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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. [ABSTRACT FROM AUTHOR]

The placental leucine aminopeptidase (P-LAP)/oxytocinase whose serum level increases with gestation is thought to contribute to the maintenance of normal pregnancy. P-LAP mRNAs are expressed in various tissues other than the placenta. In this study, we identified P-LAP protein in the brain. In contrast with the placenta where a significant portion of P-LAP is released, the enzyme was localized in the membrane fraction in brain and PC12 cells and no soluble form of the enzyme was detected. When PC12 cells were differentiated into neuronal cells by nerve growth factor (NGF), a significant increase in the expression level of P-LAP in the cell was observed. As in the case of insulin treatment of 3T3-L1 adipocytes, treatment of PC12 cells with forskolin caused the translocation of the enzyme from intracellular vesicle to the cell surface plasma membrane. In addition, P-LAP was shown to degrade several bioactive neuropeptides such as Met-enkephalin and dynorphin A (1–8). These results suggest that P-LAP plays an important role in the regulation of neuronal cell function in the brain. [ABSTRACT FROM AUTHOR]

Reports on the detection of B cell non-Hodgkin's lymphomas in archival bone marrow specimens using polymerase chain reaction methods. Immunoglobulin heavy chain gene rearrangement; Types of archival tissues; Detection sensitivity potential of microdissection of the suspicious lymphoid aggregates.

Testicular germ cell cancer is a common cancer in young adults and its incidence has risen dramatically over the past several decades in Western countries. Because RET finger protein (RFP), which belongs to the large B-box RING finger protein family, has been reported to be expressed in different stages of spermatogenesis, we investigated its expression in testicular germ cell tumors. These comprised 13 pure seminomas, five pure non-seminomatous germ cell tumors (NSGCT) and seven mixed germ cell tumors, four of which contained seminomatous component. In normal adult testis, the expression of RFP was strong in the germ cells, particularly in spermatogonia and primary spermatocytes. RFP immunoreactivity was seen uniformly and specifically in 12 of the 13 pure seminomas examined. It was also detected in seminomatous components of mixed germ cell tumors, whereas pure NSGCT were negative for RFP expression. The expression of RFP in male germ cells and seminomas together with the lack of its expression observed in highly aggressive NSGCT suggested that RFP could be associated with the regulation of germ cell proliferation and/or histological-type of germ cell tumors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the frequency and prognostic importance of neuroendocrine differentiation (NED) in Japanese breast cancer patients. Methods: We used standard immunohistochemical techniques to examine 50 patients who underwent resection of breast cancer between 1988 and 1993 at the Department of Surgery II, Nagoya University Hospital, for NED, defined as positive reactivity for four markers: neuron-specific enolase (NSE), synaptophysin, CD57, and chromogranin A (CGA). Neuroendocrine differentiation was defined by the presence of at least one marker including CGA, CD57, and synaptophysin, or at least two markers when one was positive for NSE. Results: Neuroendocrine differentiation was found in 13 (26%) of the 50 patients examined. There were no significant differences in the distribution of patients with positive or negative NED in terms of age, menopausal status, tumor size, lymph node metastasis, histological grade, ER, PgR, and HER2. We calculated the cumulative survival rates of patient groups according to NED status, and found no significant difference in overall or disease-free survival between patients with and those without NED. Conclusion: Neuroendocrine differentiation was identified in a subset (26%) of Japanese breast cancer patients, but this appeared to have no relationship with established prognostic factors or patient outcome. [ABSTRACT FROM AUTHOR]

Background/Aims: We examined whether phosphatidylcholine inhibited growth of hepatic cancer, as previously shown for menaquinone-4 (vitamin K2). Methods: Growth inhibitions by phosphatidylcholine and/or menaquinone-4 and apoptosis induction by phosphatidylcholine were evaluated in vitro using human hepatic cancer cell lines (Hep-3B, Hep-G2, HuH-7, and Alexander). Effects of these agents were then investigated in male Sprague–Dawley rats against hepatocarcinogenesis induced by diethylnitrosamine plus phenobarbital. All rats were killed to examine livers to evaluate inhibitory potential macroscopically and immunohistochemically using an antibody against the marker of carcinogenesis, glutathione S-transferase and apoptotic induction by phosphatidylcholine using TUNEL staining. Blood samples were obtained by cardiac puncture. Results: In vitro, phosphatidylcholine and menaquinone-4 each inhibited cancer cell growth and phosphatidylcholine induced apoptosis dose-dependently. Moreover, exposure to both synergistically inhibited growth in Hep-3B. In vivo, diets containing phosphatidylcholine with or without menaquinone-4 significantly reduced the number of macroscopic hepatic tumor nodules and the extent of abnormally immunoreactive foci conserving hepatic function on serum examinations compared with controls given only the carcinogens. Moreover, phosphatidylcholine supplementation induced apoptosis on TUNEL staining of liver sections. Conclusions: Given together, phosphatidylcholine and menaquinone-4 may exhibit synergy against hepatocarcinogenesis conserving hepatic function that could benefit patients at high risk for hepatocellular carcinoma. [Copyright &y& Elsevier]

Aminopeptidase A (AP-A) is a cell surface metallopeptidase which specifically cleaves the amino-terminal acidic residue from peptide substrates such as angiotensin II. AP-A is identical to the differentiation-related antigen, murine BP-1 or human kidney gp160, and is involved in regulating cell differentiation and/or neoplastic transformation of certain normal and transformed cells. We examined expression of AP-A in premalignant and malignant lesions of the uterine cervix, and investigated whether its expression was related to disease progression and neoplastic transformation. Formalin-fixed, paraffin-embedded tissue sections including 14 cervical intraepithelial neoplasms (CIN) and 23 invasive squamous cell carcinomas (SCC) were immunohistochemically evaluated. AP-A was localized in the basal cell layer in normal squamous epithelium. In CIN, AP-A expression was found on dysplastic cells, and increased with the severity of the precancerous lesions. In invasive cancer, 18 of 19 non-keratinizing-type SCCs and none of 4 keratinizing-type SCCs expressed AP-A. In addition, AP-A immunoreactivity was significantly correlated with proliferating cell nuclear antigen expression in both CIN and SCC cases. Furthermore, angiotensin II type 1 receptor was present in all AP-A-positive SCCs. These results indicate that AP-A is upregulated as the lesion progresses toward carcinoma in the cervical epithelium, and suggest that AP-A may play a regulatory role in neoplastic transformation and disease progression in cervical neoplasms and may serve as a potential tumor marker during cervical neoplasia development.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The RET finger protein (RFP), which belongs to the B box zinc finger protein family, has a tripartite motif consisting of a Ring finger, a B box finger and a coiled-coil domain. The RET finger protein becomes oncogenic when its tripartite motif is fused with the tyrosine kinase domain of the RET protein. This study examined the RFP expression in normal and tumor tissues by immunohistochemistry. RFP was detected in the nuclei of various cells, including peripheral and central neurones, hepatocytes, adrenal chromaffin cells and male germ cells. Among them, RFP was expressed at high levels in male germ cells such as primary spermatocytes and round spermatids, and formed a perinuclear cap structure in primary spermatocytes. On the other hand, high levels of cytoplasmic expression of RFP were observed in some plasma cells as well as solitary plasmacytoma and multiple myeloma. These results suggested that different nuclear/cytoplasmic distributions of RFP might play a role in the regulation of growth or differentiation of different cell types. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: 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. Materials and methods: 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. Results: 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]. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: We retrospectively analyzed the clinicopathological features and evaluated the prognostic indicators of recurrence in 132 patients with clear cell adenocarcinoma (CCC) of the ovary at reproductive age. Patients and methods: Between 1986 and 2011, as a regional population-based study, clinicopathological data on 132 young patients with CCC, collected under the central pathological review system, were subjected to uni- and multivariable analyses to evaluate recurrence-free survival (RFS). Results: The median age was 40 (27-45) years. The median follow-up period for surviving patients was 46.4 months. During the observation period, there were 16 recurrences in 87 patients with stage I tumors (18.4 %), 8 in 17 with stage II (47.1 %), and 16 in 28 with III-IV (57.1 %). Subsequently, 35 patients died of the disease. Those with stage I or II did not reach the median RFS. The median RFS of stage III-IV was 21.6 months. When analysis was confined to stage I patients, there was no significant difference in the RFS of CCC patients between IA and IC(r) (intraoperative capsule rupture) ( P = 0.7957). In contrast, CCC patients with IC excluding IC(r) [IC(non-r)] showed a poorer RFS than those with IC(r) ( P < 0.0001). In multivariable analysis confined to stage I patients, the substage group was only an independent prognostic factor for RFS [IA vs. IC(non-r)] [hazard ratio (HR) = 9.394; 95 % CI, 1.445-61.070; P = 0.0190]. Conclusion: We should keep in mind the greater risk of recurrence in patients with stage IC disease or higher, other than those stage IC patients with intraoperative rupture. [ABSTRACT FROM AUTHOR]

Objectives This study was conducted to estimate the oncologic outcome of stage I epithelial ovarian carcinoma (EOC) patients after recurrence. Study design After central pathological review and searching of the medical records of multi-institutions, a total of 103 relapsed patients with stage I EOC were analyzed. The major endpoint was postrecurrence survival (PRS). Results The median follow-up for surviving patients was 57.5 (5.7–242.0) months. The median age was 52 (14–89). Among the patients, 19 (18.4%) had FIGO IA disease, and 4 (3.9%) and 80 (77.7%) had IB and IC disease, respectively. Regarding the histological type, the clear-cell type was the most frequently observed ( N = 42: 40.8%). The 3/5-year overall and PRS rates of all patients were 63.7/47.9 and 38.2/24.0%, respectively. The 5-year PRS rates of patients with serous, endometrioid, clear-cell, and mucinous tumors were 44.9, 35.0, 19.8, and 0%, respectively. On stratifying by the histological type, the overall and postrecurrence survival rates of patients with the mucinous/clear-cell types were significantly poorer than in those with the non-mucinous/clear-cell types (OS: P = 0.0253, PRS: P = 0.0016). In multivariate analyses, the FIGO stage (IA/IB vs. IC) and histological type (clear-cell/mucinous vs. non- clear-cell/mucinous) retained their significance as prognostic factors of a poorer PRS {stage IC (vs. IA/B): HR: 2.176 (95% CI: 1.059–4.470), P = 0.0343: clear-cell/mucinous (vs. non- clear-cell/mucinous): HR: 2.486(95% CI: 1.416–4.364), P = 0.0015). Conclusions Even if at stage I, once patients with a mucinous/clear-cell histology experience recurrence, subsequent survival is extremely poor. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to clarify the clinical features of epithelial ovarian carcinoma (EOC) in younger vs. older patients in Japan. Methods: We collected data on 1,562 patients with EOC treated at multiple institutions in the Tokai Ovarian Tumor Study Group, and analyzed them retrospectively. All patients were divided into 2 groups: group A (≤40 years old) and group B (>40 years old). The data were analyzed to evaluate prognostic factors and the distribution of features in each group. Patients were subjected to univariate and multivariate analyses to evaluate overall survival (OS). Results: The median follow-up time was 45.1 months (range, 1 to 257 months). Patients in group A had a significantly higher rate of stage I disease (67.3% vs. 42.6%, respectively; p<0.001) and the mucinous type (36.7% vs. 13.5%, respectively; p<0.001) than those in group B. There was a significant difference of OS between the 2 groups (p=0.013). However, upon stratification according to the stage, there were no significant differences in the OS between the 2 groups (group A vs. B: stage I, p=0.533; stage II-IV, p=0.407). Multivariate analysis revealed that younger age was not an independent prognostic factor for OS. Conclusion: On the basis of our data, younger patients had a different clinical profile than older patients, particularly regarding the stage of the disease and pathological distribution; however, they showed a similar long-term prognosis, even upon stratification according to the stage. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Background: 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). Methods: 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. Results: 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 < 0.0001: RT (+): P = 0.0912]. In multivariable analysis, a mucinous histology predicted a significantly poorer PRS (RmOC vs. RsOC: hazard ratio (HR) 2.080, 95 % confidence interval (CI) 1.434-3.016, P = 0.0001). Confining analysis to deceased patients ( N = 302), the proportion of RmOC patients who died within 12 months following recurrence was markedly higher than that of RsOC [RmOC 69.2 %, RsOC: 41.1 % ( P < 0.0001)]. Conclusions: The clinical outcome after recurrence in patients with RmOC was extremely poor. This confirms that RmOC should be considered a different entity from other epithelial ovarian cancers. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to examine the effects of front-line chemotherapy on overall survival (OS) and postrecurrence survival (PRS) of patients with recurrent ovarian cancer, when stratifying the histologic type. Methods: Five hundred and seventy-four patients with recurrent ovarian cancer with sufficient clinical information, including front-line chemotherapy, were analyzed. The pathologic slides were evaluated by central pathologic review. The patients were divided into two groups: group A (n=261), who underwent taxane plus platinum, and group B (n=313), who underwent conventional platinum-based chemotherapy without taxanes. Results: The median age was 54 years (range, 14 to 89 years). Group A had significantly better median OS (45.0 months vs. 30.3 months, p<0.001) and PRS (23.0 months vs. 13.0 months, p<0.001) compared to group B. The OS and PRS were similar between the groups in patients with clear cell or mucinous histology. In contrast, among patients with non-clear cell, non-mucinous histologies, the OS and PRS of group A were significantly better than those of group B (OS, p<0.001; PRS, p<0.001). Multivariable analyses revealed that, among patients with non-clear cell, non-mucinous histologies, chemotherapy including taxane and platinum was an independent predictor of favorable survival outcomes. Conversely, in patients with clear cell or mucinous histology, taxane-including platinum-based combination chemotherapy did not improve the OS and PRS compared to a conventional platinum-based regimen which did not include taxanes. Conclusion: Since the emergence of taxane plus platinum, the prognosis of patients with recurrent ovarian cancer has improved. However, we here demonstrate that this improvement is limited to patients with non-clear cell, non-mucinous histologies. [ABSTRACT FROM AUTHOR]

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 <1 cm). The median age was 55 years (range: 18-84). The 5-year progression-free survival (PFS) rates of groups A and B were 46.7 and 41.9%, respectively ( P = 0.658). In addition, the 5-year overall survival (OS) rates were 62.9 and 59.0%, respectively ( P = 0.853). Subsequently, there was no significant difference in OS and PFS in the two groups stratified to histological type (serous or non-serous type). Furthermore, there was no significant difference in recurrence rates in retroperitoneal lymph nodes regardless of completion of lymphadenectomy. Conclusion: Our data suggest that aEOC patients with optimal cytoreduction who underwent SRL did not show a significant improvement in survival irrespective of each histological type. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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)]. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: 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). Methods: 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. Results: 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). Conclusions: Patients with stage I mEOC treated with FSS did not necessarily show a poorer prognosis than those receiving radical surgery. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Background and Aim: Relationships between mucin phenotype and malignant potential in gastric cancers have attracted attention. We attempted to assess the possibility of obtaining phenotypic diagnoses by confocal endomicroscopy. Methods: Confocal images of target lesions were obtained in 29 of 40 patients with gastric cancer. Appearances of the brush border, goblet cells, and gastric foveolar epithelium were investigated with immunohistochemical staining using CD10, MUC2, and human gastric mucin to evaluate phenotypic expression in gastric carcinomas. Confocal images were compared with immunohistochemical findings for goblet cells and brush borders. Results: Both the endoscopists and the pathologist obtained high accuracy rates for differential diagnosis. Sensitivity and specificity for goblet cells were 85.7% and 92.3% (Endoscopist A), and 85.7% and 88.5% (Endoscopist B). The κ-value for correspondence between two endoscopists for the diagnosis of goblet cells in confocal images was 0.73. Sensitivity and specificity for the brush border were 93.8% and 91.7% (Endoscopist A), and 81.3% and 91.7% (Endoscopist B). The κ-value for correspondence between two endoscopists for diagnosis of the brush border in confocal images was 0.79. Intestinal phenotypic gastric cancers show a brush border, goblet cells, or both. Sensitivity and specificity for the intestinal phenotype in confocal endomicroscopy were 90.9% and 77.8% (Endoscopist A), and 86.4% and 83.3% (Endoscopist B). Conclusion: The confocal endomicroscopic diagnosis of the mucin phenotype in gastric cancers was limited to intestinal and mixed phenotypes, but may be useful for the diagnosis of mucin phenotype and differential diagnosis. [ABSTRACT FROM AUTHOR]

Chordomas are locally destructive tumors with high rates of recurrence, and therapeutic strategies remain controversial. This study analyzed long-term outcomes for clival chordomas after initial aggressive surgical resection and gamma knife radiosurgery for recurrence and investigated clinical factors predicting recurrence. Clinical records were reviewed for 19 consecutive patients (11 men, 8 women; mean age, 43.1 years) with clival chordoma who underwent initial surgical resection using skull base approaches (mean follow-up after surgical resection, 87.2 months). All tumors were aggressively removed, along with the surrounding bone. Four patients were treated with radiotherapy after surgical resection. Recurrent lesions were treated with gamma knife radiosurgery or reoperation. Factors predicting tumor recurrence were analyzed, including age, tumor extension, extent of resection and MIB-1 labeling index. Patient status was evaluated using the Karnofsky performance scale (KPS). Tumor resection was total, subtotal and partial in 14, 4 and 1 patients, respectively. Tumors recurred in 11 patients. Overall, 2- and 5-year progression-free survival rates were 77.9% and 47.9%, respectively. The MIB-1 labeling index was independently associated with recurrence. The optimum cutoff point for the MIB-1 labeling index was 3.44%. All recurrent tumors were totally resected or controlled by gamma knife (mean follow-up after recurrence, 71.2 months). All patients survived and were active (mean KPS at final follow-up, 89.5%). Long-term control of clival chordomas was achieved. Recurrent tumors were controlled with gamma knife radiosurgery, since lesions were localized and small after initial aggressive resection. The MIB-1 labeling index can provide important information for predicting tumor recurrence. [ABSTRACT FROM AUTHOR]

Background and Aim: Confocal endomicroscopy is ultra-high-magnification endoscopy with histological observation during ongoing endoscopy. We planned a pilot study of the diagnosis of the depth of esophageal cancer using confocal endomicroscopy for treatment strategies. Methods: Patients had 14 superficial esophageal cancers and one dysplasia. The depth of neoplasms in 15 lesions was confirmed by endoscopic mucosal resection or surgery. We examined the rate of delineation and compared results of confocal imaging with histological findings. We classified two cellular and three microvascular patterns on confocal endomicroscopic images: CP-N for normal squamous mucosa and CP-Ca for cancerous lesion; VP-type A for normal squamous mucosa; VP-type B for T1a-EP and T1a-LPM cancers; and VP-type C for T1a-MM or a more invasive cancer pattern. We measured diameters of microvessels for the three patterns of confocal endomicroscopic images and histological specimens. Results: The rate of delineation was 73.3% (11/15) for esophageal cancer. The results of confocal imaging coincided well with microvessel distribution on horizontal histology. Two endoscopists blindly diagnosed the two types by cellular pattern and the three types by vascular pattern: their overall accuracies were 96% and 89% for the cellular pattern and 85% and 85% for the vascular pattern, respectively. The k value of the cellular pattern and the vascular pattern diagnosis was 0.84 and 0.75, respectively. Conclusion: Scoring and quantification of confocal endomicroscopic images may be useful for the differential diagnosis and diagnosis of superficial invasion by squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Background: We have tested the effects of aminopeptidase A (APA), MgSO4 and various conventional antihypertensive drugs on hypertension in pregnant spontaneously hypertensive rats (SHRs) and examined the effects on both fetal heart and kidney. Methods: We used recombinant human APA, which has been recently shown to work as an antihypertensive agent in SHRs (n =5). Each drug was administered from gestational day 10 to day 20 and each dose was increased daily up to 10 fold until the end of treatment except for MgSO4 (n =5 per each group). Blood pressure (BP) was monitored and fetal kidneys and heart were histologically examined. Results: The antihypertensive effects of the drugs were in the following order: hydralazine>aminopeptidase A and angiotensin receptor blockers (ARBs), candesartan>MgSO4 and methyldopa. Microscopic examination showed that fetal exposure to candesartan is associated with poor proximal tubular differentiation in the kidney and that to MgSO4 is associated with poor blood vessel formation in the heart, respectively. Conclusions: Our present study showed that APA is one of the candidates for antihypertensive agents in hypertension during pregnancy. [Copyright &y& Elsevier]

The unfolded protein response (UPR), which is induced by stress to the endoplasmic reticulum (ER), is involved in the functional alteration of certain cells, such as the differentiation of B cells to plasma cells. The aim of this study is to determine whether the UPR is activated during epidermal keratinocyte (KC) differentiation. Here, we show that the expression of the UPR-induced proteins Bip/GRP78 and HRD1 was increased in cells in the supra-basal layers of normal human epidermis that contain KCs undergoing differentiation as well as in skin-equivalent cultured KCs. However, Bip/GRP78 and HRD1 were poorly expressed in proliferating KCs in squamous cell carcinoma and psoriasis vulgaris tissues. The epidermal growth factor receptor tyrosine kinase inhibitor, PD153035, which induces KC differentiation, upregulated UPR-induced marker mRNAs and proteins. Furthermore, microarray analyses and quantitative PCR revealed that ER stress-inducing reagents, tunicamycin (TU), thapsigargin, and brefeldin A, altered the expression of genes essential for human epidermal KC differentiation, including C/EBPβ, KLF4, and ABCA12 in vitro. However, ABCA12 and KLF4 mRNA did not increase with TU treatment after siRNA-mediated knockdown of XBP-1. Taken together, our findings strongly suggest that the UPR is activated during normal epidermal KC differentiation and induces C/EBPβ, KLF4, and ABCA12 mRNAs.Journal of Investigative Dermatology (2009) 129, 2126–2135; doi:10.1038/jid.2009.51; published online 12 March 2009 [ABSTRACT FROM AUTHOR]

Abstract: Background: In epithelial ovarian cancer (EOC), fertility-sparing surgery (FSS) has mainly been chosen for stage IA disease. The purpose of this study was to clarify the clinical outcome of patients with clear-cell carcinoma of the ovary (CCC) who would usually undergo radical surgery. Cases: After a central pathological review and search of the medical records from multiple institutions between 1988 and 2005, a total of 10 CCC patients treated with FSS were retrospectively evaluated in the current study. The mean age was 35.9 years (range: 32–39 years). The median follow-up time was 35.4 months (range: 21.7–153.2 months). The stage was IA in 4 patients, and IC in 6 patients {IC(b) in 5 patients, and IC(2) in one}. Nine patients received adjuvant chemotherapy. Nine patients were alive and one patient with stage IC(2) died of the disease at a follow-up time of 36.8 months. Five pregnancies were observed in 4 patients. Conclusions: Although there is no worldwide criterion for FSS in CCC patients at present, it seems that, in selected patients, this surgical approach could be adopted. This should be investigated by additional studies in a larger series. [Copyright &y& Elsevier]

Perineural invasion is commonly observed in biliary tract cancer and is an independent prognostic factor. Since intrahepatic cholangiocarcinoma (ICC) develops from biliary epithelia in the liver, ICC may share the same characteristics in terms of the prognostic implications of perineural invasion. The aim of this study was to evaluate the clinical significance of perineural invasion in ICC. A total of 59 patients with ICC who underwent hepatectomy were retrospectively reviewed. The numbers of nerves with and without tumor involvement were counted. The perineural invasion index (PNI) was calculated as the number of involved nerves divided by the total number of nerves examined. Predictors for perineural invasion and prognostic factors were analyzed. Perineural invasion was observed in 47 of 59 (80%) patients, and the median PNI was 0.082. The macroscopic tumor appearance and tumor location were significantly associated with perineural invasion ( p = 0.013 and 0.032, respectively). Univariate and multivariate analyses (excluding seven in-hospital deaths) revealed that histologic grade, the presence of perineural invasion, nodal metastasis, and intrahepatic metastasis were independent prognostic factors. The survival rate of the patients with ( n = 42) or without ( n = 10) perineural invasion was 17 and 80% at 3 years; and 17 and 70% at 5 years, respectively ( p = 0.001). Perineural invasion is frequently found in patients with ICC and is an independent prognostic factor. ICC is an aggressive tumor similar to other biliary tract cancers. Because perineural invasion is a histologic marker of aggressiveness, it potentially has a role as a determinant of patient selection for adjuvant therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Twin pregnancy consisting of a complete hydatidiform mole (CHM) along with a live co-existing fetus is a rare entity and difficult to diagnose. A 37-year-old Japanese woman demonstrated a living fetus, a placenta and a multicystic mass within one gestational sac on ultrasound at 10 weeks. Termination of the pregnancy was performed, and the specimen was classified as partial mole by macro- and microscopic findings. The karyotype of the molar tissue was 46XX. DNA polymorphism analysis demonstrated that fetal DNA showed bi-parental origin while molar DNA showed paternal origin only. Thus, this case was erroneously classified by ultrasonography, macroscopic and pathologic findings, then correctly diagnosed as a twin pregnancy with a CHM and co-existing normal twin fetus by DNA polymorphism analysis. Immunohistochemistry of p57(KIP2), the paternally imprinted and maternally expressed gene, supported the genetic diagnosis. This case suggested that conventional diagnostic methods were inadequate for accurate diagnosis of CHM with a co-existing fetus. DNA polymorphism analysis should be requested for the diagnosis of hydatidiform mole, especially in cases where it is difficult to discriminate between partial hydatidiform mole and CHM with a co-existing fetus. [ABSTRACT FROM AUTHOR]

Malignant peripheral nerve sheath tumor (MPNST) can be difficult to diagnose because it lacks specific immunohistochemical markers. S-100, which is a useful marker of MPNST, has limited diagnostic utility. Recent studies suggest that nestin, which is an intermediate filament protein, is expressed in neuroectodermal stem cells. The diagnostic utility of immunostains for nestin and three other neural markers (S-100, CD56 and protein gene product 9.5 (PGP 9.5)) were evaluated in 35 cases of MPNST and in other spindle cell tumors. All MPNST cases were strongly positive for nestin and had cytoplasmic staining. Stains for S-100, CD56, and PGP 9.5 were positive in fewer cases (17/35, 11/35, and 29/35 cases, respectively), and had less extensive staining. Nestin was negative in 10/10 leiomyomas, and weak nestin expression was seen in 10/10 schwannomas, 3/10 neurofibromas, 2/8 synovial sarcomas, 2/10 liposarcomas, 4/7 carcinosarcomas and 3/7 malignant fibrous histiocytomas. In contrast, strong nestin positivity was seen in 10/10 rhabdomyosarcomas, 15/19 leiomyosarcomas, and 9/9 desmoplastic melanomas. Nestin is more sensitive for MPNST than other neural markers and immunostains for nestin in combination with other markers could be useful in the diagnosis of MPNST. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [Copyright &y& Elsevier]

Objective: To assess the expression and cellular distribution of angiotensin II (Ang II), angiotensin type 1 receptor (AT1R), angiotensin-converting enzyme (ACE), aminopeptidase A (APA), adipocyte-derived leucine aminopeptidase (A-LAP), and vascular endothelial growth factor (VEGF) in human ovarian tissue during the menstrual cycle.Design: Ovarian tissues (n = 52) and corpora lutea (n = 34) were obtained from patients undergoing hysterectomy/oophorectomy, and tissue sections were immunostained for each antigen.Setting: University hospital.Patient(s): Patients undergoing hysterectomy or oophorectomy for benign conditions.Intervention(s): Immunostaining of tissue sections using antibodies to each antigen.Main Outcome Measure(s): Microscopic evaluation to assess the presence, distribution, and cellular localization.Result(s): The luteal tissue is the major site of Ang II, ACE, AT1R, and VEGF, with highest staining intensity found during the midluteal phase and at pregnancy. The AT1R was found in theca cells. The APA was strongly immunolocalized in pericytes. Immunolocalization of AT1R was almost similar to that of VEGF including oocytes in the primordial and intermediate follicles.Conclusion(s): The expression and distinct pattern of the cellular localization of Ang II and its related proteins in human ovarian tissue during folliculogenesis and in the luteal tissue suggest their roles in the growth and differentiation of theca, granulose, and luteal cells. [ABSTRACT FROM AUTHOR]

Tumor–stromal interactions are important for the progression of malignant tumors. The purpose of the present study was to examine interactions of cholangiocarcinoma (CC) cells and stromal fibroblasts with respect to stromal-derived factor-1 (SDF-1) and transforming growth factor (TGF)-β1. Two cell lines of CC (HuCCT-1 and CCKS-1) and WI-38 fibroblast cell line were used for cell culture, and 12 CC tissue specimens for immunohistochemical studies. Invasion of CC cells was increased significantly by the supernatant from fibroblast cultures, but not by the supernatant from fibroblasts cocultured with CC cells. Expression of SDF-1 in cultured fibroblasts was downregulated by TGF-β1 treatment, and coculture with CC cells and anti-TGF-β1 neutralizing antibody restored the decreased SDF-1 expression, suggesting that TGF-β1 secreted from CC cells might have reduced the expression of SDF-1 by fibroblasts and might have reduced the increased invasion of CC cells induced by the supernatant from fibroblasts. Immunohistochemical expression of TGF-β1 in CC cells was focal or negative and that of SDF-1 was evident in stromal fibroblasts at the invasive front of CC. In conclusion, local mutual influence of TGF-β1 secreted from carcinoma cells and SDF-1 expressed by stromal fibroblasts may be involved in invasion of CC cells. [ABSTRACT FROM AUTHOR]

Abstract: Background: Infectious mononucleosis owing to primary Epstein-Barr virus (EBV) infection sometimes causes hepatitis, which is usually self-limiting with mildly elevated transaminases, but can rarely develop into severe hepatitis with jaundice. Objective: To clarify the pathogenesis of severe hepatitis by primary EBV infection. Methods: We experienced four cases of severe hepatitis with jaundice caused by primary EBV infection. These cases were analyzed virologically and histologically, and compared with infectious mononucleosis patients without jaundice. Results and discussion: Using real-time PCR, more EBV-DNA was detected in peripheral blood from patients with severe hepatitis, as compared to those without jaundice. Furthermore, CD3+, CD4+ or CD8+ cells contained more EBV DNA than did other cell populations, indicating that in severe hepatitis, T cells harbor most of the EBV. By contrast, mainly B cells were infected in infectious mononucleosis patients without jaundice. The liver was biopsied in three of the four cases. An in situ hybridization study showed that EBV infected lymphocytes, not hepatocytes. In addition, in one patient, it was confirmed that the infected lymphocytes were CD8+ T cells. These results suggest that a large EBV burden and T cell infection may play major roles in the mechanism of severe hepatitis caused by primary EB virus infection. [Copyright &y& Elsevier]

Abstract: The possible role of calcineurin in cardiac hypertrophy induced by calmodulin (CaM) overexpression in the heart was investigated. CaM transgenic (CaM-TG) mice developed marked cardiac hypertrophy and exhibited up-regulation of atrial natriuretic factor (ANF) and β-myosin heavy chain gene expression in the heart during the first 2 weeks after birth. The activity of calcineurin in the heart was also significantly increased in CaM-TG mice compared with wild-type littermates. Treatment of CaM-TG mice with the calcineurin inhibitor FK506 (1mg/kg per day) prevented the increase in the heart-to-body weight ratio as well as that in cardiomyocyte width. FK506 also inhibited the induction of fetal-type cardiac gene expression in CaM-TG mice. Overexpression of CaM in cultured rat cardiomyocytes activated the ANF gene promoter in a manner sensitive to FK506. Activation of a calcineurin-dependent pathway thus contributes to the development of cardiac hypertrophy induced by CaM overexpression in the heart. [Copyright &y& Elsevier]

Summary: The epidermal growth factor receptor (EGFR) gene has recently been reported to be mutated in a subset of non-small cell lung cancers (NSCLC), with the mutations being correlated with the patients’ drug sensitivity to gefitinib, an EGFR kinase inhibitor. In this study, we searched for EGFR mutations in patients with lung cancer using primary tumor specimens obtained at initial surgery and examined whether their recurrent tumors showed a response to gefitinib depending on the presence of the activating mutation. Among 12 lung cancers that were treated with gefitinib after recurrence, we found that all four tumors which showed a response to gefitinib had an activating mutation in EGFR, whereas none of the remaining eight tumors had a mutation. Southern blot analysis showed that two of the four responsive tumors had the EGFR gene amplification. We also examined another 73 NSCLC specimens (47 males and 26 females; 53 adenocarcinomas and 20 non-adenocarcinomas) which were not treated with gefitinib to determine whether NSCLCs with an EGFR mutation have different clinicopathological properties and/or unique genetic alterations of the other cancer-associated genes. We found that 13 (18%) of 73 tumors had a mutation of the EGFR gene, with the most being detected in female adenocarcinomas. Comparing the alterations in KRAS and P53 with the EGFR mutation, we found that 10 tumors with the KRAS mutation did not have an EGFR mutation, suggesting that each mutation occurs exclusively during the development of lung cancer. These results suggest that the mutation analysis of the EGFR gene using the specimens obtained at surgery might be useful in selecting the appropriate treatment(s) for recurrent lung cancer patients. [Copyright &y& Elsevier]

Abstract: Background: When resecting at falcine or parasagittal portion of paramedian meningiomas, intraoperative hemostasis often is difficult despite effective management of ipsilateral meningeal arteries. We attribute such difficulties to meningeal artery blood supply from the contralateral side. We retrospectively studied feeding arteries from both sides in case of paramedian meningioma in terms of patient and tumor characteristics. Methods: Forty-three patients with paramedian meningiomas underwent selective internal and external carotid angiography. We investigated how contralateral meningeal arterial feeders related to patient profiles and imaging, histopathologic, and immunohistochemical findings. Results: Contralateral meningeal supply existed for 14 of 25 falcine meningiomas and 6 of 18 parasagittal meningiomas. Patients with contralateral feeders were 8.5 years younger than the others (P = .027) and were more likely to have larger tumors (P = .028). These were histopathologically malignant (P = .048), while showing more proliferation followed by monoclonal antibody against the Ki-67 antigen index (P = .012) and angiogenetic potential associated with vascular endothelial growth factor expression (P = .0085). Conclusions: Contralateral meningeal supply may reflect strong angiogenetic recruitment from rapid tumor growth followed by high expression of vascular endothelial growth factor. This angiographical feature may predict the aggressive growth of paramedian meningiomas. [Copyright &y& Elsevier]

Aim : To investigate whether measuring prostate specific antigen complexed to α1-Antichymotrypsin (PSA-ACT) can increase sensitivity and specificity in detecting prostate cancer. Methods : In this prospective study, we measured serum total PSA, PSA-ACT, free PSA, prostate volume and transition zone volume on 210 patients with total PSA level of 4–20 ng/mL. From fitted curves between positive predictive values for prostate cancer and age, prostate volume, transition zone volume, total PSA, PSA-ACT or F/T ratio, each function predicting prostate cancer was determined. Relative probabilities for prostate cancer (RPpca) which were defined by combined functions of age, F/T ratio, prostate volume or transition zone volume, and total PSA or PSA-ACT were calculated. Furthermore, using logistic regression, analysis was performed to determine the probability of prostate cancer. Receiver-operating characteristic analysis was performed to clarify the areas under the curve (AUC) for conventional single parameters, RPpca and logistic regression probability. Results : F/T ratio showed the largest AUC among conventional parameters. The AUC of RPpca was larger than those of F/T ratio and logistic regression probability. RPpca using the functions of age, transition zone volume, PSA-ACT and F/T ratio showed the largest AUC and highest specificity at sensitivity 95% level, however, specificities at sensitivity 90% and 85% were identical to those of RPpca using the functions of age, prostate volume, total PSA and F/T ratio. Conclusions : RPpca using the functions of age, transition zone volume, PSA-ACT and F/T ratio was the best way to detect prostate cancer, however, the usefulness of PSA-ACT appears limited, considering the cost. [ABSTRACT FROM AUTHOR]

The authors have recently defined the clinopathological entity of a mucin-producing bile duct tumor (MPBT), and divided MPBT into two distinct subtypes: ‘columnar-type’ and ‘cuboidal-type’ MPBT. Mucin core protein 6 (MUC6), which is present in normal pyloric glands, had higher expression levels in cuboidal-type tumors than in columnar-type tumors. In the pyloric glands, a carbohydrate antigen detected by monoclonal antibody HIK1083 (CA/HIK1083) is also expressed. In order to evaluate the coexpression pattern of MUC6 and CA/HIK1083 in MPBT, expression profiles were evaluated in 38 surgically excised mucin-producing bile duct carcinomas (MPBC; cuboidal-type, n = 15; columnar-type, n = 23), using immunohistochemistry. The staining rate was graded as follows: –, <5% of neoplastic cells stained; +, 5% to <20%; + +, 20% to <50%; + + +, ≥50%. In cuboidal-type MPBC, MUC6 was positive in all cases (+ + +, 13/15; + +, 1/15; +, 1/15), whereas CA/HIK1083 was negative in all cases (–, 15/15; P < 0.0001). In columnar-type MPBC, MUC6 was positive in 65% of cases (+ + +, 6/23; + +, 8/23; +, 1/23; –, 8/23), and CA/HIK1083 was positive in 52% (+ +, 3/23; +, 9/23; –, 11/23; not significant). Our results clearly demonstrate that cuboidal-type MPBC have an aberrant pyloric glandular phenotype, that is, MUC6+/CA/HIK1083–. This unique profile may be related to different outcomes of patients with MPBC. [ABSTRACT FROM AUTHOR]

To investigate whether using a new concept of relative probability for prostate cancer (RPpca) can increase sensitivity and specificity in detecting prostate cancer.For 217 patients with total prostate-specific antigen (PSA) level of 4–20 ng/mL, prostate volume and free to total PSA (F/T) ratio were measured. From the fitted curves between positive predictive values for prostate cancer and age, prostate volume, total PSA or the F/T ratio, each function predicting prostate cancer was determined. RPpca defined by the combined functions of age, prostate volume, total PSA and F/T ratio was calculated for each individual patient. The probability of prostate cancer was also calculated, using logistic regression analysis (LRPpca). Receiver-operating characteristic analysis was performed to elucidate the areas under the curve (AUC), sensitivities and specificities and cutoff values of the conventional and new parameters. Finally, we investigated the applicability of the above parameters in the other patient group using a different PSA assay kit (AxSYM).Although RPpca had the largest AUC in the total PSA range of 4–20 ng/mL, it did not reach statistical significance between RPpca and F/T ratio or LRPpca. The cutoff values of F/T ratio, LRPpca and RPpca were determined as 0.15, 0.12 and 0.20, respectively. Using these cutoff values in AxSYM data, RPpca had the highest sensitivity (91%) and specificity (57%).RPpca can provide more precise information to avoid unnecessary biopsy than LRPpca or F/T ratio. RPpca could be valuable to decide whether to perform prostate biopsy when using various PSA kits. [ABSTRACT FROM AUTHOR]