Targeting Inhibitor of κB Kinase ß Prevents Inflammation-Induced Preterm Delivery by Inhibiting IL-6 Production from Amniotic Cells.

Preterm delivery (PTD) remains a serious challenge in perinatology. Intrauterine infection and/or inflammation, followed by increased inflammatory cytokines, represented by IL-6, are involved in this pathology. Our aim was to identify IL-6-producing cells in the placenta and to analyze the potential of targeting IκB kinase ß (IKKß) signaling to suppress IL-6 production for the treatment of PTD. Immunohistochemical analyses using placentas complicated with severe chorioamnionitis revealed that IL-6 is mainly expressed in human amniotic mesenchymal stromal cells (hAMSCs). Primary hAMSCs were collected, and strong IL-6 expression was confirmed. In hAMSCs, the treatment of tumor necrosis factor-α or IL-1ß drastically induced IL-6 production, followed by the phosphorylation of IKKs. A novel IKKß inhibitor, IMD-0560, almost completely inhibited IL-6 production from hAMSCs. Using an experimental lipopolysaccharide-induced PTD mouse model, the therapeutic potential of IMD-0560 was examined. IMD-0560 was delivered vaginally 4 hours before lipopolysaccharide administration. Mice in the IMD-0560 (30 mg/kg, twice a day) group had a significantly lower rate of PTD [10 of 22 (45%)] without any apparent adverse events on the mice and their pups. In uteri collected from mice, IMD-0560 inhibited not only IL-6 production but also production of related cytokines, such as keratinocyte-derived protein chemokine/CXCL1, macrophage inflammatory protein-2/CXCL2, and monocyte chemoattractant protein-1/chemokine ligand 2. Targeting IKKß signaling shows promising effects through the suppression of these cytokines and can be explored as a future option for the prevention of PTD.

Ovarian insufficiency following allogeneic hematopoietic stem cell transplantation.

Ovarian insufficiency is a serious complication for young women who undergo hematopoietic stem cell transplantation (HSCT). Reduced-intensity conditioning (RIC) has been utilized more widely due to its reduced toxicity; however, there is a lack of data concerning ovarian function after HSCT with RIC. We investigated the ovarian function in patients who received HSCT with RIC, compared to those who received myeloablative conditioning (MAC). The records of 69 female patients who received allogeneic HSCT at the institution under 40 years of age at transplantation from 1991 to 2012 were retrospectively analyzed. Prevalence of ovarian insufficiency was significantly lower in patients conditioned with RIC than in those conditioned with MAC (4/27 = 14.8% for RIC and 36/42 = 85.7% for MAC, p < 0.0001). A younger age at HSCT was associated with a lower risk of ovarian insufficiency. Among the 40 patients with ovarian insufficiency, four patients recovered ovarian function, and two conceived following hormone-replacement therapy (HRT). A higher serum E2 level prior to HRT was a significant predictor for the restoration of ovarian function (p = 0.0028). In conclusion, RIC was significantly less toxic to ovarian function compared with MAC. HSCT-associated ovarian insufficiency is not irreversible, and a higher E2 level may predict the restoration of ovarian function.

Whole-exome sequencing confirmation of a novel heterozygous mutation in RUNX1 in a pregnant woman with platelet disorder.

We describe a successful pregnancy and delivery in a patient with platelet disorder. Prophylactic platelet transfusions ensured that there were no bleeding complications during and after cesarean section. Following delivery, we performed whole exome sequencing, using next generation sequencing, to analyze the DNA samples of the patient and her family, and to identify the disease-causing mutation or variant. To identify de-novo mutations systematically, we also analyzed DNA isolated from the parents of the patient and the neonate. We successfully identified a causative novel mutation c.419 G > A (p.S140N) in RUNX1 in the patient and the neonate. Mutations of RUNX1 have been reported to be associated with familial platelet disorder and with a predisposition for myelodysplasia and/or acute myeloid leukemia. The patient and the neonate require careful long-term hematological follow-up. Identification of mutations by a through whole-exome analysis using next-generation sequencing may be useful in the determination of a long-term follow-up schedule for the patient.

Investigation of the clinicopathological features of squamous cell carcinoma of the vulva: a retrospective survey of the Tohoku Gynecologic Cancer Unit.

BACKGROUND: This multi-institutional study was conducted to clarify the clinicopathological features of squamous cell carcinomas of the vulva. METHODS: The medical records of vulvar cancer patients treated between 2002 and 2012 were retrospectively reviewed following approval by the Institutional Review Board of each institution. RESULTS: One hundred and eleven patients with vulvar malignancies were included. Of these, 63 patients had squamous cell carcinoma (57 %). Initial treatment was surgery, radiation therapy (RT), and concurrent chemoradiotherapy (CCRT) in 34 (54 %), 15 (24 %), and 11 (17 %) patients, respectively. Nineteen, 11, 26, and 7 patients had stage I, II, III, and IV disease, respectively. Of the 34 patients who had surgical treatment, 50 % had stage I disease, while 74 % of those who received CCRT had stage III or IV disease. Complete response (CR) rates for the surgery, RT, and CCRT groups were 73, 60, and 64 %, respectively. The 5-year survival rates for stage I/II and III/IV disease were 64 and 39 %, respectively (P = 0.019). The 5-year survival rates for the surgery, RT, and CCRT groups were 53, 38, and 50 %, respectively, and the prognosis of patients treated with surgery or CCRT was significantly better than that of patients who received RT (P < 0.05). In multivariate analysis, clinical response to initial treatment was an independent prognostic factor (P < 0.001). CONCLUSIONS: Although many patients had advanced-stage disease in the CCRT group, the therapeutic outcome for the surgery and CCRT groups was similar. Thus, CCRT may be a promising treatment for squamous cell carcinoma of the vulva.

miR-92a inhibits peritoneal dissemination of ovarian cancer cells by inhibiting integrin α5 expression.

Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin α5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin α5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin α5 expression correlates with a poor prognosis in Japanese patients with International Federation of Gynecology and Obstetrics stage III ovarian cancer. Based on an miRNA algorithm search, we identified hsa-mir-92a (miR-92a) as a candidate. The level of miR-92a expression was significantly inversely correlated with ITGA5 expression in various cancer cells. Transfection of precursor miR-92a reduced integrin α5 expression in ovarian cancer cells, which was accompanied by the inhibition of cancer cell adhesion, invasion, and proliferation. miR-92a overexpression reduced the luciferase activity of the ITGA5 3'-untranslated region, suggesting that ITGA5 mRNA is a direct target of miR-92a. In in vivo ovarian cancer xenografts, the enforced expression of miR-92a in HeyA-8 cells suppressed peritoneal dissemination. Although we still have a long way to go before an effective and nontoxic miRNA-based cancer therapy can be introduced into the clinic, the inhibition of integrin α5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment.

Uterine prolapse during late pregnancy in a nulliparous woman.

A pregnancy that is complicated by a uterine prolapse is rare and primarily occurs in multiparous women during their first or second trimester. In the present report, we describe a case of a 31-year-old nulliparous woman who experienced sudden uterine prolapse at 38 weeks' gestation without labor pains. The cervix was congested, the cervical mucosa was partially lacerated, and bleeding was noted; the protruding cervix could not be repositioned into her vagina. Although the cervical congestion worsened over time, she still did not experience any labor pains. She was delivered by emergency cesarean section. Following delivery, the prolapse promptly improved and did not recur before her 1-month postpartum examination. To our knowledge, this is the first case where uterine prolapse occurred in a nulliparous woman during late gestation.

Paclitaxel-carboplatin for advanced or recurrent carcinosarcoma of the uterus: the Japan Uterine Sarcoma Group and Tohoku Gynecologic Cancer Unit Study.

BACKGROUND: Paclitaxel and carboplatin (PC) have shown antitumor activity in carcinosarcoma of the uterus (CS). The purpose of this prospective multi-institutional study was to determine the response rate (RR), progression-free survival (PFS) and overall survival (OS) and to assess the toxicity of paclitaxel and carboplatin in patients with CS. METHODS: We conducted a phase II study in which patients were administered paclitaxel 175 mg/m(2) over a 3-h period followed by carboplatin (area under the serum concentration-time curve = 6) intravenously over a 30-min period on day 1 of each treatment cycle (3 weeks) until disease progression or adverse effects prohibited further therapy. Eligible patients had histologically confirmed, advanced stage (III or IV), persistent or recurrent measurable disease, and no prior chemotherapy. RESULTS: Six patients were enrolled between February 2006 and April 2009. The median age of the patients was 61 (range 48-77) years; one patient was stage IIIC (17 %) and five were stage IVB (83 %). Three patients (50 %) (1 at stage IIIC and 2 at stage IVB) received total abdominal hysterectomy plus bilateral salpingo-oophorectomy as part of the initial treatment; five (83 %) had homologous tumors and one (17 %) had a heterologous tumor. The median cycle number administered was 4.8 (range 2-7). The RR was 66.7 % (complete response, 2; partial response, 2); the PFS was 9.1 months and OS was not reached. The frequently observed Grade 4 toxicities were neutropenia (3 patients, 50 %). Manageable neutropenic sepsis developed in one patient. CONCLUSION: This is the first prospective multi-institutional study in Asia showing that PC may be effective and tolerable for the treatment of advanced or recurrent CS.

Targeting interleukin-6 receptor inhibits preterm delivery induced by inflammation.

Intrauterine infection is still a common trigger of preterm delivery (PTD) and also a determinant risk factor for the subsequent development of neurodevelopmental abnormalities in neonates. In this study, we examined the expressional pattern of various inflammatory cytokines such as interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α) in placentae complicated with severe chorioamnionitis (CAM) and found that IL-6 is mainly expressed in macrophages in villous mesenchyme by immunohistochemical analysis with anti-CD-68 antibody. Using an experimental lipopolysaccharide (LPS)-induced PTD model, the therapeutic potential of targeting this cytokine was investigated. Anti-IL-6 receptor antibody (MR16-1) was delivered 6 h before LPS treatment. Mice in the MR16-1 group had a significantly lower rate of PTD (17%) than in the controls (53%, P = 0.026). As a result, MR16-1 treatment significantly prolonged the gestational period (control; 18.4 ± 1.7d, MR16-1; 19.8 ± 1.5d, P = 0.007) without any apparent adverse events on the mice and their pups. In primary human amniotic epithelial cells, pretreatment with a humanized anti-human IL-6 receptor antibody, tocilizumab, significantly inhibited the production of prostaglandin E2 induced by IL-6. In conclusion, IL-6 was strongly expressed mainly in macrophages in villous mesenchyme in placentae complicated with CAM. Anti-IL-6R antibody significantly decreased the rate of PTD in LPS-induced inflammatory model in mice, and inhibited PGE2 production from human primary amniotic epithelial cells. Targeting IL-6 signaling could be a promising option for the prevention of PTD and needs to be further explored for future clinical application.

Ovarian tumors with functioning stroma: a clinicopathologic study with special reference to serum estrogen level, stromal morphology, and aromatase expression.

Ovarian tumors with functioning stroma often show estrogenic manifestations. The range of serum estrogen level, however, has not been analyzed, nor the correlation with the stromal morphology. We reviewed the preoperative serum level of estradiol (E2) in 20 postmenopausal ovarian tumors that contained lutein- or theca-like cells in the stroma. Tumor histology included mucinous (n=7), endometrioid (n=4), clear (n=4), or Brenner tumor (n=2), carcinosarcoma (n=2), and Krukenberg tumor (n=1). Overall, the preoperative serum level of E2 ranged widely from 12.1 to 162.4 pg/mL (reference range, 10-30 pg/mL). The range of serum E2 was 24.9 to 162.4 pg/mL (mean, 58.0 pg/mL) in 7 tumors containing lutein-like cells, and 12.1 to 157.8 pg/mL (mean, 57.0 pg/mL) in 13 tumors containing theca-like cells alone. There was no significant difference in the serum E2 level between the 2 groups. To determine whether the functioning stroma is capable of final conversion of androgens to estrogens, the expression of P450 aromatase was examined immunohistochemically. P450 aromatase was exclusively expressed in the stromal cells, both lutein- and theca-like cells, in 16 tumors. In all tumors, however, it was focally or sparsely distributed, and there was no correlation between the immunoreactivity for P450 aromatase and the serum E2 level. These findings indicate that the functioning stroma, regardless of cell morphology, has a capacity for converting androgens to estrogens, but a significant amount of serum estrogens is finally qualified in the aromatase-rich peripheral tissues.

Yolk sac tumor of the ovary: a retrospective multicenter study of 33 Japanese women by Tohoku Gynecologic Cancer Unit (TGCU).

Yolk sac tumor (YST) of the ovary is a rare germ cell tumor comprising about 1% of all ovarian malignancies. YST usually occurs as a rapidly growing unilateral tumor in young women. With the introduction of cisplatin, YST has been changed from a fatal tumor to a curable tumor. The standard treatment of YST consists of fertility-preserving surgery and 3 or 4 courses of adjuvant combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP). However, the long-term prognosis of BEP-treated YST patients has not been well studied. We therefore conducted a retrospective multicenter study to investigate the prognostic factors of 33 YST patients, including 25 patients treated with BEP. The median age at initial treatment was 20 years (range 10-53). There were 15 patients (at stage I), one (stage II), 16 (stage III), and one (stage IV). Nominal and grouped numerical values were analyzed by the Kaplan-Meier method. All patients had unilateral tumor, with right-side predominance (23 patients; P = 0.02). Eighteen patients had pure YST, 13 had mixed germ cell tumor with YST component, and other 2 patients were not specified. Twenty-eight patients received fertility-preserving surgery. Twenty-seven patients had optimal surgery with less than 1 cm residual tumor diameter. Median number of chemotherapy courses was 5. Median follow-up period was 49 months. The cumulative 5-year survival rate was 87%. Univariate analysis revealed the following significant prognostic factors (P < 0.05): stage, tumor diameter, and residual tumor. Extensive debulking surgery to minimize residual tumor would improve the prognosis.

Spontaneous perforation of pyometra: a report of seven cases and review of the literature.

BACKGROUND/AIMS: The spontaneous perforation of pyometra is very rare and is associated with a poor prognosis. The present study aimed to evaluate the clinical characteristics and prognostic factors for patient survival. PATIENTS AND METHODS: We reported on 7 patients with spontaneous rupture of pyometra. We also reviewed 47 additional published cases. Thus, all 54 patients were analyzed for mortality. RESULTS: We investigated the prognosis in 44 of 54 patients, excluding 8 patients with undocumented outcome and 2 who died of other diseases. The mortality rate was 25% (11 of 44). In univariate analysis, variables such as age, correct preoperative diagnosis, comorbidities, the presence of malignancy, and hysterectomy were not significant between surviving and deceased patients. In bacterial cultures from the peritoneal cavity, the most common etiological organisms were Escherichia coli and anaerobes such as Bacteroides and Peptococcus species. The rate of isolation of anaerobic bacteria was significantly increased in patients who died (odds ratio, 6.33; 95% confidence interval, 1.28-31.02; p = 0.04). CONCLUSION: Antibiotic therapy for E. coli and anaerobes should be considered in patients with spontaneous perforation of pyometra.

Effects of different trehalose concentrations in a warming medium on embryo survival and clinical outcomes in vitrified human embryos.

BACKGROUND/AIMS: In the present study, we examined the effects of different concentrations of trehalose in a warming medium on both embryo survival and clinical outcomes in vitrified-warmed embryo transfer cycles. METHODS: We retrospectively analyzed a total of 209 vitrified-warmed cycles from 177 patients who underwent in vitro fertilization or intracytoplasmic sperm injection and embryo transfer. Embryos were cryopreserved by the vitrification method and warmed in solutions containing either 0.5 or 1.0 M trehalose. We compared the 0.5 and 1.0 M trehalose warming solution groups with respect to the embryo survival rate after warming and clinical outcomes. RESULTS: The embryo survival rate in the 1.0 M trehalose group (96.5%) was significantly higher than that in the 0.5 M trehalose group (57.0%). The percentage of embryo transfers after warming in the 1.0 M trehalose group (94.3%) was significantly higher than that in the 0.5 M trehalose group (83.7%). The clinical pregnancy rate in the 1.0 M trehalose group (25.0%) was significantly higher than that in the 0.5 M trehalose group (11.1%). CONCLUSION: Embryo survival and clinical pregnancy rates were higher when a 1.0 M trehalose solution was used than when a 0.5 M trehalose solution was used during the embryo warming process.

Molecular mechanism of poor embryo development in postovulatory aged oocytes: mini review.

Oocyte quality is a key factor in determining embryo development; however, we have a poor understanding of what constitutes oocyte quality or the mechanisms governing it. Postovulatory aging of oocytes that have not been fertilized for a prolonged time after ovulation is known to significantly impair oocyte quality and subsequent embryo development after fertilization. Embryos derived from postovulatory-aged oocytes are prone to undergo apoptosis due to the decreased Bcl-2 expression. Postovulatory aging of oocytes changes the patterns of Ca(2+) oscillations at fertilization as a result of impaired Ca(2+) regulation in the endoplasmic reticulum. Moreover, postovulatory aging of oocytes impairs mitochondrial adenosine triphosphate production as a result of increasing oxidative stresses. Oxidative stresses also affect intracellular Ca(2+) regulation and impair embryo development after fertilization. Collectively, the mechanism of postovulatory oocyte aging might be involved in reactive oxygen species-induced mitochondrial injury followed by abnormal intracellular Ca(2+) regulation in the endoplasmic reticulum.

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

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

Estrogen induces neurite outgrowth via Rho family GTPases in neuroblastoma cells.

Estrogen (E2) has direct in vivo and in vitro effects, such as inducing neurite outgrowth, on neurons. We investigated the morphological changes and intracellular signaling pathway induced by E2 in neuroblastoma (SH-SY5Y) cells. The effect of medroxyprogesterone acetate (MPA) or progesterone (P4) on the E2-induced neurite outgrowth was also examined using SH-SY5Y cells. Neurite outgrowth was induced by E2 in association with the phosphorylation of Akt, and these effects of E2 were abolished by MPA but not by P4. Progesterone receptor antagonist RU486 blocked the inhibitory effects of MPA. Estrogen receptor antagonist ICI 182,780 and phosphatidylinositol 3-kinase inhibitor LY294002 inhibited the E2-induced neurite outgrowth. Because the Rho family of small GTPases has been shown to be involved in the regulation of neurite outgrowth, we examined the cross-talk among Rac1, Cdc42 and RhoA in the E2-induced neurite outgrowth. E2 immediately increased the Rac1 and Cdc42 activity and decreased the RhoA activity. E2-induced neurite outgrowth was attenuated in cells expressing dominant-negative mutants for Rac1 or Cdc42. These results suggest that regulation of Rho family GTPase activity by E2 is important for the neurite outgrowth in neuroblastoma cells, and that MPA may have an antagonistic effect against E2.

A case of boomerang dysplasia with a novel causative mutation in filamin B: identification of typical imaging findings on ultrasonography and 3D-CT imaging.

Boomerang dysplasia is a rare lethal osteochondrodysplasia characterized by disorganized mineralization of the skeleton, leading to complete nonossification of some limb bones and vertebral elements, and a boomerang-like aspect to some of the long tubular bones. Like many short-limbed skeletal dysplasias with accompanying thoracic hypoplasia, the potential lethality of the phenotype can be difficult to ascertain prenatally. We report a case of boomerang dysplasia prenatally diagnosed by use of ultrasonography and 3D-CT imaging, and identified a novel mutation in the gene encoding the cytoskeletal protein filamin B (FLNB) postmortem. Findings that aided the radiological diagnosis of this condition in utero included absent ossification of two out of three long bones in each limb and elements of the vertebrae and a boomerang-like shape to the ulnae. The identified mutation is the third described for this disorder and is predicted to lead to amino acid substitution in the actin-binding domain of the filamin B molecule.

Bezafibrate restores the inhibition of FSH-induced follicular development and steroidogenesis by tumor necrosis factor-alpha through peroxisome proliferator-activated receptor-gamma pathway in an in vitro mouse preantral follicle culture.

We recently reported that bezafibrate, a lipid-lowering drug of the fibrate class, administered in addition to clomiphene citrate (CC) successfully induced ovulation in CC-resistant polycystic ovary syndrome (PCOS) patients. We hypothesized that bezafibrate may directly affect ovarian follicle development. Insulin resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS. In this study, we first examined the effects of tumor necrosis factor-alpha (TNF), which plays a role in insulin resistance, on follicle development by using the follicle culture system. TNF significantly inhibited follicle-stimulating hormone (FSH)-induced follicle development, 17beta-estradiol (E2) secretion, and ovulation rate in a dose-dependent manner. We then examined whether bezafibrate treatment could rescue the inhibition of FSH-induced follicle development and steroidogenesis by TNF. Bezafibrate treatment rescued inhibition of follicle development, secretion of E2, and ovulation rate by TNF. We examined the expression of peroxisome proliferator-activated receptor (PPAR) subtypes in mouse preantral follicles. As the protein expression of only PPARG was observed in mouse preantral follicles, we examined whether bezafibrate could affect follicle development and steroidogenesis through PPARG pathways. Treatment with GW1929, a selective PPARG agonist, restored inhibition of FSH-induced follicle development and steroidogenesis by TNF, whereas treatment with GW9662, a selective PPARG antagonist, canceled the restorative effects of bezafibrate. Collectively, the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by TNF through the PPARG pathway.

Validation of the histologic grading for ovarian clear cell adenocarcinoma: a retrospective multi-institutional study by the Japan Clear Cell Carcinoma Study Group.

Pathologic slides from 150 patients with clear cell adenocarcinoma from the collaborating institutions were reviewed independently by 2 pathologists, and each tumor was graded histologically using the Shimizu-Silverberg and International Federation of Gynecology and Obstetrics (FIGO) grading systems. For the Shimizu-Silverberg grading system, 3 parameters-architectural pattern, nuclear pleomorphism, and mitotic activity-were assessed and scored as 1 to 3. When the summed scores of these parameters were 3 to 5, 6 to 7, and 8 to 9, grades 1, 2, and 3 were assigned, respectively. The FIGO grade was based on the ratio of glandular/papillary growth versus solid growth: grade 1, less than 5% solid tumor; grade 2, 5% to 50% solid tumor; grade 3, greater than 50% solid tumor. Interobserver agreement levels for assignment of both gradings were fair (κ=0.32 and 0.24, respectively). After consensus had been acquired, 82 (55%), 56 (37%), and 12 (8%) tumors were classified as grades 1, 2, and 3 by the Shimizu-Silverberg grading system, and 88 (59%), 38 (25%), and 24 (16%) were classified as grades 1, 2, and 3 by the FIGO grading system, respectively. Survival analyses indicated that patients with grade 3 tumors, as defined by both the grading systems, tended to have a poor outcome, but any differences between them were not statistically significant. Multivariate analysis showed that only the presence of residual tumor after initial surgery was an independent prognostic factor for overall survival. These results suggest that the 2 tested grading systems have limited value for the prognostication of patients with clear cell adenocarcinoma, and that a more effective grading system for this tumor may be required.

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

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

Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study).

OBJECTIVE: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. PATIENTS AND METHODS: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). RESULTS: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). CONCLUSIONS: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.