ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors.

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Large Plaque-type Blue Nevus with GNAQ Q209P Mutation, Involving Mammary Gland Tissue: Under-Recognized Mammary Condition as an Origin of Primary Mammary Melanocytic Tumors.

ABSTRACT: Plaque-type blue nevus is a rare variant of blue nevi that was first described in 1954. This article presents clinical, macroscopic, histopathological, and genetic findings for a case of large plaque-type blue nevus expanding into the mammary gland tissue as well as the skin of the right breast. A 63-year-old woman presented with a congenital, large, blue-colored macule limited to the hypochondriac area of the right breast. A nodule 8 mm in diameter was also present in the mammary gland tissue. Magnetic resonance imaging was unable to detect diffuse melanin deposition in the mammary gland tissue, but pigmentation in the whole mammary parenchyma was observed in the cut surfaces of the mastectomy specimen. Histopathology revealed a sparse distribution of dendritic melanocytes in whole sections of the mammary fibrous tissue and partial sections of the dermis. The histopathological criteria for atypical cellular blue nevus were fulfilled for the mammary tumor. Nodal blue nevus was diagnosed in the sentinel lymph node. Sanger sequencing confirmed the GNAQ Q209P mutation, which was also identified in all 4 literature cases of plaque-type blue nevus, but rarely in conventional blue nevi and uveal melanoma. It should be noted that plaque-type blue nevus can expand into the mammary gland tissue, even if the pigmented lesion does not exist on the overlying breast skin. The mammary condition can be the origin of primary mammary melanocytic tumors. Mosaicism of the GNAQ Q209P mutation can be a characteristic genetic alteration to extensive blue nevi, including plaque-type blue nevus.

Dose-dense paclitaxel and carboplatin vs. conventional paclitaxel and carboplatin as neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: a retrospective study.

BACKGROUND: The purpose of this study was to determine the optimal regimen of neoadjuvant chemotherapy (NAC) for advanced epithelial ovarian, fallopian tube, and peritoneal cancers. METHODS: A clinical information survey involving 171 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer was conducted. These patients underwent NAC followed by interval debulking surgery at the Hyogo Cancer Center (Hyogo, Japan) between January 2006 and December 2015. RESULTS: The median observation period was 41 (range 4-138) months. Dose-dense paclitaxel and carboplatin (TC) was administered in 101 patients (59%); tri-weekly TC was administered 70 patients (41%). Median progression-free survival was 21 [95% confidence interval (CI) 18-23] months and 15 (95% CI 13-17) months in the dose-dense TC and conventional-TC group [hazard ratio (HR) = 0.69, 95% CI 0.46-0.96; p = 0.02], respectively. The median overall survival was 59 (95% CI 46-72) and 40 (95% CI 32-57) months in the dose-dense TC group and conventional-TC group (HR = 0.72, 95% CI 0.48-1.06; p = 0.09). Multivariate analysis for progression-free survival demonstrated that dose-dense TC represented an independent prognostic factor (HR = 0.70, 95% CI 0.50-0.99; p = 0.04). CONCLUSIONS: Dose-dense TC is a promising regimen of NAC for advanced epithelial ovarian cancer.

Correlation between pre-operative and final histological diagnosis on endometrial cancer.

OBJECTIVE: We conducted a retrospective study to evaluate the correlation between pre-operative and post-operative histological diagnoses on endometrial cancer, and to describe the treatments and outcomes when post-operative diagnoses are downgraded from pre-operative histology. METHODS: Patients who underwent surgery for endometrial cancer in our facility between 2010 and 2013 were enrolled in the study. The definition of downgrade discordance is in accordance with the following criteria: 1) the pre-operative and post-operative histological diagnoses were both endometrioid and the final pathology was a lower grade than the pre-operative pathology and 2) the pre-operative diagnosis was not endometrioid, whereas the post-operative diagnosis was endometrioid grade 2 or less. RESULTS: A total of 250 patients were enrolled, and the concordance rates were 56% for endometrioid adenocarcinoma grade 1 (EMG1), 67% for EMG2, 67% for EMG3, 82% for carcinosarcoma, 71% for serous carcinoma, and 67% for clear cell carcinoma. Eighteen cases (6.6%) were identified as downgrade discordancy. Of the 18 patients, the triage for adjuvant therapy remained the same for 15 cases (83%), all of whom had no evidence of disease at their last visit. Three cases had discordances with respect to triage for adjuvant therapy; the therapies were triaged based on post-operative diagnosis. Of these patients one had a recurrence. CONCLUSIONS: Good correlation was observed between pre-operative and final histological diagnoses of endometrioid carcinoma (56%-67%) and type 2 carcinoma (67%-82%). Approximately 7% (18/250) of patients had downgrade discordancy; however, triage for adjuvant therapy did not change for approximately 80% (15/18) of the patients with downgrade discordancy. Further studies are needed to evaluate the effectiveness of triages that are based on post-operative diagnoses.

Immunohistochemical expression of CD44v9 and 8-OHdG in ovarian endometrioma and the benign endometriotic lesions adjacent to clear cell carcinoma.

AIM: Expression of CD44 variant isoforms (CD44v) promotes the synthesis of reduced glutathione and contributes to reactive oxygen species defense through up-regulation of the intracellular antioxidant. The aim of the study was to investigate the expression of CD44v9 and oxidative DNA damage marker, 8-OHdG, in benign ovarian endometrioma (OE) and OE harboring clear cell carcinomas (CCC). METHODS: A retrospective study was performed at the Department of Gynecology, Nara Medical University hospital from January 2006 to December 2012. Patients with histologically confirmed benign OE (n = 27) and OE harboring areas of CCC (n = 8) were selected. Tissue samples were immunohistochemically analyzed for the presence of CD44v9 and 8-OHdG using avidin-biotin complex method. RESULTS: CD44v9 was located on the cell membrane of endometriotic epithelial cells and expressed in 88.9% (24/27) of benign OE tissues. Only 25.0% (2/8) of benign endometriotic lesions adjacent to CCC was found to stain weakly for CD44v9. Percentage of CD44v9 positive cells was 68.5 ± 20.2% (mean ± standard deviation) of benign OE, 16.7 ± 16.5% of CCC endometriotic tissue (P < 0.001). Compared to benign OE, CCC endometriotic tissue showed a significant increase in the proportion of 8-OHdG expression (77.3 ± 22.5% vs 94.9 ± 3.0%, P = 0.049). A significant negative correlation was observed between CD44v9 status and 8-OHdG nuclear expression (r = -0.458, P  =  0.006). CONCLUSION: Alterations in CD44v9 and 8-OHdG may be associated with malignant transformation of benign OE.

Malignancy during pregnancy in Japan: an exceptional opportunity for early diagnosis.

BACKGROUND: Malignancy during pregnancy has become a significant cause of maternal death in developed countries, likely due to both an older pregnant population, and increases of cervical cancer in younger women. Our aim is to investigate the clinical aspects of malignancy during pregnancy in Japan and to use this information to identify opportunities for earlier detection and treatment. METHODS: We provided a questionnaire to 1508 secondary or tertiary care hospitals in Japan. We reviewed the clinical characteristics of cases with malignancy during pregnancy for the period of January to December, 2008. From the 760 institutions which responded, we obtained clinical information for 227 unique cases. The questionnaire provided clinical information, including disease site, pregnancy outcome and how the disease was detected. RESULTS: The most common type of malignancy was cervical cancer (n = 162, 71.4%) followed by ovarian (n = 16, 7.0%) and breast cancer (n = 15, 6.6%). Leukemia (n = 7, 3.1%), colon cancer (n = 5, 2.2%), gastric cancer (n = 5, 2.2%), malignant lymphoma (n = 4, 1.8%), thyroid cancer (n = 3, 1.3%), brain cancer (n = 3, 1.3%), endometrial cancer (n = 2, 0.9%), and head and neck cancer (n = 2, 0.9%) accounted for the remaining cases. Overall, gynecological malignancies accounted for 79.3% (95% confidence interval 74.0-84.6) of pregnancy associated malignancies diagnosed in the present study. The majority of cervical cancers, 149 (92.0%) of 162, were diagnosed by a Pap (Papanicolaou) smear during early gestation. Ten (62.5%) of the ovarian cancer cases were diagnosed by ultrasonography during a prenatal checkup or at the time of initial pregnancy diagnosis. Out of 14 breast cancers, only one (7.1%) was diagnosed by screening breast exam. CONCLUSIONS: From this study, we reaffirm the clear and significant benefits of prenatal checkups starting at an early gestational age for the detection of gynecological cancers during pregnancy. Conversely, breast cancer detection during pregnancy was poor, suggesting new strategies for early identification of this disease are required.

A preoperative low cancer antigen 125 level (≤25.8 mg/dl) is a useful criterion to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in epithelial ovarian cancer.

OBJECTIVE: The purpose of this study is to investigate the clinical characteristics to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. METHODS: We reviewed the charts of women with advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer who underwent interval debulking surgery following neoadjuvant chemotherapy at our cancer center from April 2006 to April 2014. RESULTS: There were 139 patients, including 91 with ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) Stage IIIc in 56 and IV in 35], two with fallopian tube cancers (FIGO Stage IV, both) and 46 with primary peritoneal cancer (FIGO Stage IIIc in 27 and IV in 19). After 3-6 cycles (median, 4 cycles) of platinum-based chemotherapy, interval debulking surgery was performed. Sixty-seven patients (48.2%) achieved complete resection of all macroscopic disease, while 72 did not. More patients with cancer antigen 125 levels ≤25.8 mg/dl at pre-interval debulking surgery achieved complete resection than those with higher cancer antigen 125 levels (84.7 vs. 21.3%; P< 0.0001). Patients with no ascites at pre-interval debulking surgery also achieved a higher complete resection rate (63.5 vs. 34.1%; P< 0.0001). Moreover, most patients (86.7%) with cancer antigen 125 levels ≤25.8 mg/dl and no ascites at pre-interval debulking surgery achieved complete resection. CONCLUSIONS: A low cancer antigen 125 level of ≤25.8 mg/dl and the absence of ascites at pre-interval debulking surgery are major predictive factors for complete resection during interval debulking surgery and present useful criteria to determine the optimal timing of interval debulking surgery.

Clinical Features of Neuroendocrine Carcinoma of the Uterine Cervix: A Single-Institution Retrospective Review.

OBJECTIVE: Neuroendocrine carcinoma of the cervix is a rare and aggressive subtype of cervical cancer and includes small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). We conducted a single-institution retrospective review to explore the pattern of treatments and outcomes with the aim of defining an optimum treatment strategy for these carcinomas. METHODS: Twenty-three consecutive patients with SCNEC or LCNEC of the cervix diagnosed at the Hyogo Cancer Center between 1996 and 2013 were included in this study. Pertinent information, including clinical and pathological characteristics, and survival data were collected from clinical records and/or telephone surveys. The pathological review was conducted by a pathologist specializing in gynecologic cancer. RESULTS: Eleven patients had SCNEC and 12 had LCNEC. Eighteen patients with International Federation of Gynecology and Obstetrics (FIGO) stage I/II underwent type III radical hysterectomy with pelvic lymphadenectomy. After surgery, 9 received adjuvant chemotherapy (8, irinotecan plus cisplatin; 1, paclitaxel plus carboplatin), 7 received concurrent chemoradiation therapy (CCRT; 6, nedaplatin; 1, cisplatin), and 2 received radiation therapy (RT). Patients who received adjuvant chemotherapy had a better overall survival than did patients who received CCRT or RT (hazard ratio, 0.21; 95% confidence interval, 0.030-1.51; P = 0.12). Although the overall survival rates are not statistically significant, the 9 patients who underwent radical hysterectomy followed by adjuvant chemotherapy are all alive. Among the remaining 5 patients who did not undergo radical hysterectomy, 2 with FIGO stage III and 1 with stage IVa received CCRT, and 2 with stage IVb received palliative RT or chemotherapy. These 5 patients with FIGO stage III/IV died of disease within 36 months. CONCLUSIONS: Radical hysterectomy followed by platinum-based chemotherapy, especially the irinotecan plus cisplatin combination, is beneficial for long-term survival in patients with early-stage neuroendocrine carcinoma of the cervix.

Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1ß transcription factor: chemosensitivity is regulated by checkpoint kinase CHK1.

OBJECTIVE: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1ß (HNF-1ß) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1ß in regulation of the cell cycle in CCA. METHODS: To clarify the effects of HNF-1ß on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1ß had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1ß (+) cells were arrested in G2 phase because of DNA damage. RESULTS: HNF-1ß (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1ß (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1ß (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. CONCLUSIONS: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1ß. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.

Histopathology predicts clinical outcome in advanced epithelial ovarian cancer patients treated with neoadjuvant chemotherapy and debulking surgery.

OBJECTIVE: To analyze the factors prognostic of survival in patients with advanced epithelial ovarian cancer (EOC) treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery. METHODS: Outcomes were retrospectively in patients with advanced EOC or peritoneal cancer who received neoadjuvant paclitaxel and carboplatin chemotherapy every 3 weeks for three to four cycles, followed by interval debulking surgery and three additional cycles of the same regimens from January 2001 to November 2010. Therapeutic response was assessed histopathologically as grade 0 to 3, based on the degree of disappearance of cancer cells, displacement by necrotic and fibrotic tissue, and tumor-induced inflammation. Factors prognostic of progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: The 124 enrolled patients had a median age of 62 years (range, 35-79 years). Viable cancer cells were observed in specimens resected from 72 patients (58%) at interval debulking surgery after NAC. Multivariate analysis using the Cox proportional hazard model showed that advanced (stage IV) disease (hazard ratio [HR]=1.94, p=0.003), residual cancer at the end of surgery ≥1cm (HR=3.78, p<0.001), and histological grade 0-1 (HR=1.65, p=0.03) were independent predictors of decreased OS. Grade 0-1 was also an independent predictor of increased risk of relapse within 6 months (odds ratio=8.42, p=0.003). CONCLUSIONS: Residual disease of ≥1cm, advanced stage, and the presence of more viable disease in resected specimens are prognostic factors for survival in advanced EOC patients receiving NAC followed by interval debulking surgery.

L1 gene methylation in high-risk human papillomaviruses for the prognosis of cervical intraepithelial neoplasia.

OBJECTIVE: The purpose of this study was to investigate the clinical significance of DNA methylation of the human papillomavirus (HPV) genome as a prognostic biomarker for cervical intraepithelial neoplasia (CIN). METHODS AND MATERIALS: Clinical samples (paraffin-embedded tissues obtained by conization/hysterectomy or initial punch biopsy) were collected from patients at the Gynecologic Oncology of the Hyogo Cancer Center with informed consent. We evaluated the methylation status of the L1 gene of the HPV genome by bisulfite sequencing, calculating the methylation ratio (L1MR) as (number of methylated CpGs in the analyzed region of the L1 gene) / (number of all CpGs in the analyzed region of the L1 gene) × 100. The methylation analysis and in situ hybridization were performed with serial tissue-section slices. RESULTS: DNA methylation was observed in the L1 gene, but not in the long control region of HPV-16, -18, or the other high-risk HPV types including HPV-31, -52, and -58. L1MR was associated with the CIN grade; the median L1MR was 2.3%, 11.2%, 35.2%, and 50.0% for CIN1, CIN2, CIN3, and squamous cell carcinoma, respectively. L1MRs also seemed to indicate physical status (integrated or episomal form) of the HPV genome in the host cell. L1MR of the progression group was significantly higher than that of the regression group. CONCLUSIONS: L1MR was associated with the CIN grade and indicated the HPV genome status in the host cell: high L1MR indicated HPV genome integration linked to progression from early-stage CINs, whereas low L1MR indicated an episomal HPV genome location in host cells. L1MR may be a prognostic indicator of CIN.

Absence of human papillomavirus infection and activation of PI3K-AKT pathway in cervical clear cell carcinoma.

OBJECTIVE: Cervical cancer is the second most common cancer in females worldwide, and the majority of squamous cell carcinomas and adenocarcinomas are associated with high-risk human papillomavirus (HPV) infection. However, the relationship between clear cell carcinoma of the cervix (CCCC) and HPV is unclear. In this study, we sought to determine if HPV infection is associated with CCCC and to elucidate the signaling pathways involved. METHODS: We collected samples from 13 CCCC patients and collated the relevant clinicopathologic data. We then evaluated the presence of HPV types 16, 18, 31, 33, 35, 52, and 58 by broad-spectrum amplification by polymerase chain reaction and HPV types 39, 45, 51, 56, 59, and 68 by nested polymerase chain reaction assay that combines degenerate E6/E7 consensus primers and type-specific primers from extracted genomic DNA. Immunohistochemistry was used to analyze the expression of EGFR (epidermal growth factor receptor), HER2, PTEN (phosphatase and tensin homolog), phospho-AKT, phospho-mTOR (mammalian target of rapamycin), p16, and p53. EGFR and HER2 gene amplification was determined by fluorescence in situ hybridization. RESULTS: Patients with stage IB CCCC had a better 3-year overall survival rate compared with those with advanced-stage cancer (100% vs 44%; P = 0.014). High-risk HPVs were not detected in any of the cases examined. EGFR immunostaining was observed in 9 (75%) of 12 patients, HER2 in 3 (25%) of 12, PTEN in 6 (50%) of 12, and phospho-AKT in 7 (58%) of 12, and phospho-mTOR in 6 (50%) of 12. EGFR amplification could not be detected, but HER2 amplification was identified in 1 of (12.5%) 8 cases. CONCLUSIONS: Patients with stage I CCCC demonstrated good overall survival and rare recurrence. Clear cell carcinoma of the cervix is unrelated to high-risk HPV infection; hence, current vaccines will not prevent the incidence of CCCC. However, increased EGFR or HER2 expression or activation of AKT or mTOR was observed in all cases, indicating that inhibitors of tyrosine kinases or the AKT-mTOR pathway may be suitable treatment regimens for CCCC.

Endometrial stromal sarcoma: clinicopathological and immunophenotypic study of 16 cases.

PURPOSE: Endometrial stromal sarcomas (ESSs) are rare tumors and are divided into two groups: low-grade endometrial stromal sarcoma (ESS-LG) and undifferentiated endometrial sarcoma (UES). The purpose of this study was to compare the clinicopathological features and immunophenotypes of ESS-LG and UES. METHODS: The authors evaluated 16 patients diagnosed with ESS at the Hyogo Cancer Center, reviewed their files and data, and performed an immunohistochemical study for oncogenic proteins (EGFR, PDGFR-α, and PDGFR-ß) and cell cycle regulators (cyclin D1, cyclin E, p16(INK4a), p21(cip1), p27(kip1), and p53) to compare ESS-LG and UES using the World Health Organization (WHO) classification. RESULTS: Four cases (25 %) were classified as ESS-LGs and 12 (75 %) as UES. Patients with UES had a significantly worse overall survival than did those with ESS-LG (p = 0.0445). Although no ESS-LGs showed expression of p16(INK4a), 10 of 12 (83 %) UESs showed expression of p16(INK4a). UESs showed a trend toward higher expression of cyclin D1, p21(cip1), and p53 compared with ESS-LGs. CONCLUSIONS: Our data emphasize the clinical importance of the WHO classification of ESS. It is of utmost importance to establish a proper classification to increase the consistency of data that may be useful for improving clinical and therapeutic management of patients with ESS.

Type II versus type III fertility-sparing abdominal radical trachelectomy for early-stage cervical cancer: a comparison of feasibility of surgical outcomes.

OBJECTIVE: The purpose of this study was to compare surgical outcomes using modified (type II) and traditional (type III) abdominal radical trachelectomy (ART) for fertility-sparing surgery in early cervical cancer. METHODS: A prospectively maintained database of ART procedures was analyzed. Data were collected regarding age, stage, histology, operative outcome, surgical complication, and fertility outcome. RESULTS: We performed 23 fertility-sparing ARTs for patients with International Federation of Gynecology and Obstetrics stages IA to IB1 tumors of less than 2 cm between 2006 and 2010. Type III ART was attempted in 8 patients and modified ART in 15 patients. The median operating time was greater in the type III group compared with that in the type II group (305 vs 247 minutes; P < 0.02). The median surgical blood loss was greater in the type III ART group (580 mL; range, 250-988 mL) compared with that in the modified type II group (366 mL; range, 200-850 mL; P < 0.05). The median time to recovery of bladder dysfunction was less in the type II group (9 days; range, 3-10 days) than that in the type III group (13 days; range, 10-23 days; P < 0.01). There were no recurrences at the time of this report. CONCLUSIONS: Type II ART provides surgical and pathological outcomes with better recovery of bladder function similar to those in type III ART. For patients with early cervical cancer who wish to preserve reproductive function, type II ART is a feasible and safe operation.

Molecular-targeted therapies for ovarian cancer: prospects for the future.

Ovarian cancer accounts for approximately 4 % of cancer deaths in women worldwide, with around 225,000 estimated new cases diagnosed each year and 140,000 related deaths. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stages of the disease; consequently, 50 % of cases present with advanced metastatic cancer, and 5-year survival rates are limited to 10-30 %. Furthermore, disease recurrence occurs in a high proportion of cases, and the survival rate is only 30 % even in patients who are sensitive to platinum-based chemotherapy. This review describes the increased characterization of the molecular mechanisms involved in the development and progression of ovarian cancer, and how this has resulted in improved therapeutic strategies with molecular-targeted agents. These include targeting BRCA mutations to affect DNA repair, inhibition of the mTOR and MAPK pathways, and anti-angiogenesis therapies. Ultimately, personalized therapy using novel biomarkers in parallel with improved early detection techniques could significantly enhance the prognosis of ovarian cancer patients.

Pigment epithelium-derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages.

Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium-derived factor (PEDF) as a promoting factor of OC dissemination, which functions through induction of CD206+ Interleukin-10 (IL-10)-producing macrophages. High PEDF gene expression in tumors is associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum are significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors reduce PEDF expression and limit both OC cell survival and CD206+ macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein-PEDF-IL-10 axis as a promising therapeutic target for OC.

Proximal-type epithelioid sarcoma in pubic region expressing L-type amino acid transporter 1: A case report.

Proximal-type epithelioid sarcoma is an aggressive malignant soft-tissue neoplasm, a "proximal" variant of epithelioid sarcoma, resistant to multimodal therapy and involved in early tumor-related death. Pertinent treatments are, therefore, continually being explored. A 24-year-old woman with nonmetastatic proximal-type epithelioid sarcoma, originating subcutaneously on the right side of the vulva, underwent surgical resection; the lesion recurred, however, leading to death 3 months after the second surgery. Here described is a case of proximal-type epithelioid sarcoma expressing L-type amino acid transporter 1 (LAT1) that transports essential amino acids and p-borono-L-phenylalanine (BPA)-the chemical compound used in boron neutron capture therapy (BNCT)-and is highly expressed in many malignant tumors. Recently, LAT1 has drawn attention, and relevant treatments have been studied-LAT1 inhibitor and BNCT. LAT1 expression in proximal-type epithelioid sarcoma may lead to cogent treatments for the disease.

Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype.

A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.