Coexistence of ovarian cancer and peritoneal tuberculosis: a case report.

Peritoneal tuberculosis (TB) is known to mimic advanced ovarian cancer. In this case report, we describe a unique case of ovarian cancer (endometrioid carcinoma grade 3) at the International Federation of Gynecology and Obstetrics (FIGO) stage IC1 with pulmonary and peritoneal TB, which was suspected preoperatively to be a coexistence of advanced ovarian cancer and pulmonary TB. A 68-year-old woman presented with a prominent abdominal mass and fever. Laboratory investigations, imaging, and sputum analysis indicated a probable diagnosis of ovarian cancer at FIGO stage IIIC, characterized by peritoneal dissemination and para-aortic lymph node metastasis, which was further complicated by coexisting pulmonary TB. Surgical management included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy. Intraoperatively, the tumor was localized to the right ovary with significant peritoneal thickening and adhesions indicative of peritoneal TB. The surgery was completed without apparent complications. Postoperative histopathological evaluation confirmed grade 3 endometrioid carcinoma in the right ovary along with evidence of peritoneal TB. Given the extent of adhesions attributed to TB, lymph node dissection for staging was deemed challenging and was thus not pursued. Initiation of anti-TB treatment on postoperative day 2 resulted in marked regression of the preoperatively identified pulmonary nodules and para-aortic lymph node enlargement, suggesting their inflammatory origin from TB. Although postoperative chemotherapy is typically advocated for patients with stage IC1 endometrioid carcinoma grade 3, the patient opted against it. Consequently, no adjuvant therapy was administered and the patient remained under close observation.

Successful fertility preservation in stage II endometrial carcinoma with long-term progestin therapy: A case report.

Progestin therapy is a fertility-sparing treatment option for well-differentiated stage IA endometrioid carcinomas without myometrial invasion. Here, we present a case of successful pregnancy and live birth following long-term progestin therapy in a patient with stage II well-differentiated endometrioid carcinoma. A 30-year-old nulliparous woman with an unremarkable medical history presented with abnormal uterine bleeding. A 45 mm mass was identified in the lower uterine segment. An endometrial biopsy revealed grade 1 endometrioid carcinoma, leading to a diagnosis of stage II uterine corpus cancer based on hysteroscopic findings. The patient refused surgical treatment and underwent oocyte retrieval and cryopreservation at another hospital. A subsequent endometrial biopsy revealed a marked reduction in the Ki-67 index from approximately 60 % to less than 10 %, suggesting the possibility of a hormone-sensitive tumor. The patient persistently refused surgery. Therefore, progestin therapy with medroxyprogesterone acetate (MPA) at a dose of 400 mg/day was initiated as a temporary measure until the patient would accept surgery. The tumor gradually reduced in size and eventually disappeared after 9 months. The MPA therapy was discontinued uneventfully after 20 months. Sixteen months after the discontinuation of MPA therapy, atypical endometrial hyperplasia was detected, and a second round of MPA therapy was initiated. Progestin retreatment was successful and was discontinued at 6 months. Four years after the initial treatment, the patient achieved pregnancy through timed intercourse and delivered a healthy baby at 38 weeks of gestation.

Vaginal malignant peripheral nerve sheath tumor treated with complete surgical resection and postoperative radiation therapy.

Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms originating from or differentiating into nerve sheaths of peripheral nerves. Vaginal origin is rare, with only six vaginal primary cases reported to date. A 55-year-old woman presented to our hospital with a 7 cm vulvar mass. Tumor biopsy results were suspicious of sarcoma, and pelvic magnetic resonance imaging and hysterofiberscopy showed that the tumor originated from the lower vagina. The mass was transvaginally excised, and histological examination confirmed the diagnosis of a vaginal MPNST with negative surgical margins. The patient underwent radiotherapy because the risk of recurrence was high, owing to the large tumor size and high mitotic index. The patient remained recurrence-free for 1 year after the primary treatment. This is the first case of a high-risk vaginal MPNST that avoided early disease recurrence with additional radiotherapy after complete tumor resection.

Multidirectional Traction Method Using SURGICEL NU-KNIT and Surgical Suture in Robot-assisted Laparoscopic Surgery for Endometrial Cancer.

OBJECTIVE: To describe a novel approach to robot-assisted laparoscopic total hysterectomy (RH) for endometrial cancer that minimizes cancer sell spillage and develops a stable surgical field. DESIGN: Demonstration of the multidirectional traction method with narrated video footage. SETTING: Many reports have indicated that RH for endometrial cancer has the same or superior short-term results compared with conventional laparoscopic hysterectomy (LH), and the long-term prognosis is the same [1,2]. However, there are no randomized controlled trials of RH versus LH, and some previous reports [3] have suggested that RH has a worse prognosis than LH, so the long-term prognosis should be considered with caution. Factors that may affect the long-term prognosis include the use of uterine manipulators [4] and compression of the uterine body with robotic forceps without tactile sensation [3]. However, to the best of our knowledge, no surgical technique capable of avoiding these factors has been established yet. Herein, we report a multidirectional traction method using SURGICEL NU-KNIT (Ethicon; Johnson & Johnson Medical Ltd., Tokyo, Japan), a local hemostatic agent, and surgical sutures. INTERVENTION: Cut 2-0 Prolene (Ethicon; Johnson & Johnson Medical Ltd., Tokyo, Japan) with straight needles (ST-70) thread to 35 cm, stick a 1 × 2 cm piece of SURGICEL NU-KNIT, and make knots Fig. 1. This implement is used to puncture the incisional margins of the peritoneum and then the abdominal wall to bring the thread to the surface of the body, where it is grasped with forceps and fixed. By repeating this operation, multidirectional traction can be obtained Fig. 2. A manipulating suture is also attached to the uterus to minimize the compression of the uterine body with robotic forceps. CONCLUSION: The multidirectional traction method allows for reproducible stable surgical field development and minimizes cancer cell spillage by reducing uterine grasping by robotic forceps without the use of uterine manipulators.

Predictive score for postpartum hemorrhage in vaginal deliveries following frozen embryo transfer.

Objective: To develop a predictive score for life-threatening severe postpartum hemorrhage in vaginal deliveries following frozen embryo transfer. Materials and Methods: We conducted a retrospective cohort study of 315 singleton vaginal deliveries following frozen embryo transfer from 2017 to 2022. Severe postpartum hemorrhage was defined as hemorrhage exceeding 1500 mL. A predictive score was generated from maternal characteristics and obstetric complications before delivery. We performed multivariable logistic regression analysis using 2017-2020 data and assigned points to identified risk factors. The predictive score's accuracy was evaluated using 2021-2022 data. Results: A large baby (birth weight ≥3500 g), pre-delivery maternal body mass index ≥25 kg/m2, marginal or velamentous umbilical cord insertion, and history of postpartum hemorrhage were identified as risk factors. We assigned one point to a large baby, a pre-delivery maternal body mass index ≥25 kg/m2, and marginal or velamentous umbilical cord insertion, and two points to a history of postpartum hemorrhage. The sum of the points was defined as the predictive score. The cut-off was set at two points, with a score ≥2 points being the high-risk group and a score ≤1 point being the low-risk group. The predictive score demonstrated a sensitivity of 47.8%, specificity of 85.4%, positive predictive value of 45.8%, and negative predictive value of 86.4% in the 2021-2022 validation cohort. Conclusion: The predictive score identified severe postpartum hemorrhage in approximately half of the high-risk cases. Implementing measures such as autologous blood storage may facilitate rapid response during heavy bleeding and improve maternal prognosis.

The impact of assisted reproductive technology on the risk of postpartum hemorrhage: Difference by the mode of delivery and embryo transfer.

AIM: The frequency of postpartum hemorrhage (PPH) is increasing in developed countries, and some reports suggest that assisted reproductive technology (ART) increases various perinatal complications, including PPH. We investigated whether the effect of ART pregnancies on the incidence of PPH is modified by the mode of delivery. METHODS: A retrospective cohort study was performed. We analyzed the medical records of 2914 pregnant women, including 411 pregnancies achieved by ART, which were delivered in our hospital from 2017 to 2020. PPH was defined as hemorrhage exceeding the 90th percentile of blood loss per the mode of delivery and number of fetuses. Multivariable logistic regression analysis was used to assess the association between ART and PPH. Propensity score-matched analyses were used to assess the difference in the incidence of PPH by the mode of delivery. RESULTS: As previously reported, multivariable logistic regression analysis showed that ART pregnancy is an independent risk factor for PPH. Propensity score-matched analysis for with and without ART showed a 3.39-fold higher incidence of PPH for ART pregnancy in the vaginal delivery group (p < 0.001). CONCLUSIONS: The effect of ART pregnancies on the incidence of PPH differed depending on the mode of delivery. Only in vaginal delivery, ART pregnancy increased the incidence of PPH.

Analysis of gastric-type mucinous carcinoma of the uterine cervix - An aggressive tumor with a poor prognosis: A multi-institutional study.

OBJECTIVE: Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients. METHODS: Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome. RESULTS: Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P < 0.0001) and overall survival (P < 0.0001) were poorer in patients with GAS than in those with UEA. CONCLUSIONS: GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry: UMIN000007987.

Combination of Aprepitant, Azasetron, and Dexamethasone as Antiemetic Prophylaxis in Women with Gynecologic Cancers Receiving Paclitaxel/Carboplatin Therapy.

BACKGROUND The aim of this study was to evaluate the antiemetic effect of aprepitant and to determine how to provide triple combination therapy (aprepitant/azasetron/dexamethasone) to women receiving paclitaxel/carboplatin moderately emetogenic chemotherapy (MEC). MATERIAL AND METHODS The current study was a prospective study of 163 women with gynecologic cancers. We compared the digestive symptoms scores (nausea, vomiting, appetite loss, and dietary intake) of 37 women with ovarian cancers before and after aprepitant administration. We also compared these symptoms in women who underwent 193 cycles of triple combination therapy with symptoms of women who underwent 226 cycles of double combination therapy. For triple combination therapy, azasetron, dexamethasone (reduced dose: 40% of 20 mg), and aprepitant (125 mg) were administered on Day 1, followed by only aprepitant (80 mg) administration on Days 2 and Day 3. RESULTS In 37 women with ovarian cancer, three symptoms, nausea, appetite loss, and dietary intake, were significantly improved by primarily adding aprepitant to double combination therapy in the delayed phase of MEC. Upon comparing their digestive symptoms in all cycles, however, these three symptoms were not significantly different in the delayed phase. Furthermore, all four symptoms in all cycles were worse following triple combination therapy than following double combination therapy in the acute phase (p<0.02). The control of digestive symptoms was generally insufficient without the administration of dexamethasone. CONCLUSIONS Primary aprepitant as an addition to MEC demonstrated efficacy in improving digestive symptoms in the delayed phase. However, its effect may decrease with repeated use. To improve the antiemetic effect, the dose reduction of dexamethasone should be restricted on Day 1 and dexamethasone should be used throughout the delayed phase as well.

Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells.

PURPOSE: High VEGF expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSC), in ovarian cancer. EXPERIMENTAL DESIGN: High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and IHC for VEGF, CD8, and CD33. VEGF receptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1+ MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. In addition, the therapeutic effects of anti-Gr-1 antibodies were examined. RESULTS: Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocyte-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8+ T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8+ T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment. CONCLUSIONS: VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587-99. ©2016 AACR.

Groin lymph node detection and sentinel lymph node biopsy in vulvar cancer.

OBJECTIVE: To identify suitable diagnostic tools and evaluate the efficacy of sentinel lymph node (SLN) biopsy for inguinal lymph node metastasis in vulvar cancer. METHODS: Data from 41 patients with vulvar cancer were evaluated retrospectively, including magnetic resonance imaging (MRI) measurements, SLN biopsy status, groin lymph node metastasis, and prognosis. RESULTS: SLN biopsy was conducted in 12 patients who had stage I to III disease. Groin lymphadenectomy was omitted in five of the nine patients with negative SLNs. All SLN-negative patients who did not undergo groin lymphadenectomy showed no evidence of disease after treatment. On MRI, the long and short diameters of the inguinal node were significantly longer in metastasis-positive cases, compared with negative cases, in 25 patients whose nodes were evaluated pathologically (long diameter, 12.8 mm vs. 8.8 mm, p=0.025; short diameter, 9.2 mm vs. 6.7 mm, p=0.041). The threshold of >10.0 mm for the long axis gave a sensitivity, specificity, positive predictive value, and negative predictive value of 87.5%, 70.6%, 58.3%, and 92.3%, respectively, using a binary classification test. Decision tree analysis revealed a sensitivity, specificity, and accuracy of 87.5%, 70.6%, and 76.0%, respectively, with the threshold of >10.0 mm for the long axis on MRI. The criteria of >10.0 mm for the long axis on MRI predicted an advanced stage and poorer prognosis using a validation set of 15 cases (p=0.028). CONCLUSION: Minimally invasive surgery after preoperative evaluation on MRI and SLN biopsy is a feasible strategy for patients with vulvar cancer.

Comprehensive assessment of the expression of the SWI/SNF complex defines two distinct prognostic subtypes of ovarian clear cell carcinoma.

Somatic mutations in the ARID1A tumor-suppressor gene have been frequently identified in ovarian clear cell carcinoma (CCC) cases. BAF250a encoded by ARID1A is a member of the SWI/SNF complex, but the expression and mutation status of other SWI/SNF subunits have not been explored. The current study aimed to elucidate the biological and clinical significance of the SWI/SNF complex subunits, by assessing the expression and mutation status of SWI/SNF subunits, and distinct genomic aberrations associated with their expression. Of 82 CCC specimens, 38 samples presented no BAF250a expression, and 50 samples exhibited the loss of at least one subunit of the SWI/SNF complex. Cases which lack at least one SWI/SNF complex component exhibited significantly more advanced stages, faster growth and stronger nuclear atypia compared with SWI/SNF-positive samples (p<0.05). Although BAF250a expression is not related to poor prognosis, the group presenting the loss of at least one SWI/SNF complex subunit exhibited significantly shorter overall and progression-free survivals (p<0.05). A multivariate analysis suggested that the expression status of the SWI/SNF complex serves as an independent prognostic factor (p<0.005). The cases positive for all SWI/SNF subunits demonstrated significantly greater DNA copy number alterations, such as amplification at chromosomes 8q.24.3 and 20q.13.2-20q.13.33 (including ZNF217) and deletion at chromosomes 13q12.11-13q14.3 (including RB1), 17p13.2-17p13.1 (including TP53) and 19p13.2-19p13.12. In conclusion, the CCCs exhibiting the loss of one or multiple SWI/SNF complex subunits demonstrated aggressive behaviors and poor prognosis, whereas the CCCs with positive expression for all SWI/SNF components presented more copy number alterations and a favorable prognosis.

Magnetic resonance imaging findings and prognosis of gastric-type mucinous adenocarcinoma (minimal deviation adenocarcinoma or adenoma malignum) of the uterine corpus: Two case reports.

Our group previously documented the first, very rare case of primary gastric-type mucinous adenocarcinoma of the uterine corpus. Although this type of endometrial cancer appears to be similar to the gastric-type adenocarcinoma of the uterine cervix, its main symptoms, appearance on magnetic resonance imaging (MRI) and prognosis have not been fully elucidated due to its rarity. We herein describe an additional case of gastric-type mucinous adenocarcinoma of the endometrium and review the relevant literature. The two cases at our institution (Kyoto University Hospital, Kyoto, Japan) involved postmenopausal women with a primary complaint of abnormal genital bleeding. Microscopic examination of the hysterectomy specimens indicated a highly differentiated mucinous adenocarcinoma with a desmoplastic stromal reaction. Immunohistochemistry for HIK1083 and/or MUC6 was positive in both cases, suggesting a gastric phenotype. Both patients were diagnosed at an advanced stage, they relapsed or recurred immediately after adjuvant chemotherapy, and eventually succumbed to the disease. The main symptom of gastric-type mucinous adenocarcinoma of the uterine cervix is watery discharge, whereas abnormal genital bleeding in addition to watery discharge is mainly observed in the mucinous type of endometrial adenocarcinoma. Cystic cavities in the tumor are present on MRI in cases of endometrial origin, and prognosis is very poor due to resistance to chemotherapy. Thus, gastric-type mucinous adenocarcinoma of the uterine endometrium exhibits a clinical behavior that is similar to tumors originating from the uterine cervix, but is associated with distinguishing clinical symptoms. The incidence of gastric-type endometrial adenocarcinoma may be higher than expected.

Prediction of taxane and platinum sensitivity in ovarian cancer based on gene expression profiles.

OBJECTIVE: Prognoses of ovarian cancer (OC) have improved with the paclitaxel-carboplatin regimen. However, it remains unclear which cases exhibit a genuine benefit from taxane or from platinum. We aimed to predict taxane and platinum sensitivity in OC via gene expression. METHODS: We identified differentially expressed genes in responsive and resistant cases from advanced OC biopsy expression dataset GSE15622, containing responses to paclitaxel or carboplatin monotherapy. These genes generated a scoring system for prediction of drug response by applying single-sample gene set enrichment analysis. Discriminative metrics termed the T-score and C-score were derived. RESULTS: High C-score levels were significant in responders compared to non-responders in a separate cisplatin treatment dataset (GSE18864, p=0.043). High C-score groups also had significantly better progression-free survival in three OC datasets (The Cancer Genome Atlas, TCGA: p=0.02; GSE9891: p=0.03; GSE30161: p=0.001). In two additional datasets of advanced OC, high T-scores could associate taxane and platinum regimens with better survival than non-taxane and platinum regimens (GSE9891: p<0.0001; GSE3149: p=0.045), whereas in cases with low T-scores, different chemotherapeutic regimens did not result in a significant difference. Assessing TCGA and GSE9891, T-scores were elevated in the C1/Mesenchymal subtype, whereas C-scores were elevated in the C5/Proliferative subtype and were lower in the C1/Mesenchymal subtype (p<0.0001, respectively). C- and T-scores negatively correlated with each other, suggesting complementary roles of taxane and platinum. CONCLUSIONS: Our proposal and finding of a scoring system that could predict platinum or taxane response could be useful to develop individualized treatments to ovarian cancer.

Establishment of a Novel Histopathological Classification of High-Grade Serous Ovarian Carcinoma Correlated with Prognostically Distinct Gene Expression Subtypes.

Recently, The Cancer Genome Atlas data revealed four molecular subtypes of high-grade serous ovarian carcinoma (HGSOC) exhibiting distinct prognoses. We developed four novel HGSOC histopathological subtypes by focusing on tumor microenvironment: mesenchymal transition, defined by a remarkable desmoplastic reaction; immune reactive by lymphocytes infiltrating the tumor; solid and proliferative by a solid growth pattern; and papilloglandular by a papillary architecture. Unsupervised hierarchical clustering revealed four clusters correlated with histopathological subtypes in both Kyoto and Niigata HGSOC transcriptome data sets (P < 0.001). Gene set enrichment analysis revealed pathways enriched in our histopathological classification significantly overlapped with the four molecular subtypes: mesenchymal, immunoreactive, proliferative, and differentiated (P < 0.0001, respectively). In 132 HGSOC cases, progression-free survival and overall survival were best in the immune reactive, whereas overall survival was worst in the mesenchymal transition (P < 0.001, respectively), findings reproduced in 89 validation cases (P < 0.05, respectively). The CLOVAR_MES_UP single-sample gene set enrichment analysis scores representing the mesenchymal molecular subtype were higher in paclitaxel responders than nonresponders (P = 0.002) in the GSE15622 data set. Taxane-containing regimens improved survival of cases with high MES_UP scores compared with nontaxane regimens (P < 0.001) in the GSE9891 data set. Our novel histopathological classification of HGSOC correlates with distinct prognostic transcriptome subtypes. The mesenchymal transition subtype might be particularly sensitive to taxane.

The BMP signaling pathway leads to enhanced proliferation in serous ovarian cancer-A potential therapeutic target.

Members of the transforming growth factor-ß (TGF-ß) superfamily transduce signals via SMAD proteins. SMAD2 and SMAD3 mediate TGF-ß signaling, whereas SMAD1, SMAD5, and SMAD8/9 transduce bone morphogenetic protein (BMP) signals. We would like to identify the function of BMP/SMAD5 signaling in serous ovarian cancer. The protein levels of total SMAD5 and phosphorylated SMAD5 (pSMAD5) were examined by immunohistochemical analysis using clinical serous ovarian cancer samples. Following treatment with either recombinant BMP2 (rBMP2) or Dorsomorphin (DM), western blotting was performed to observe pSMAD5 protein in the cytoplasm and the nucleus, separately. Cell proliferation was detected in SMAD5 knockdown serous ovarian cancer cell lines cultured with DM or rBMP2. The impact of DM or rBMP2 on tumor growth was observed in a mouse model of serous ovarian cancer. An inverse correlation was observed between pSMAD5 levels in the nucleus and the prognosis of patients with serous ovarian cancer. The treatment of SK-OV-3 with rBMP2 stimulated pSMAD5 translocation from the cytoplasm to the nucleus, and the addition of DM inhibited this effect. The proliferation of ovarian cancer cell lines was enhanced by BMP2 and suppressed by DM via SMAD5 in vitro. In vitro and in vivo experiments clearly demonstrated BMP2-stimulated proliferation of serous ovarian cancer and inhibition of this effect by DM. Our data suggests that BMP/SMAD5 signaling plays an important role and, therefore, becomes a potential therapeutic target in serous ovarian cancer. © 2015 Wiley Periodicals, Inc.

Genomic profile predicts the efficacy of neoadjuvant chemotherapy for cervical cancer patients.

BACKGROUND: Neoadjuvant chemotherapy (NAC) using platinum and irinotecan (CPT-11) followed by radical excision has been shown to be a valid treatment for locally advanced squamous cervical cancer (SCC) patients. However, in NAC-resistant or NAC-toxic cases, surgical treatment or radiotherapy might be delayed and the prognosis may be adversely affected. Therefore, it is important to establish a method to predict the efficacy of NAC. METHODS: Gene expression microarrays of SCC tissue samples (n = 12) and UGT1A1 genotyping of blood samples (n = 23) were investigated in terms of their association with NAC sensitivity. Gene expression and drug sensitivity of SCC cell lines were analyzed for validation. RESULTS: Microarray analysis revealed that the glutathione metabolic pathway (GMP) was significantly up-regulated in NAC-resistant patients (p < 0.01), and there was a positive correlation between 50 % growth inhibitory concentrations of CPT-11 and predictive scores of GMP activation in SCC cells (r = 0.32, p < 0.05). The intracellular glutathione (GSH) concentration showed a highly positive correlation with GMP scores among 4 SCC cell lines (r = 0.72). UGT1A1 genotyping revealed that patients with UGT1A1 polymorphisms exhibited significantly higher response rates to NAC than those with the wild-type (79.5 vs. 49.5 %, respectively, p < 0.05). CONCLUSIONS: These results indicate that GMP scores of cancerous tissue combined with UGT1A1 genotyping of blood samples may serve as highly potent markers for predicting the efficacy of NAC for individual SCC patients.

Metabolic alterations caused by HNF1ß expression in ovarian clear cell carcinoma contribute to cell survival.

HNF1ß is expressed exclusively in ovarian clear cell carcinoma (OCCC) and not in other ovarian cancers, regarded as a hallmark of this tumor. This implies its central role in the unique character of OCCC, including resistance to chemotherapy, but its exact role and influence in cancer biology or the molecular bases of its function are largely unknown. Using comprehensive metabolome analysis of HNF1ß_shRNA-stable cell lines, we show here that HNF1ß drastically alters intracellular metabolism, especially in direction to enhance aerobic glycolysis, so called the "Warburg effect". The consequence of the metabolic change contributed cell survival under stresses such as hypoxia and chemo-reagent, only when sufficient glucose supply was available. Augmented cell survival was based on the reduced ROS activity derived from metabolic alteration such as shift from oxidative phosphorylation to glycolysis and increased intracellular anti-oxidant, glutathione (GSH). One of the cystine transporters, rBAT is likely to play a major role in this GSH increase. These data suggest that HNF1ß, possibly induced by stressful microenvironment in the endometriotic cyst, confers survival advantage to the epithelial cells, which leads to the occurrence of OCCC, a chemo-resistant phenotype of ovarian cancer.

Menstrual cyclic change of metastin/GPR54 in endometrium.

Metastin/kisspeptin is encoded by KISS1 and functions as an endogenous ligand of GPR54. Interaction of metastin with GPR54 suppresses metastasis and also regulates release of gonadotropin-releasing hormone, which promotes secretion of estradiol (E2) and progesterone (P4). We have previously demonstrated epigenetic regulation of GPR54 in endometrial cancer and the potent role of metastin peptides in inhibiting metastasis in endometrial cancer. However, little is known about how the metastin-GPR54 axis is regulated in the endometrium, the precursor tissue of endometrial cancer. Endometrial stromal cells (ESCs) and endometrial glandular cells (EGCs) within the endometrium show morphological changes when exposed to E2 and P4. In this study, we show that metastin expression is induced in ESCs through decidualization, but is repressed in glandular components of atypical endometrial hyperplasia (AEH) and endometrial cancer relative to EGCs. The promoter of GPR54 is unmethylated in normal endometrium and in AEH. These results indicate metastin may function in decidualized endometrium to prepare for adequate placentation but this autocrine secretion of metastin is deregulated during oncogenesis to enable tumor cells to spread.

Clear cell carcinoma arising from a uterus-like mass.

A uterus-like mass is an extrauterine mass with a cavity lined by endometrial tissue and a smooth muscle layer resembling the uterine corpus. It is a rare condition of unknown histogenesis. Herein, we describe a case of clear cell carcinoma arising from a uterus-like mass located in the retroperitoneal space. The patient, a 67-year old nulliparous woman, had been followed with the diagnosis of an ovarian endometriotic cyst for 14 years until ultrasonography and magnetic resonance imaging (MRI) demonstrated an enlargement of the cystic mass with a thickened irregular wall. Suspicion of malignant transformation prompted us to excise the lesion. At laparotomy, the uterus and right ovary appeared normal, and a mass measuring 8 cm was identified in the retroperitoneal space without any connection to the uterus. Grossly, the removed mass was composed of a cyst filled with blackish-brownish fluid and a thick wall resembling uterine myometrium. Microscopically, endometrial tissue inside the cyst, which was diffusely lined by clear cell carcinoma, was identified. Although the histogenesis of a uterus-like mass remains unclear, this case indicates that malignant tumors may occur from a uterus-like mass through the pathway similar to the carcinogenesis of endometriosis-related ovarian neoplasms.

STAT1 drives tumor progression in serous papillary endometrial cancer.

Recent studies of the interferon-induced transcription factor STAT1 have associated its dysregulation with poor prognosis in some cancers, but its mechanistic contributions are not well defined. In this study, we report that the STAT1 pathway is constitutively upregulated in type II endometrial cancers. STAT1 pathway alteration was especially prominent in serous papillary endometrial cancers (SPEC) that are refractive to therapy. Our results defined a "SPEC signature" as a molecular definition of its malignant features and poor prognosis. Specifically, we found that STAT1 regulated MYC as well as ICAM1, PD-L1, and SMAD7, as well as the capacity for proliferation, adhesion, migration, invasion, and in vivo tumorigenecity in cells with a high SPEC signature. Together, our results define STAT1 as a driver oncogene in SPEC that modulates disease progression. We propose that STAT1 functions as a prosurvival gene in SPEC, in a manner important to tumor progression, and that STAT1 may be a novel target for molecular therapy in this disease.