Differential roles of the Wip1-p38-p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is one of the most lethal types of ovarian cancer. Early-stage OCCC can be cured by surgery; however, advanced-stage disease shows poor prognosis due to chemoresistance unlike the more common high-grade serous carcinoma. METHODS: We explored the differential roles of the Wip1-p38-p53 DNA damage response pathway in respective early- or advanced-stage OCCC by immunohistochemistry of Wip1, phospho-p38, p53, and phospho-p53 from consecutive 143 patients. RESULTS: High Wip1 expression correlated with positive p53 (p=0.011), which in turn correlated with low nuclear phospho-p38 expression (p=0.0094). In the early stages, positive p53 showed trends toward worse overall survival (OS) (p=0.062), whereas in the advanced stages, high Wip1 correlated with worse OS (p=0.0012). The univariate and multivariate analyses of prognostic factors indicated that high Wip1 was significant and independent for worse OS (p=0.011) in the advanced stages, but not in the early stages. Additionally, high Wip1 showed trends toward shorter treatment-free interval (TFI) in the advanced stages, but not in the early stages (p=0.083 vs. 0.93). Furthermore, high Wip1 was significantly associated with positive p53 only in the patients with shorter TFI (<6 months), but not in those with longer TFI (≥6 months) (p=0.036 vs. 0.34). CONCLUSIONS: Wip1 appears to play a crucial role for the prognosis of OCCC through chemoresistance specifically in the advanced stages, implicating that Wip1 possibly serves as a reasonable therapeutic target for improving chemoresistance and poor prognosis of advanced-stage OCCC.

Ovarian metastases from ileum cancer in a patient with germline EPCAM gene deletion successfully treated with surgical resection and CAPOX chemotherapy: a case report.

BACKGROUND: Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery. CASE PRESENTATION: A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months. CONCLUSIONS: We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.

PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas.

BACKGROUND: Tumor microenvironment (TME) including the immune checkpoint system impacts prognosis in some types of malignancy. The aim of our study was to investigate the precise prognostic significance of the TME profile in endometrial carcinoma. METHODS: We performed immunohistochemistry of the TME proteins, PD-L1, PD-1, CD4, CD8, CD68, and VEGF in endometrial carcinomas from 221 patients. RESULTS: High PD-L1 in tumor cells (TCs) was associated with better OS (p = 0.004), whereas high PD-L1 in tumor-infiltrating immune cells (TICs) was associated with worse OS (p = 0.02). High PD-L1 in TICs correlated with high densities of CD8+ TICs and CD68+ TICs, as well as microsatellite instability (p = 0.00000064, 0.00078, and 0.0056), while high PD-L1 in TCs correlated with longer treatment-free interval (TFI) after primary chemotherapy in recurrent cases (p = 0.000043). High density of CD4+ TICs correlated with better OS and longer TFI (p = 0.0008 and 0.014). Univariate and multivariate analyses of prognostic factors revealed that high PD-L1 in TCs and high density of CD4+ TICs were significant and independent for favorable OS (p = 0.014 and 0.0025). CONCLUSION: The current findings indicate that PD-L1 and CD4+ helper T cells may be reasonable targets for improving survival through manipulating chemosensitivity, providing significant implications for combining immunotherapies into the therapeutic strategy for endometrial carcinoma.

Prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer.

AIM: Postoperative pulmonary embolism can be a fatal surgical complication and is thought to occur secondary to asymptomatic venous thromboembolism (VTE) that exists preoperatively in some patients. The purpose of this study was to clarify the frequency and risk factors of pretreatment VTE in gynecological cancer patients. METHODS: This study investigated 2086 patients with gynecological cancer (cervix, n = 754; endometrium, n = 862; ovary, n = 470) who underwent initial treatment between 2004 and 2017. Pretreatment VTE screening was performed with D-dimer (DD) levels in these patients. Based on this, the associated risk factors were retrospectively analyzed. RESULTS: Pretreatment VTE was discovered in 7.3% of patients with cervical cancer, 11.5% of those with endometrial cancer and 27.0% of those with ovarian cancer. Significant independent risk factors were: age greater than or equal to 60 years and tumor long diameter greater than or equal to 40 mm for cervical cancer; age greater than or equal to 60 years, stage III/IV advanced disease, clear cell carcinoma and tumor long diameter greater than or equal to 60 mm for endometrial cancer; and age greater than or equal to 60 years, clear cell carcinoma and massive ascites for ovarian cancer. CONCLUSION: Pretreatment asymptomatic VTE is very frequent in gynecological cancer patients. It may be beneficial to consider measuring DD or performing venous ultrasonography in patients with the above risk factors.

Predictors of favorable survival after secondary cytoreductive surgery for recurrent endometrial cancer.

OBJECTIVE: The selection criteria for secondary cytoreductive surgery (SCS) for recurrent endometrial cancer (EC) remain to be defined. The present study aimed to identify predictors for favorable survival after SCS for the disease. METHODS: We retrospectively reviewed the medical records of 112 patients who relapsed by 2016 among 1052 who were diagnosed with primary EC between 1985 and 2014. Characteristics associated with overall survival (OS) after SCS were identified using univariate and multivariate analyses. RESULTS: Twenty-nine of the 112 patients who relapsed underwent SCS. Complete resection was achieved in 18 (62%) patients, whose OS after SCS was significantly better than that of patients receiving incomplete resection (68 vs. 20 months; p = 0.001). Endometrioid histology and performance status (PS) 0 were significant and independent factors for a favorable OS (p = 0.005, and 0.049). The OS of patients with both factors was better than patients with one or no factors (median 75, 19 and 4 months; p = 0.001 and 0.00001). The number of predictors was associated with the rate of complete resection (p = 0.001). CONCLUSIONS: Patients with endometrioid histology and PS 0 should be offered SCS for recurrent EC. Prospective trials are warranted to verify this proposal.

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

OBJECTIVES: Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. METHODS: We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. RESULTS: Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021). CONCLUSIONS: The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.

Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.

OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma.

Proposal for selection criteria of secondary cytoreductive surgery in recurrent epithelial ovarian, tubal, and peritoneal cancers.

BACKGROUND: The selection criteria for secondary cytoreductive surgery (SCS) in recurrent ovarian cancer are yet to be defined. The aim of this study was to propose the selection criteria through identifying predictive factors for successful SCS. METHODS: All patients who underwent SCS for recurrent epithelial ovarian, tubal, and peritoneal cancers between 1982 and 2012 at our institution were identified through our database. Potential prognostic factors were evaluated in univariate and multivariate analyses. Survival after SCS was examined by the grouping model based on the number of prognostic factors. RESULTS: We performed SCS in 80 consecutive patients, 48 (60 %) of whom achieved complete resection. Complete/incomplete resection significantly influenced survival (median 65 vs. 26 months; p = 0.0005). Among favorable prognostic factors determined before SCS, treatment-free interval >12 months, absent distant metastasis, solitary disease, and performance status 0 were independently associated with better survival (p = 0.0009, 0.00003, 0.0004, and 0.015, respectively). Patients with 3-4 of those factors had better survival than those with 2 or 0-1 factors (median 79, 26, and 19 months; p < 0.00001 and <0.0000000001, respectively). Complete resection of visible tumors was achieved in 79 % of patients with 3-4 factors, in 40 % of those with 2 factors, and in 33 % of those with 0-1 factor. Importantly, even when tumor removal was incomplete at SCS, median survival of patients with 3-4 factors was still quite favorable (83 vs. 67.5 months for complete/incomplete resection, respectively), while those of patients with 2 factors (41 vs. 25 months) and 0-1 factor (19 vs. 19 months) were not. CONCLUSION: We strongly recommend SCS for patients with 3-4 of the above favorable factors at recurrence. As for patients with 2 factors, SCS may be considered if complete resection is expected to be achieved. Prospective studies are warranted to validate our proposal.

High Pretreatment Plasma D-dimer Levels Are Associated With Poor Prognosis in Patients With Ovarian Cancer Independently of Venous Thromboembolism and Tumor Extension.

OBJECTIVE: Elevated plasma D-dimer (DD) is associated with decreased survival among patients with breast, lung, and colon cancers. The present study clarifies the prognostic significance of pretreatment plasma DD levels in patients with epithelial ovarian cancer (EOC). METHODS: We investigated pretreatment DD levels and other variables for overall survival using univariate and multivariate analyses in 134 consecutive patients with EOC stages II to IV who were initially treated between November 2004 and December 2010. RESULTS: The median follow-up period was 53 (7-106) months. Univariate analysis significantly associated elevated pretreatment DD (≥2.0 µg/mL) levels to poor 5-year overall survival rates irrespective of previously treated venous thromboembolism (72.2% vs 52.6%, P = 0.039). Cancer antigen 125 levels of 200 U/mL or higher (P = 0.011), distant metastases (P = 0.0004), residual tumors (P < 0.0001), and International Federation of Gynecology and Obstetrics stage III/IV (P = 0.0033) were also poor prognostic factors. Multivariate analysis independently associated DD levels of 2.0 µg/mL or higher (P = 0.041), distant metastases (P = 0.013), and residual tumors (P < 0.0001) with poor overall survival. CONCLUSIONS: High pretreatment DD levels are associated with poor overall survival in patients with EOC independently of venous thromboembolism and tumor extension and might comprise a promising prognostic biomarker for patients with EOC.

HPV genotyping for triage of women with abnormal cervical cancer screening results: a multicenter prospective study.

BACKGROUND: In cervical cancer screening programs, women with abnormal cytology are referred for colposcopy for histological evaluation. We examined whether a human papillomavirus (HPV) genotyping assay could be used to identify women who do not need immediate colposcopy and biopsy because of low risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). METHODS: We prospectively evaluated test performance for 2 carcinogenic HPV genotypes (HPV16/18), for 8 types (HPV16/18/31/33/35/45/52/58), and for 13 types (HPV16/18/31/33/35/45/51/52/56/58/59/68) for prediction of histological CIN3+ results among 427 screen-positive women referred for colposcopy. The study subjects consisted of 214 women with low-grade squamous intraepithelial lesion (LSIL), 184 with high-grade squamous intraepithelial lesion (HSIL), and 29 with atypical squamous cells, cannot exclude HSIL (ASC-H). RESULTS: Among women with LSIL cytology, HPV16/18 positivity was 29.4 % and increased to 58.9 % for 8 types and to 74.8 % for 13 types (P < 0.001). The risk of CIN3+ biopsy results was still 7.9 % for women testing negative for HPV16/18, but decreased to 0.0 % for those testing negative for at least eight types of HPV (HPV16/18/31/33/35/45/52/58). Although HPV genotyping results enabled additional risk stratification among women with HSIL/ASC-H cytology, the risk of histological CIN3+ diagnosis among women testing negative for eight types or more was still sufficiently high (>35 %) to warrant immediate colposcopy referral. CONCLUSIONS: Of women with LSIL cytology, those testing negative for at least eight of the highest-risk types of HPV (HPV16/18/31/33/35/45/52/58) may not need immediate colposcopy and biopsy. This would reduce the number of colposcopy referrals by approximately 40 %. However, the HPV genotyping assay is not likely to alter the clinical management of women with HSIL/ASC-H.

Safety and efficacy of substituting nedaplatin after carboplatin hypersensitivity reactions in gynecologic malignancies.

AIM: Repeated treatment with carboplatin increases the incidence of hypersensitivity reactions. Current managements for carboplatin hypersensitivity reactions involve premedication, desensitization, and replacing agents. However, preventive effects for recurrent reactions by the former two methods are still limited, and substituting non-platinum agent can attenuate efficacy against platinum-sensitive diseases. The aim of this study was to evaluate the safety and efficacy of substituting nedaplatin, another platinum compound, as a strategy to deal with carboplatin hypersensitivity reactions in gynecologic cancers. MATERIAL AND METHODS: Patients who experienced carboplatin hypersensitivity reactions and subsequently switched to nedaplatin between 2001 and 2009 were identified through our database. The incidence and severity of nedaplatin hypersensitivity were examined. Response to nedaplatin therapy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and serum CA-125 levels. RESULTS: Forty-six of 570 patients (8.1%) experienced carboplatin hypersensitivity reactions, and the increased cycle numbers of carboplatin-based regimens correlated with the high incidence of hypersensitivity (≤6, 0.9% vs ≥7, 19.2%). Of these 46 patients, 38 subsequently switched to nedaplatin-based regimens (ovarian, tubal or peritoneal carcinoma, 30; endometrial carcinoma, 6; cervical carcinoma, 2). Three of the 38 patients (7.9%) eventually developed hypersensitivity against nedaplatin, and all their reactions were grade 2. The response rate to nedaplatin therapy among 32 evaluable patients was 31.3%. CONCLUSION: Replacing carboplatin with nedaplatin provided a safe and efficacious approach to manage carboplatin hypersensitivity. To the authors' knowledge, this study is the first to indicate the usefulness of nedaplatin after carboplatin hypersensitivity reactions. Further evaluations are warranted to confirm our finding.

Hachimijiogan, a traditional herbal medicine, modulates adipose cell function and ameliorates diet-induced obesity and insulin resistance in mice.

Hachimijiogan (HJG) has originally been used to ameliorate a variety of symptoms associated with low ambient temperatures. However, its pharmacological action in metabolic organs remains unclear. We hypothesized that HJG may modulate metabolic function and have a potential therapeutic application to metabolic diseases. To test this hypothesis, we investigated metabolic action of HJG in mice. Male C57BL/6J mice chronically administered with HJG showed a reduction in adipocyte size with increased transcription of beige adipocyte-related genes in subcutaneous white adipose tissue. HJG-mixed high-fat diet (HFD)-fed mice showed alleviation of HFD-induced weight gain, adipocyte hypertrophy, liver steatosis with a significant reduction in circulating leptin and Fibroblast growth factor 21 despite no changes in food intake or oxygen consumption. Feeding an HJG-mixed HFD following 4-weeks of HFD feeding, while a limited effect on body weight, improved insulin sensitivity with a reversal of decreased circulating adiponectin. In addition, HJG improved insulin sensitivity in the leptin-deficient mice without significant effects on body weight. Treatment with n-butanol soluble extracts of HJG potentiated transcription of Uncoupling protein 1 mediated by ß3-adrenergic agonism in 3T3L1 adipocytes. These findings provide evidence that HJG modulates adipocyte function and may exert preventive or therapeutic effects against obesity and insulin resistance.

Do neutralizing antibody responses generated by human papillomavirus infections favor a better outcome of low-grade cervical lesions?

To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low-grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n = 42), abnormal cytology persisted longer in those positive for HPV 16-specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16-specific neutralizing antibodies (P = 0.03, log-rank test). In women infected with types other than HPV 16 (n = 200), detection of HPV 16-specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low-grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression.

Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer: Main analysis of second progression-free survival in the phase III PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. METHODS: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. RESULTS: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. CONCLUSION: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.

Impact of clean intermittent catheterization on quality of life of patients with neurogenic lower urinary tract dysfunction due to radical hysterectomy: A cross-sectional study.

AIMS: We investigated the quality of life (QOL) of a homogenous group of ambulant patients with neurogenic lower urinary tract dysfunction without significant comorbidities to elucidate the impact of clean intermittent catheterization (CIC) on QOL. METHODS: The subjects were 71 female patients who underwent radical hysterectomy (RH) without recurrent disease. QOL was cross-sectionally measured with the Short-Form 36-Item Health Survey (SF-36) and King's Health Questionnaire (KHQ). We divided urinary management into spontaneous voiding (SV) and CIC as well as postoperative elapsed time into the entire period, less than 24 months (<24 months) and 24 months or more (≥24 months). RESULTS: Patients with CIC showed significantly poorer QOL than patients with SV in some subscale/domain scores on SF-36 and KHQ for the entire period as well as <24 months after RH. In contrast, significant differences were not revealed between scores on both measures of patients with CIC and SV ≥24 months after RH. Moreover, in patients with CIC ≥24 months, some subscale/domain scores on both measures were significantly better than in those with <24 months. Norm-based scoring of SF-36 revealed that all subscales of patients with CIC <24 months were below the average score of healthy Japanese people, while only four subscales of those ≥24 months remained below the average. CONCLUSIONS: QOL in patients with CIC was worse than in patients with SV in the short term, but similar in the long term, which suggests that QOL probably might improve with time in patients with CIC.

Ovarian and non-ovarian teratomas: a wide spectrum of features.

Teratoma is a germ cell tumor (GCT) derived from stem cells of the early embryo and the germ line. Teratoma is the most common neoplasm of the ovaries and is usually diagnosed easily using imagings by detecting fat components. However, there are various histopathological types and the imaging findings differ according to the type. Teratoma usually occurs in the gonads or in the midline due to migration of primordial germ cells during development. The clinical course of teratomas depends on the age of the patient, histological type, and anatomical site. Sometimes teratomas show unusual manifestations, such as mature teratoma without demonstrable fat components, torsion, rupture, growing teratoma syndrome, anti-N-methyl-D-aspartate receptor encephalitis, and autoimmune hemolytic anemia. For all of these reasons, teratomas demonstrate a wide spectrum of imaging features and radiologists should be familiar with these variabilities. The present article aims to introduce a model encompassing types of GCTs based on their developmental potential, and to review several histopathological types in various anatomical sites and unusual manifestations of teratomas, with representative imaging findings.

Interleukin-10 -1082 gene polymorphism and susceptibility to cervical cancer among Japanese women.

Polymorphisms in cytokine genes can influence immune responses to human papillomavirus infection, possibly modifying risks of cervical cancer. Using an amplification refractory mutation system-polymerase chain reaction method, we analyzed a single nucleotide polymorphism (A/G) at position -1082 in interleukin-10 promoter region in 440 Japanese women: 173 women with normal cytology, 163 women with cervical intraepithelial neoplasia and 104 women with invasive cervical cancer. The carrier frequency of interleukin-10 -1082 G alleles associated with higher interleukin-10 production increased with disease severity: 9.8% for normal cytology; 19.6% for cervical intraepithelial neoplasia; 29.8% for invasive cervical cancer (P for trend < 0.001). Among cytologically normal women, human papillomavirus infections were more common in those who were positive for an interleukin-10 -1082 G allele (P = 0.04). In conclusion, our data suggest that interleukin-10 -1082 gene polymorphism may serve as a marker of genetic susceptibility to cervical cancer among Japanese women.

Pretreatment thrombocytosis as an independent predictive factor for chemoresistance and poor survival in epithelial ovarian cancer.

BACKGROUND: Thrombocytosis is related to tumor stage and survival in ovarian cancer in addition to the common complications of malignant diseases, such as anemia and inflammation. The aim of our study was to clarify the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. METHODS: We retrospectively analyzed 280 consecutive patients who were treated for epithelial ovarian cancer at our institution between 2001 and 2011. RESULTS: Pretreatment thrombocytosis was observed in 18.9% of all patients and was associated with advanced FIGO stage, primary treatment, operation achievement, histologic subtype, microcytic hypochromic anemia (MHA), and nonmalignant inflammatory condition (P = 0.0018, 0.0028, 0.00050, 0.034, 0.00090 and 0.0022). In the patients who relapsed after primary adjuvant chemotherapy (n = 126), thrombocytosis was associated with a shorter treatment-free interval (TFI) (P = 0.0091). The univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA (P = 0.021 and 0.0091). Patients with thrombocytosis had worse progression-free survival (PFS) and overall survival (OS) than those without thrombocytosis (P <  0.0001 and <  0.0001). The multivariate analyses for prognostic factors demonstrated that thrombocytosis was significant for poor PFS and OS (P = 0.0050 and 0.022) independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition and MHA. CONCLUSIONS: The current findings indicate that the detrimental survival impact of pretreatment thrombocytosis in epithelial ovarian cancer may be independent of tumor extent but rather attributed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in the disease.

Human papillomavirus infections among Japanese women: age-related prevalence and type-specific risk for cervical cancer.

To obtain baseline data for human papillomavirus (HPV) screening and vaccination in Japan, we analyzed HPV DNA data from 2282 Japanese women (1517 normal cytology, 318 cervical intraepithelial neoplasia [CIN] grade 1, 307 CIN2-3, and 140 invasive cervical cancer [ICC]) that visited the University of Tsukuba Hospital or Ibaraki Seinan Medical Center Hospital for screening or treatment of cervical diseases between 1999 and 2007. An L1-based PCR method was used for individual HPV genotyping. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16 (40.5%), HPV18 (24.4%), HPV52 (8.4%), HPV58 (3.1%), and HPV33 (3.1%). Based on the comparison of HPV type distributions between normal cytology and CIN2-3 and ICC, estimated risk of disease progression varied considerably by genotype: HPV16, HPV18, HPV31, HPV33, HPV35, HPV52, and HPV58 (prevalence ratio, 1.92; 95% confidence interval 1.58-2.34); other oncogenic types (0.31, 95% confidence interval 0.19-0.50); and non-oncogenic types (0.09, 95% confidence interval 0.03-0.43). HPV16 and/or HPV18, including coinfections with other types, contributed to 67.1% of ICC and 36.2% of CIN2-3 among Japanese women. More importantly, the overall prevalence of HPV16 and/or HPV18 varied greatly according to the women's age: highest in women aged 20-29 years (ICC, 90.0%; CIN2-3, 53.9%), decreasing with age thereafter, and lowest in women aged 60 years or older (ICC, 56.3%; CIN2-3, 25.0%). In conclusion, type-specific HPV testing may help identify Japanese women at high risk of progression to CIN2-3 and cancer. In Japan, current HPV vaccines are estimated to provide approximately 70% protection against ICC and may be more useful in reducing the incidence of cervical cancer and precancer in young women of reproductive age.

Abnormal accumulation of p53 predicts radioresistance leading to poor survival in patients with endometrial carcinoma.

Type II endometrial carcinoma mainly originates from p53 aberration. However, the detailed prognostic significance of p53 aberration in endometrial carcinoma remains to be clarified. In the present study, abnormal p53 accumulation was analyzed using immunohistochemical techniques in endometrial carcinoma samples derived from 221 consecutive patients. The expression levels of p53 were associated with clinicopathological parameters and patient survival. P53 overexpression was observed in 37/221 patients (17%), and was associated with non-endometrioid histology, post-menopause and advanced tumor stage (III/IV; P=0.0006, P=0.03 and P=0.025, respectively). Survival analysis indicated that patients with p53-overexpressing tumors exhibited poor overall survival (OS) compared with patients without p53 overexpression (P<0.000001). Univariate and multivariate analyses demonstrated that the parameters p53 overexpression, age ≥70, non-endometrioid histology and advanced stage were significant and independent prognostic factors for poor OS (P=0.00012, P=0.00048, P=0.0027 and P=0.0015, respectively). Additionally, adjuvant radiotherapy was associated with increased OS in patients without p53 overexpression. This finding was not observed for patients with adjuvant chemotherapy. In contrast to patients without p53 overexpression, patients with p53 overexpression exhibited no association with OS (P=0.02 vs. P=0.40). Notably, adjuvant radiotherapy was identified to be a significant prognostic factor for favorable OS in the subset of patients that did not exhibit p53 overexpression and received post-operative treatment (P=0.026). The findings suggested that abnormal p53 accumulation may influence patient survival via unfavorable biological tumor properties, including rapid progression and radioresistance. The present study offered valuable insights for the genome-directed management of endometrial carcinoma.