する.症例 : 20 代女性. 右下腹部痛にて当院に来院し, 腹部超音波検査で右側腹部嚢胞性腫瘤が認められた. 経皮的穿刺吸引液を用いて細胞診が 3 回行われたが, 粘液様物質が吸引されたものの, 上皮性細胞は認められず, 確定診断が困難であった. 開腹手術が行われ, 術中採取された茶褐色粘液状検体を用いて細胞診標本が作製された. 細胞所見では, 粘液性背景を伴って腺細胞の集団が多数認められた. 腺細胞は高円柱状で細胞質には粘液を認め, シート状, 索状, 乳頭状に配列していた. 組織所見では, 嚢胞内面に腺上皮細胞が, 平坦にあるいは乳頭状に増生していた. 間質への浸潤はなく, 低悪性度粘液性嚢胞性腫瘍と診断された. 腫瘍の間質細胞は, 免疫染色で「卵巣間質細胞」と同じ染色性を示した.結論 : 後腹膜の嚢胞性腫瘤の穿刺細胞診で, 粘液が認められた場合は, 上皮細胞が認められなくても鑑別診断すべき疾患のなかに粘液性嚢胞性腫瘍を入れておく必要がある.

N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyses beta1-6 branching of N-acetylglucosamine on asparagine-linked oligosaccharides of cell proteins. The present study aimed to investigate GnT-V expression and its prognostic significance in endometrial cancer. N-acetylglucosaminyltransferase V expression was studied by immunohistochemistry in 74 surgically resected endometrial cancers, and the staining intensity was evaluated. High GnT-V expression in tumour cells was found in 43 (58.1%) of the 74 cases, and was positively correlated with advanced patient age, histological grade, and lymph vascular space involvement. Patients with high GnT-V expression had significantly impaired overall survival and progression-free survival (PFS) (P=0.0041 and P=0.0023, respectively) compared to patients with low expression of GnT-V. On multivariate analysis, GnT-V expression was an independent prognostic factor for PFS (P=0.0364). beta1-6 branching of asparagine-linked oligosaccharides was also detected in GnT-V-positive endometrial cancer cells by leukoagglutinating phytohaemagglutinin (L(4)-PHA) staining, and the molecular size of the major glycoproteins recognised by L(4)-PHA was approximately 60-200 kDa by lectin blot analysis. These results suggested that high GnT-V expression was correlated with an unfavourable clinical outcome, and that GnT-V is involved in the malignant potential of endometrial cancer by increasing the synthesis of beta1-6 branching of asparagine-linked oligosaccharides.

Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown. Objective: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis. Design: We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue. Results: Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios. Conclusion: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.

The aim of this study was to determine whether estrogen plays any role in the hepatic regeneration of nonligated lobe following portal branch ligation (PBL). Male rats were subjected to PBL on the left and middle lobes. Two and 7 days after PBL, the rats were killed and blood and liver samples were analyzed. Sham animals underwent only laparotomy. The serum estradiol levels were significantly elevated on day 2 following PBL and returned to normal levels on day 7. The expression of estrogen receptors (ER) in the liver evaluated by Western blotting did not show any change in the nonligated lobe compared with shams. Immunohistochemical study for ER showed a predominant ER expression in the hepatocyte nucleus in periportal area ( zone 1), although there was no apparent difference in the amount and expression pattern between sham and PBL. However, chronic inhibition of ER by an ER antagonist (ICI 182,780) showed a significantly lower regeneration rate of the nonligated lobe compared with vehicle treatment. Liver regeneration-associated genes also were less activated in the ICI group. Moreover, portal venous flow, determined by fluorescent microsphere injection, was significantly lower in the ICI group compared with vehicle group. These changes correlated with the attenuated expression of endothelial nitric oxide synthase mRNA in both superior mesenteric arteries and veins. In conclusion, these results indicate that the estrogen's contribution on hepatic regeneration following PBL is at least partly mediated through maintaining mesenteric blood flow by mesenteric endothelial nitric oxide synthase upregulation rather than directly activating liver regeneration in the liver.

Background and study aims Advances in endoscopy have led to imaging of the details of the gastric mucosa, but the histological diagnosis usually has to be confirmed by endoscopic biopsy. A method of confocal endomicroscopy that has recently been developed allows the observation of living cells in vivo. Several investigators have reported that the technique is of value, but there have as yet been no studies describing its application in gastric cancer. Patients and methods Twenty-seven patients with early gastric cancer underwent confocal endomicroscopy (Pentax EG-3870CIK; Pentax, Tokyo, Japan). After intravenous administration of fluorescein sodium, confocal images obtained from the normal mucosa and from cancerous lesions were interpreted by two pathologists independently and compared with the histological findings, including CD34 immunostaining of biopsy specimens or resected specimens from the same sites. Results Fluorescein yielded high-quality confocal images of the gastric mucosa; if cancer could be targeted (59%) images were mostly graded good. The images corresponded to the hematoxylin-eosin staining of transverse sections of specimens from the same sites. In the results for the interpretation by the two pathologists, the accuracy for the diagnosis of gastric cancer was 94.2% (pathologist A), and 96.2% (pathologist B), respectively. The accuracy decreased substantially when poor images and inaccessible lesions were included. Conclusions Confocal endomicroscopy is useful in the diagnosis of gastric cancer but good quality images cannot always be obtained. In the future, it may allow virtual biopsy and help reduce unnecessary biopsies.

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1β was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Endothelin-1 (ET-1) in human endometrium has been proposed to have a potential paracrine role, for its receptors are also present within this tissue. In addition, the expression of ET-1 varies during the menstrual cycle, and therefore, ET-1 may be involved in the cyclic change of the human endometrium, such as proliferation and decidualization. However, neither the inactivation of ET-1 in the endometrium nor the paracrine effect of ET-1 on endometrial cells has been determined. We investigated the production of ET-1 and the presence of neutral endopeptidase (NEP), which cleaves and inactivates ET-1, in primary cultured human endometrial cells. We found primary cultured endometrial epithelial cells, not stromal cells, to be the major source of ET-1. Western blot analysis and RT-PCR demonstrated that NEP was predominantly expressed by endometrial stromal cells. We also demonstrated that ET-1 stimulated the phosphorylation of Akt and DNA synthesis in endometrial stromal cells via the ETA receptor and phospahtidylinositol-3 kinase signaling pathways. The effect of ET-1 was regulated by NEP expressed by stromal cells. We also found that conditioned medium containing ET-1 from endometrial epithelial cell culture stimulated phosphorylation of Akt via the ETA receptor. In conclusion, ET-1 has a paracrine effect of Akt phosphorylation and cell proliferation on endometrial stromal cells, which occurs via the ETA receptor and phospahtidylinositol-3 kinase signaling pathways, and is regulated by cell-surface NEP.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolising enzyme inducing immune tolerance. The present study aimed to investigate IDO expression and its prognostic significance in endometrial cancer. Indoleamine 2,3-dioxygenase expression in endometrial cancer tissues (n = 80) was immunohistochemically scored as four groups (IDO-, 1+, 2+, and 3+). The high IDO expression (IDO2+ or 3+) in tumour cells was found in 37 (46.3%) of the 80 cases, and was positively correlated with surgical stage, myometrial invasion, lymph-vascular space involvement, and lymph node metastasis, but not with the histological grade. Patients with high IDO expression had significantly impaired overall survival and progression-free survival (PFS) (P = 0.002 and P = 0.001, respectively) compared to patients with no or weak expression of IDO (IDO- or 1+). The 5-year PFS for IDO-/1+, 2+, and 3+ were 97.7, 72.9, and 36.4%, respectively. Even in patients with early-stage disease (International Federation of Gynecology and Obstetrics I/II, n = 64), the PFS for IDO2+/3+ was significantly poor (P = 0.001) compared to that for IDO-/1+. On multivariate analysis, IDO expression was an independent prognostic factor for PFS (P = 0.020). These results indicated that the high IDO expression was involved in the progression of endometrial cancer and correlated with the impaired clinical outcome, suggesting that IDO is a novel and reliable prognostic indicator for endometrial cancer.

We report the case of a woman with gefitinib-sensitive lung adenocarcinoma, who was successfully re-treated with gefitinib for carcinomatous meningitis as the disease recurrence. The good response to gefitinib treatment was supported in part by the existence of epidermal growth factor receptor mutation in carcinoma cells in the specimen obtained from transbronchial lung biopsy, in which E709G in exon 18 and L858R in exon 21 were shown. Although carcinomatous meningitis had been well controlled by the treatment with gefitinib, serum carcinoembryonic antigen (CEA) level increased with re-growth of primary tumor and development of lymphangitic carcinomatosis. Immunohistochemical findings revealed de novo emergence of CEA-producing carcinoma cells in the biopsy specimen taken after recurrence of pulmonary lesion during re-treatment of gefitinib, but revealed little or no CEA expression in the specimen obtained at first presentation. These facts may suggest the possibility of oligo clonality of carcinoma cells in this case.

Background and Objectives There were a few reports of a large number of patients with clear cell adenocarcinoma (CCA) of the ovary because of the low incidence of CCA. This study compared the clinical factors affecting long-term survival of patients with CCA to those with serous cystadenocarcinoma (SCA). Methods One hundred and seventy-eight CCA and 311 SCA patients treated between 1987 and 2000 were retrospectively evaluated. Differences in survival rates were calculated using log-rank test and Cox's proportional hazards analysis was used to identify independent prognostic factors. Results The ratio of stage I was significantly higher than that of SCA. There was no significant difference of 8-year survival rate in each stage between CCA and SCA. However, the patients with stage IIIb or IIIc CCA showed significantly worse prognosis than those with SCA. Positive peritoneal or ascitic cytology, the presence of residual tumor, more than 100 ml ascites were demonstrated to have the significant impact on survival by univariate analysis. Multivariate analysis demonstrated that stage, more than 100 ml ascites, and the presence of residual tumor were significant prognostic factors of CCA overall survival. Conclusions Distribution of stage and substage differed between CCA and SCA in this study. Thus, substaging is quite important for comparison of prognoses between histologies, and CCA showed poorer prognoses than serous adenocarcinoma in stages IIIb and IIIc. J. Surg. Oncol. 2006;94:138–143. © 2006 Wiley-Liss, Inc.

症例は56歳の男性で, 2004年5月頃より心窩部痛が出現し近医を受診した. 精査の結果, 下行結腸癌と診断し同時に肝右葉と膵頭部に充実性の腫瘤を認め, 膵腫瘤による中下部胆管狭窄も認めた. PTBDの後, 結腸左半切除術が施行され, 肝膵の手術目的にて当科に紹介, 入院となった. 術前画像上は主膵管の拡張などは認めず, 結腸癌肝転移および肝病巣から転移したリンパ節の膵浸潤を最も疑ったが, DUPAN-2が高値で膵頭部癌の肝転移も考えられた. 前者であれば外科切除で根治が望める病態と判断し, 7月膵頭十二指腸切除+肝右葉切除術を施行した術後の病理検索では, 結腸癌は高分化な部分と中分化な部分が存在し, リンパ節の転移所見は中分化型で, 肝・膵腫瘍の組織型と酷似していた. また, 結腸と膵病変のCEA, CK7, CK20による免疫染色ではともにCK7陰性, CEA/CK20陽性で, 下行結腸原発, 同時性肝・膵転移と判断した. 術後12か月, 肝・骨転移により死亡した.