Visceral-to-subcutaneous fat ratio is a possible prognostic factor for type 1 endometrial cancer.

BACKGROUND: Associations have been observed between obesity defined by the body mass index (BMI) and the incidence of endometrial cancer. However, the impact of obesity on the prognosis of endometrial cancer is not yet clear. Recently, visceral fat has been considered to have a greater impact on malignant disease in obese patients than subcutaneous fat. In this study, we investigated the association between prognostic factors of type 1 and type 2 endometrial cancer and obesity parameters. METHODS: The impacts of clinical factors on the progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in 145 primary endometrial cancer patients. The factors included age, BMI, pathological findings, Federation of Gynecology and Obstetrics (FIGO) stage, status of lymph node metastasis, and the amounts of visceral and subcutaneous fat obtained from computed tomography (CT) data. RESULTS: Only the visceral-to-subcutaneous fat ratio (V/S ratio) (cutoff value 0.5) corresponded to a significant difference in OS and PFS in type 1 endometrial cancer (p = 0.0080, p = 0.0053) according to the results of log-rank tests of Kaplan-Meier curves. The COX regression univariate analysis revealed that only the V/S ratio was a significant prognostic factor for PFS, but not OS (p = 0.033 and p = 0.270, respectively). CONCLUSION: A V/S ratio > 0.5 is a possible factor for poor prognosis in type 1 endometrial cancer. Further research is needed to investigate the preventive and therapeutic effects of reducing visceral fat on the prognosis of this type of cancer.

Serum lactate dehydrogenase is a possible predictor of platinum resistance in ovarian cancer.

OBJECTIVE: The need for tailoring ovarian cancer treatments to individual patients is increasing. This study aimed to evaluate the prognostic value of pretreatment laboratory test data for predicting the response and survival outcomes of platinumbased chemotherapy in ovarian cancer. METHODS: We enrolled 270 patients with ovarian cancer diagnosed at the Kyoto Medical Center (n=120; group A) and Kyoto University (n=150; group B). Data on 9 blood parameters (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte rate [PLR], C-reactive protein, lactate dehydrogenase [LDH], glucose, total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein, and triglyceride levels), cancer pathology, cancer stage, cytoreduction outcomes, serum cancer antigen 125 levels, platinum-free interval (PFI), disease-free survival (DFS), and overall survival were assessed retrospectively. RESULTS: NLR, PLR, LDH, and HDL were significantly different in advanced stage patients (P<0.001, <0.001, 0.029, and <0.001, respectively). The Kaplan-Meier curves revealed that high LDH level (≥250 U/L) was associated with reduced PFI (P=0.037 and 0.012) and DFS (P=0.007 and 0.002) in groups A and B, respectively. High NLR (≥4) was associated with reduced DFS in both groups (P=0.036 and 0.005, respectively). LDH showed higher area under the curve (AUC) values in predicting platinum resistance with a PFI of less than 6 months and 12 months (AUC=0.606 and 0.646, respectively) than NLR. In the multivariate analysis, LDH remained significant (P=0.019) after adjusting for the 9 blood parameters. CONCLUSION: Serum LDH level may possibly predict platinum resistance and prognosis in ovarian cancer and may be useful when developing precision medicine for individual patients.

Association of Dietary Change during Pregnancy with Large-for-Gestational Age Births: A Prospective Observational Study.

Being born with large birthweight is considered as a risk of non-communicable diseases later in life. However, it is not fully understood what kind of maternal dietary intake during pregnancy affect large birthweight. Therefore, we examined the association of dietary intakes and its changes during pregnancy with large-for-gestational-age (LGA) births in Japanese pregnant women. In the prospective study, 245 pregnant women who visited Kyoto Medical Center were enrolled. Nutrition survey using brief-type self-administered diet history questionnaire (BDHQ) at all trimester was completed in 171 pregnant women. Based on birthweight and gestational age, participants were divided into three groups, such as small-for-gestational-age (<10th, SGA, n=17), appropriate-for-gestational-age (≥10th and <90th, AGA, n=144), and LGA (≥90th, n=10) groups. Compared with those without LGA births, mothers with LGA births showed: 1) greater weight gain during pregnancy (LGA: 14.0±3.2 kg, AGA: 9.9±3.9 kg, SGA: 8.4±3.1 kg, p<0.05); 2) higher energy intake throughout pregnancy (LGA: 310±368 kcal, AGA: 7±490 kcal, SGA: -97±293 kcal, ptrend<0.05); 3) larger changes in plant oil and sucrose consumptions from the 1st to 2nd trimester, probably due to the results of greater consumption of bread, Western confectionery, Japanese confectionery, and mayonnaise and dressing during the same period (ptrend<0.05, respectively). Our results suggest that higher energy intake throughout pregnancy, as well as greater consumption of plant oil and sucrose from the first to second trimester could be associated with LGA births.

Full-term low birth weight infants have differentially hypermethylated DNA related to immune system and organ growth: a comparison with full-term normal birth weight infants.

OBJECTIVE: Low birth weight (LBW) is a major public health issue as it increases the risk of noncommunicable diseases throughout life. However, the genome-wide DNA methylation patterns of full-term LBW infants (FT-LBWs) are still unclear. This exploratory study aimed to analyze the DNA methylation differences in FT-LBWs compared with those in full-term normal birth weight infants (FT-NBWs) whose mothers were nonsmokers and had no complications. Initially, 702 Japanese women with singleton pregnancies were recruited. Of these, four FT-LBWs and five FT-NBWs were selected as references for DNA methylation analysis, and 862,260 CpGs were assessed using Illumina Infinium MethylationEPIC BeadChip. Gene ontology enrichment analysis was performed using DAVID v6.8 software to identify the biological functions of hyper- and hypomethylated DNA in FT-LBWs. RESULTS: 483 hyper-differentially methylated genes (DMGs) and 35 hypo-DMGs were identified in FT-LBW promoter regions. Hyper-DMGs were annotated to 11 biological processes; "macrophage differentiation" (e.g., CASP8), "apoptotic mitochondrial changes" (e.g., BH3), "nucleotide-excision repair" (e.g., HUS1), and "negative regulation of inflammatory response" (e.g., NLRP12 and SHARPIN). EREG was classified into "ovarian cumulus expansion" within the "organism growth and organization" category. Our data imply that LBW might be associated with epigenetic modifications, which regulate the immune system and cell maturation.

Association between socioeconomic status and small-for-gestational-age in Japan: A single center retrospective cohort study.

AIM: Small-for-gestational-age (SGA) status has negative health consequences in neonates and later life. Low socioeconomic status (SES) is a reported risk factor for adverse birth outcomes, such as SGA and preterm birth (PTB). The present study investigated whether maternal SES is associated with adverse outcomes in Japanese pregnant women. METHODS: Retrospective data were collected for 1970 Japanese women with singleton pregnancies who delivered between January 2007 and December 2011 at a single center: low SES group (n = 197); and controls (n = 1773). Low SES was defined according to the criteria of the Japanese pregnant-childbirth hospitalization support policy system. RESULTS: The low SES group included a significantly higher proportion of young women, women with single marital status, greater parity, pre-pregnancy smoking and a lack of regular employment (P < 0.001, respectively). The crude odds ratio (OR) for the association between low maternal SES and SGA was 1.80 (95% confidence interval [CI] 1.15-2.82, P = 0.010). After adjustment for baseline maternal age, parity, body mass index, smoking and gestational weight gain, the adjusted OR for the association between low maternal SES and SGA was 1.92 (95% CI 1.17-3.17, P = 0.010). No significant association was found between maternal SES and PTB. CONCLUSION: The present results suggest that low maternal SES is associated with SGA births in the Japanese population. Mitigation of low maternal SES could be urgent public health to prevent disadvantage birth outcome.

Primary retroperitoneal squamous cell carcinoma: a case report with review of the literature.

Squamous cell carcinoma originating in the retroperitoneal cavity is an exceedingly rare disease, and little is known about it. Here, we report the case of primary retroperitoneal squamous cell carcinoma. A 76-year-old gravida four para two woman with a history of hysterectomy for unknown reasons was referred to our hospital for an infant-head-sized multicystic pelvic mass. She was initially diagnosed with ovarian cancer Stage IIB, poorly differentiated carcinoma by exploratory laparotomy in which only a tumor biopsy was performed due to severe adhesion. She underwent 5 courses of combination chemotherapy with paclitaxel and carboplatin, which reduced the tumor from 14 to 6.5 cm. Interval debulking surgery proved that the tumor was in the retroperitoneal cavity and not associated with the ovaries. She was finally diagnosed with squamous cell carcinoma originating in the retroperitoneal cavity. Human papilloma virus type 16 was identified using polymerase chain reaction. Three more courses of paclitaxel and carboplatin were administered, and she has been without evidence of disease for 6 months. A comprehensive literature search identified seven similar cases of which four individuals had a history of abdominal hysterectomy. Four out of the seven cases were tested for the presence of P16, two for HPV; all the results were positive. These findings suggest that HPV could be the cause of squamous cell carcinoma on the pelvic peritoneum, and that past hysterectomy is a possible contributing factor.

Prevalence and Risk Factors of Elevated Liver Enzymes in Japanese Women With Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among reproductive-aged women. While PCOS is associated with an increased risk of obesity and insulin resistance, little is known regarding the prevalence of and risk factors for nonalcoholic fatty liver disease (NAFLD) among Japanese women with PCOS. We estimated the prevalence of and risk factors for elevated liver enzymes, as the index of NAFLD, in Japanese women with PCOS. METHODS: We retrospectively reviewed 102 reproductive-aged women who visited the Department of Gynecology, Kyoto Medical Center in Japan from January 2000 to September 2016. Inclusion criterion was confirmed diagnosis of PCOS using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10) codes. Exclusion criteria were women with a history of liver diseases, missing body mass index (BMI) and serum alanine aminotransferase (ALT) data, and pregnancy. Data regarding age; BMI; and levels of blood glucose, serum lipid, liver enzymes, and sex hormones were obtained from medical records. Elevated liver enzymes was defined as ALT > 19 IU/L. Optimal cutoffs for risk factors for elevated liver enzymes were calculated to determine predictors of elevated liver enzymes using area under the curve (AUC) by receiver-operating characteristics (ROC). RESULTS: The prevalence of elevated liver enzymes was 33.3%. BMI was significantly higher in PCOS patients than in those without elevated liver enzymes (25.3 vs. 20.7 kg/m2, P < 0.05). ROC analyses were performed using BMI and blood glucose and testosterone levels because BMI and blood glucose showed differences between the groups and testosterone is related to fatty liver. AUC of the model including BMI and blood glucose and testosterone levels was 0.861 (sensitivity, 66.7%; specificity, 100%). CONCLUSIONS: These findings suggest that elevated liver enzymes are common in women with PCOS. An algorism using BMI and blood glucose and testosterone levels might be useful to determine elevated liver enzymes in women with PCOS. Our finding may be useful for the study of NAFLD among Japanese women with PCOS since several previous studies have indicated elevated liver enzymes to be related to the potential presence of NAFLD. Further examination, including abdominal ultrasonography and/or liver biopsy data, is required to confirm these results.

Peutz-Jeghers syndrome-associated atypical mucinous proliferation of the uterine cervix: a case of minimal deviation adenocarcinoma ('adenoma malignum') in situ.

We describe a case of a non-invasive precursor of minimal deviation adenocarcinoma (MDA) of the uterine cervix, associated with Peutz-Jeghers syndrome (PJS). A 27-year-old woman, who had been followed for PJS, was referred to the gynecology clinic. Colposcopic examination demonstrated a small polypoid lesion in the transformation zone. Microscopic examination of the biopsy specimen demonstrated papillary proliferation of the mucinous epithelium with bland nuclear morphology. Conization revealed lobular endocervical glandular hyperplasia (LEGH) with distinct nuclear anaplasia, as well as papillary proliferation of the mucinous epithelium with mild to moderate nuclear abnormalities. This case suggests that the incipient phase of PJS-associated MDA is related to atypical LEGH ("MDA in situ"), and indicates the importance of early screening and surveillance by gynecologists in cases of PJS to detect cervical adenocarcinomas.

Mutational analysis of the PTEN gene in women with premature ovarian failure.

Recent studies in mammals have suggested that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) - phosphatidylinositol-3, 4, 5-trisphosphate pathway in oocytes might be related to the pathogenesis of premature ovarian failure (POF). The aim of this study was to investigate whether mutations of the PTEN gene are present in women with POF. We analyzed the coding region of the PTEN gene in 20 women with idiopathic POF and 20 normal controls. The PTEN gene was amplified by the polymerase chain reaction using genomic DNA isolated from blood samples. Amplified DNA was analyzed by denaturing gradient gel electrophoresis and direct sequencing. No causative mutation was detected in the coding regions of this gene. Although we found a point variation in exon 7 of one POF patient, this was a single nucleotide polymorphism that has already been reported.

Stress affects uterine receptivity through an ovarian-independent pathway.

BACKGROUND: Although stress is known to disturb natural fertility through the inhibition of the hypothalamic-pituitary-gonadal (HPG) axis, the impact of stress on infertile women who receive exogenous gonadal hormones is not well defined. This is probably due to lack of experimental models for evaluating the impacts of stress through an ovarian-independent pathway. The objective of this study was to investigate the possible impact of stress on uterine receptivity, independent of HPG axis dysfunction, using a mouse implantation model maintained with hormone supplementation. METHODS: Blastocysts from donor mice were transferred into the uterine lumen of ovariectomized (OVX) Balb/c female recipient mice following supplementation with estradiol and progesterone. The recipients were divided into two groups: those exposed (stress group) or not exposed (control group) to intermittent sonic exposure prior to embryo transfer (ET). The number of implantation sites (IS) was compared between these groups. Microarray analysis was performed to elucidate stress-induced molecular alterations in uteri during the implantation period. Sequential gene expression of leukemia inhibitory factor (Lif), an estradiol-inducible gene, was also analyzed using real-time PCR. RESULTS: A non-mating OVX model with satisfactory implantation rates was established. The number of IS in the stress group (n = 20) was significantly less than that in the control group (n = 18) (Mann-Whitney test, P = 0.0375). Implantation-related genes and ovarian-hormone-responsive genes were repressed in the stress group despite ovarian hormone supplementation. The expression of Lif was suppressed in the stress group. CONCLUSIONS: Stress can cause decreased uterine receptivity through an ovarian-independent pathway.

Lactoferrin is associated with a decrease in oocyte depletion in mice receiving cyclophosphamide.

OBJECTIVE: To investigate new important molecules involved in the regulation of chemotherapy-induced ovarian damage and, based on those results, to examine the effect of lactoferrin on cyclophosphamide (CPM)-induced ovarian failure. DESIGN: Complementary DNA microarray and the administration of lactoferrin. SETTING: Experimental animal study. ANIMAL(S): Female imprinting control region mice. INTERVENTION(S): Administration of CPM to mice, isolation of ovaries, isolation of RNA, microarray hybridization, and statistical analysis. According to the results of the microarray assay, administration of lactoferrin to CPM-treated mice, isolation of ovaries, isolation of RNA, and evaluation using quantitative polymerase chain reaction and histomorphometric analyses. MAIN OUTCOME MEASURE(S): A list of nine down-regulated and two up-regulated genes with reliable hybridization signals was obtained. Several target molecules were then investigated. RESULT(S): Among the listed genes, we focused on the mouse lactoferrin gene, because of its CPM-induced expression pattern and its multiple novel functions. Oral administration of bovine lactoferrin prevented down-regulation of the ovulation-related, Adamts1 and partial recovery of follicle depletion induced by CPM treatment. CONCLUSION(S): The present report suggests that lactoferrin helps to rescue the ability to ovulate and partially to prevent oocyte depletion in mouse ovaries.

Malignant transformation of mature cystic teratoma of the ovary including three cases occurring during follow-up period.

The aim of this study was to seek for factors which lead to the early diagnosis of malignant transformation from mature cystic teratoma. Fourteen patients with malignant transformation from mature cystic teratoma of the ovary were analyzed retrospectively for precise clinicopathology and prognosis. The results demonstrated that although all the patients with stage Ia disease were disease-free, only 2 out of 7 patients were stage Ic to IV and disease-free in the follow-up period. Pre-operative imaging correctly diagnosed tumors as malignant in all stage Ic to IV cases, but only in 2 out of 4 stage Ia cases with magnetic resource and none of the 2 cases with computed tomography, respectively. In malignant cases, elevation of the serum SCC and CEA was observed in 90.9 and 88.9%, respectively. On the other hand, in benign cases, a false positive elevation of the serum SCC and CEA was observed in 23.5 and 14.3%, which turned out to be normal in 40 and 52.9% cases in the repeated study, respectively. In conclusion neither imaging analysis nor tumor markers including SCC and CEA accurately diagnose malignant transformation of mature cystic teratoma in its early stage, suggesting that a combination of diagnostic means is important. In the follow-up cases, repeated measurement of serum markers proved useful in ruling out false positive cases.

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: utilization for ovarian cancer treatment.

Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L) has been considered to be a major route of delivery for tumor immunotherapy because expression of its receptor, FLT3, was detected predominantly in hematopoetic progenitor cells. However, several studies indicate that FLT3L locally overexpressed in tumor or dendritic cells (DCs) also shows an anti-tumor effect. In the current study, we found that FLT3 expression is not present in monocytes but is instead induced in DCs through the differentiation process resulting from stimulation by GM-CSF and IL-4. Addition of FLT3L further augmented FLT3 induction and also increased CD40 expression in DCs, leading to enhanced induction of lymphoblastoid cell line-targeted cytotoxic T-lymphocyte response and CD107a mobilization in CD8+ T cells. Furthermore, FLT3L also induced FLT3 expression in peripheral blood NK cells that showed an enhanced response detected by CD107a mobilization. In a murine ovarian cancer model, locally expressed FLT3L showed anti-tumor effects. Collectively, the current study indicates that FLT3L has an immunostimulatory effect on peripheral blood cells and FLT3L targeted to mature peripheral blood cells may serve as a useful tool for cancer immunotherapy.

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress.

PURPOSE: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and endometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress. EXPERIMENTAL DESIGN: Contents of human ovarian cysts, including 21 endometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in endometriotic cyst were determined in vitro. RESULTS: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-OHdG were also significantly higher in endometriotic cysts (P < 0.01). There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01). The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of endometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts. CONCLUSIONS: Abundant free iron in the contents of endometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.

Intractable recurrent cervical cancer with pelvic bone involvement successfully treated with external hemipelvectomy.

The indication of external hemipelvectomy for lateral recurrent cervical cancer involving the pelvic bone is controversial. We report the second longest surviving patient of recurrent cervical cancer successfully treated by external hemipelvectomy. A 38-year-old woman who had undergone conization for stage Ia1 cervical cancer six years earlier had severe right inguinal pain. A large multicystic recurrent tumor was identified in the right obturator region. After chemotherapy and chemoradiation, the tumor regressed, but soon relapsed. The patient's symptoms flared and the tumor was enlarged involving the right iliac bone. We performed right external hemipelvectomy with amputation of the right lower extremity, right iliac wing and ischiopubic bone. There was no major complication after the operation and the patient was discharged on postoperative day 48. After 27 months of follow-up, she has no complaints and is without evidence of recurrence. In selected cases of intractable lateral recurrent cervical cancer with pelvic bone involvement, relief from tumor-related pain and a possibility of prolonged survival can be expected by external hemipelvectomy.

Anatomic identification and functional outcomes of the nerve sparing Okabayashi radical hysterectomy.

OBJECTIVES: To clarify the anatomy necessary for the nerve sparing Okabayashi's radical hysterectomy, we meticulously separated the blood vessels and connective tissues to preserve the pelvic splanchnic nerve, the hypogastric nerve, and the bladder branch of the inferior hypogastric plexus under magnification (x2.5) during the Okabayashi radical hysterectomy. METHODS: Twenty-four patients (FIGO stage IB, n=22, and stage IIA, n=2) underwent meticulous nerve sparing radical hysterectomy during 2004 to 2006. Postoperative assessment of bladder function consisted of the time to (a) achieve a postvoid residual urine volume (PVR) less than 50 ml, (b) obtain a sensation of bladder fullness, and (c) obtain satisfaction of micturition. RESULTS: Isolation of the deep uterine vein could preserve one of the branches of the pelvic splanchnic nerve. The hypogastric nerve in the lateral rectal wall was isolated to the inferior hypogastric plexus. During the division of the posterior leaf of the vesicouterine ligament (VUL), isolation of the inferior vesical vein could reveal the bladder branch from the inferior hypogastric plexus. Only the uterine branch from the inferior hypogastric plexus was isolated and divided. Then, the T-shaped nerve plane consisting of the hypogastric nerve, the pelvic splanchnic nerve and the bladder branch from the inferior hypogastric plexus is preserved. Urinary functions: (a) 11 out of 24 patients had measured PVR of less than 50 ml by postoperative day (POD) 14 and all patients had achieved this by day 21 (mean POD: 14.64+/-2.04). (b) Twenty-two out of 24 patients reported a sensation of bladder fullness by POD 14 and all by POD 21 (mean POD: 11.25+/-1.78). (c) Seventeen out of 24 patients reported satisfaction of micturition by POD 14 and all by POD 21 (mean POD: 12.34+/-2.32). CONCLUSION: In order to accomplish the nerve sparing Okabayashi's radical hysterectomy, it is necessary to meticulously divide the posterior leaf of the vesicouterine ligament. By the separation of the inferior vesical vein in the posterior leaf of the vesicouterine ligament, the bladder branch from the inferior hypogastric plexus can be identified and preserved. All patients recovered their urinary function completely by POD 21.

Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity.

Ovarian cancer is the leading cause of death in women with gynecological malignancies, with prognosis of advanced stage tumors determined by chemotherapeutic response and the success of tumor resection. Since aberrant RAS pathway activation is frequent in ovarian cancer, study of in vitro RAS-induced transformation and accompanying genomic expression changes in ovarian surface epithelial cells is imperative for development of new therapeutic modalities and for understanding tumorigenesis. cDNA microarray analysis revealed TROPHONIN (TRO), a homophilic adhesion molecule involved in blastocyst implantation, was among the genes most downregulated by RAS induction. TRO expression is higher in cisplatin-sensitive cancer cell lines and positively correlates with prognoses in ovarian cancers. TRO knockdown by RNA interference conferred cisplatin resistance and led to increased invasiveness of cultured ovarian cancer cells. These findings underscore the importance of TRO in tumorigenesis, and suggest that TRO may be a useful biomarker for cisplatin sensitivity and invasive potential.

Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer.

The ligands for programmed cell death 1 (PD-1), an immunoinhibitory receptor belonging to CD28/cytotoxic T lymphocyte antigen 4 family, are PD-1 ligand 1 and 2 (PD-Ls). Recent reports suggest that the aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune evasion of the tumor cells. Although an inverse correlation between the expression level of PD-Ls and patients' prognosis has been reported for several malignant tumors, the follow-up period was limited because of the lack of the antibody (Ab) applicable to paraffin-embedded specimens. Here we generated a new Ab against PD-1 ligand 1 (PD-L1) and analyzed the expression level of PD-Ls in human ovarian cancer using paraffin-embedded specimens. Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-1 ligand 2 also had a poorer prognosis, the difference was not statistically significant. A significant inverse correlation was observed between PD-L1 expression and the intraepithelial CD8(+) T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor CD8(+) T cells. Multivariate analysis showed the expression of PD-L1 on tumor cells and intraepithelial CD8(+) T lymphocyte count are independent prognostic factors. The PD-1/PD-L pathway can be a good target for restoring antitumor immunity in ovarian cancer.

Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition.

OBJECTIVE: Neuropilin-1 (NRP-1) is a receptor for both semaphorin and vascular endothelial growth factor and is up-regulated in a variety of human cancers. While there are some reports of NRP-1 expression in ovarian neoplasm, those results differ in pattern of its expression and its role in ovarian cancer is still unclear. We sought to investigate the expression pattern and role of NRP-1 in ovarian cancer. METHODS: NRP-1 expression was analyzed with eighty-seven ovarian tissue samples by immunohistochemistry and four ovarian cell lines by quantitative RT-PCR and Western blotting. To detect its molecular role in ovarian cancer, WST-1 assay, invasion assay and soft agar assay were performed with or without NRP-1 suppression by the introduction of short hairpin RNAs. RESULTS: NRP-1 expression was found to be enhanced in ovarian cancer compared with ovarian surface epithelium (OSE), benign adenoma and tumors of low malignant potential. In vitro, NRP-1 expression was augmented threefold during malignant transformation of OSE cells with oncogene ras, suggesting an association between NRP-1 and oncogenesis. Suppression of NRP-1 reduced cell proliferation in a dense state, indicating that persistently high expression of NRP-1 in ovarian cancer enhances proliferation through evasion of contact inhibition. Suppression of NRP-1 also decreased cell growth in soft agar and invasion to the extracellular matrix in vitro. CONCLUSIONS: These results suggest that NRP-1 is not only associated with oncogenesis, but also with ovarian cancer malignancy, and this molecule is a targeting candidate for the treatment of ovarian malignancies.