ROS1 as a possible prognostic biomarker of cervical adenocarcinoma: An exploratory analysis with next-generation sequencing.

OBJECTIVES: Given the differences in clinical and biological characteristics between cervical adenocarcinoma and squamous cell carcinoma, this study aimed to conduct an exploratory analysis to examine the molecular characteristics of cervical adenocarcinoma in a Japanese population. METHODS: This study explored the simultaneous testing of multiple mutations targeting cervical adenocarcinoma using next-generation sequencing (NGS). The following genes were analyzed: BCAR4, CD274, PDCD1LG2, KRAS, ARID1A, PTEN, ALK, EGFR, ROS1, BRAF, PIK3CA, EP300, EBXW7, SHCBP1, TGFBR2, SMAD4, ERBB2, ERBB3, and KLF5. Tumor tissue and blood samples were obtained at the time of primary treatment. The NGS-based molecular profiles obtained from Tokai University (49 specimens) were compared with the registered data in The Cancer Genome Atlas (TCGA) database (133 specimens). RESULTS: The study cohort had higher rates of adenocarcinoma than the TCGA cohort (44.9% vs. 18.0%; P = 0.001). The adenocarcinomas in the study cohort had more alterations in ROS1, EGFR, EP300, SHCBP1, ALK, and PIK3CA than those in the TCGA cohort. Among them, ROS1 had the highest number of gene alterations (median, 7.00 ± 2.63). In the study cohort, patients with a high number of ROS1 alterations had a significantly higher recurrence rate (5-year recurrence rate, 48.8% vs. 14.6%; hazard ratio [HR], 4.32; 95% confidence interval [CI], 1.20-15.50; P = 0.014) and lower overall survival than those with low alterations (5-year survival rate, 70.7% vs. 93.1%; HR, 7.15; 95% CI, 1.08-58.22; P = 0.032). CONCLUSION: The current exploratory analysis suggests that ROS1 gene alteration may be a prognostic biomarker in cervical adenocarcinoma in Japanese patients.

Epidemiological guideline influence on the therapeutic trend and patient outcome of uterine cervical cancer in Japan: Japan society of gynecologic oncology guideline evaluation committee project.

OBJECTIVE: The Japan Society of Gynecologic Oncology published its first clinical guidelines for uterine cervical cancer in 2007 which has been revised twice in 2011 and 2017. The aim of this study was to investigate the influence of the first guideline publication on the therapeutic trend and patient outcome by analyzing uterine cervical cancer cases registered to the cancer registry organized by the Japan Society of Obstetrics and Gynecology. METHODS: Data of uterine cervical cancer cases registered to the cancer registry from 2000 to 2012 were provided. Epidemiological and clinical trend were analyzed by the Chi-squared test with subsequent standardized residual analysis. Overall survival among the patients registered between 2004 and 2009 was analyzed using the Fine and Gray competing risk model. RESULTS: 68,707 cases were registered during the study period. A trend analysis revealed that the guideline publication may have led to a decrease in neoadjuvant chemotherapy in parallel with an increase in radiation therapy mainly in stage II and III patients undergoing primary treatment. A survival analysis indicated that the introduction of the guideline may have improved overall survival among stage III uterine cervical cancer patients, even though a significant difference was not observed in all of the cases. CONCLUSIONS: This study demonstrated the potential influence of the guideline publication on the clinical trend and patient outcome. As this is the first assessment of the guideline for uterine cervical cancer in Japan, continuous evaluation is necessary to further comprehend the significance of this guideline.

Value and limitation of conization as a diagnostic procedure for cervical neoplasm.

AIM: In the recent years, the number of cervical conization procedures performed for diagnostic or therapeutic purposes is increasing, accompanied by increased cervical neoplasia among young women. This study aimed to analyze the clinical data of patients who underwent conization in Japan. METHODS: Among the 14 832 cases of conization registered in 205 facilities over 2 years (2009-2011), the data of 2409 and 12 417 patients who underwent conization for diagnostic and therapeutic purposes, respectively, were retrospectively analyzed. RESULTS: The median age of the patients in diagnostic and therapeutic conization groups was 44 and 37 years, respectively. When comparing the diagnostic and therapeutic groups, 25.5% of the patients in the former were suspected with invasive cancer preoperatively, which is higher than that in the latter (2.7%). About 25.7% in the diagnostic and 14.1% in the therapeutic group had positive margin in the conization specimens. Additional treatment was required for 36.0% and 5.5% of the patients in the diagnostic and therapeutic groups, respectively, which are high figures for both. The risk factors of pathological upgrade in the conization specimens were diagnostic purpose, postmenopausal status and glandular lesion. Additional hysterectomy was performed in 1304 patients after conization, and pathological diagnosis was upgraded in 550 cases. Multivariate analysis revealed that postmenstrual status was an independent risk factor. CONCLUSION: This study revealed that cervical lesions of glandular lineage and patients with postmenopausal status benefit from diagnostic conization. However, in postmenopausal patients, the underlying disease cannot be excluded in the preserved uterus even by diagnostic conization.

The Clinical Features of Recurrent Endometrial Cancer in Japan: Chemotherapy Instead of Radiotherapy as Postoperative Adjuvant Treatment.

OBJECTIVE: Chemotherapy is a standard adjuvant treatment after primary surgery for endometrial cancer in Japan. We aimed to characterize the clinical features of recurrent endometrial cancer (REC) patients in Japan. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 112 REC patients who were primarily treated at 1 of 3 university hospitals in Japan from 2005 to 2012. We analyzed overall survival since the first recurrence (R-OS) in accordance with several factors. RESULTS: Median patient age was 64 years. The median follow-up period was 48 months. The distributions of cancer stage and histological subtype lacked distinctive features, and most patients had a high risk for recurrence at the time of the primary surgery. Although approximately 78% of patients received adjuvant chemotherapy, 85/112 patients (76%) experienced recurrence within 2 years after the initial treatment ended. For patients receiving adjuvant chemotherapy, regional lymph node (LN) and distant-site recurrence were more frequent (>40%) than vaginal or intra-abdominal recurrence. Median survival and 5-year R-OS were 27 months and 26.1%, respectively. The R-OS was significantly better for patients aged 65 years or older, those with negative peritoneal cytology at the time of primary surgery, those with recurrence within regional LN (eg, pelvic LN or para-aortic LN under the renal vein) and/or vagina, and those who underwent surgery and/or radiotherapy after recurrence. A multivariate analysis indicated that positive peritoneal cytology, a disease-free interval of less than 12 months, recurrent lesions in 2 or 3 areas, and treatment excluding surgery or radiotherapy were independent predictors of poor prognosis after recurrence. CONCLUSIONS: Adjuvant chemotherapy was insufficient to reduce the incidence of distant recurrence. The prognosis of patients recurred within regional LN and/or vagina was significantly better than that of patients with recurrence in other lesions because of treatment with surgery and/or radiotherapy. The disease-free interval was a significant prognostic factor for REC patients.

UPLC-MS/MS based diagnostics for epithelial ovarian cancer using fully sialylated C4-binding protein.

Serum levels of fully sialylated C4-binding protein (FS-C4BP) are remarkably elevated in patients with epithelial ovarian cancer (EOC) and can be used as a marker to distinguish ovarian clear cell carcinoma from endometrioma. This study aimed to develop a stable, robust and reliable liquid chromatography-hybrid mass spectrometry (UPLC-MS/MS) based diagnostic method that would generalize FS-C4BP as a clinical EOC biomarker. Glycopeptides derived from 20 µL of trypsin-digested serum glycoprotein were analyzed via UPLC equipped with an electrospray ionization time-of-flight mass spectrometer. This UPLC-MS/MS-based diagnostic method was optimized for FS-C4BP and validated using sera from 119 patients with EOC and 127 women without cancer. A1958 (C4BP peptide with two fully sialylated biantennary glycans) was selected as a marker of FS-C4BP because its level in serum was highest among FS-C4BP family members. Preparation and UPLC-MS/MS were optimized for A1958, and performance and robustness were significantly improved relative to our previous method. An area under the curve analysis of the FS-C4BP index receiver operating characteristic curve revealed that the ratio between A1958 and A1813 (C4BP peptide with two partially sialylated biantennary glycans) reached 85%. A combination of the FS-C4BP index and carbohydrate antigen-125 levels further enhanced the sensitivity and specificity.

Fully sialylated alpha-chain of complement 4-binding protein (A2160): a novel prognostic marker for epithelial ovarian carcinoma.

PURPOSE: Fully sialylated alpha-chain of complement 4-binding protein (A2160) is a member of the glycoprotein family and has recently been identified as a diagnostic biomarker for epithelial ovarian cancer. This study examined the utility of A2160 as a prognostic biomarker for this disease. METHODS: This is a retrospective analysis of prospectively collected plasma samples from 93 women with stage I-IV epithelial ovarian cancer who underwent primary cytoreductive surgery between 2009 and 2014. Pretreatment A2160 levels were correlated to clinico-pathological factors and survival outcome. RESULTS: Women with advanced-stage disease had significantly higher 2160 levels compared to those with early stage disease (stage I-II versus III-IV, median 2.17-2.70 versus 5.31-8.70 U/mL, P < 0.01). Women with high-grade serous ovarian carcinoma had higher A2160 levels compared to other histologies (6.60 versus 3.01 U/mL, P = 0.05). Women who had suboptimal cytoreduction had significantly higher A2160 levels than those who achieved optimal/complete cytoreduction (7.02 versus 2.30-3.17 U/mL, P < 0.01). On univariable analysis, higher A2160 levels were significantly associated with decreased progression-free survival (64-100 versus 1-33%ile, 5-year rates 53.4 versus 78.9%, P = 0.029). After controlling for age, CA-125 level, cytoreductive status, histology, and stage, higher A2160 levels remained an independent prognostic factor for decreased progression-free survival (adjusted-hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.01-6.11, P = 0.049). Similarly, higher A2160 levels were independently associated with decreased cause-specific survival on multivariable analysis (adjusted-HR 3.07, 95% CI 1.19-7.93, P = 0.021). CONCLUSION: Our study suggests that A2160 may be a useful prognostic biomarker for epithelial ovarian cancer, and higher pretreatment levels of A2160 predicts poor survival outcome.

Efficacy of the oral neurokinin-1 receptor antagonist aprepitant for nausea and vomiting induced by cisplatin and carboplatin in Japanese patients with gynecological cancer.

AIM: This study was conducted to evaluate the efficacy and the difference in effects of the oral neurokinin-1(NK-1) receptor antagonist aprepitant for chemotherapy-induced nausea/vomiting (CINV) in Japanese patients with gynecological cancer receiving highly emetogenic (cisplatin) and moderately emetogenic (carboplatin) chemotherapy. METHODS: Aprepitant was added during the second course of chemotherapy in Japanese patients with grade ≥ 2 (Common Terminology Criteria for Adverse Events, version 3.0) nausea and vomiting during the first course despite receiving antiemetic therapy (a first-generation 5-hydroxytryptamine 3 receptor antagonist + dexamethasone), and in patients who requested stronger antiemetic therapy despite only having grade 1 nausea and vomiting. The incidence of nausea and vomiting was compared between the first and second courses in each group. RESULTS: Ninety-six (55.5%) out of 173 patients received add-on therapy with aprepitant. There was a significant increase in the complete response (CR: no vomiting or salvage therapy) rate in the patients receiving aprepitant, with marked improvement being confirmed for delayed CINV. Stratified analysis showed that patients with delayed CINV treated with carboplatin had a significantly higher CR rate, while patients with both acute and delayed CINV treated with cisplatin had significantly higher CR rates. There was a positive correlation between the incidence of nausea and the incidence of vomiting in the patients treated with aprepitant. CONCLUSION: The oral NK-1 receptor antagonist aprepitant could be effective for both acute and delayed CINV with cisplatin and for delayed CINV with carboplatin in Japanese gynecological cancer patients.

Fully-sialylated alpha-chain of complement 4-binding protein: Diagnostic utility for ovarian clear cell carcinoma.

OBJECTIVE: While a certain fraction of endometriomas can develop de novo epithelial ovarian cancer (EOC) such as clear cell carcinoma (OCCC), there is currently no useful biomarker available for early detection of OCCC from endometriomas. The aim of this study was to describe the diagnostic utility of a novel biomarker for EOC especially for OCCC to distinguish from endometrioma. METHODS: More than 100,000 glycan structures of serum glycoproteins obtained from 134 pretreatment all stage EOC patients (including 45 OCCCs) and 159 non-cancer control women (including 36 endometriomas) were explored for a mass spectrum approach. Diagnostic accuracy of identified biomarker was compared to the one of CA-125 by comparing area under curve (AUC) and positive/negative predictive values (PPV and NPV). RESULTS: A2160, a fully-sialylated alpha-chain of complement 4-binding protein, was identified as a candidate target marker. A2160 was significantly elevated in all stages of OCCC compared to with endometriomas. Diagnostic accuracy of A2160 (cutoff 1.6U/mL) to distinguish early stage OCCC from endometrioma is significantly higher than that of CA-125 (cutoff 35IU/L): AUC for A2160 versus CA-125, 0.92 versus 0.67; PPV 95% versus 64%; and NPV 85% versus 58%. In addition, fully-sialylated glycans had a higher accuracy for diagnosing EOC as compared to partially-sialylated glycans of alpha-chain of complement 4-binding protein. CONCLUSION: Our study suggested that A2160 may be a useful biomarker to distinguish early-stage OCCC from endometrioma. This new biomarker can be potentially applied for the monitoring of endometrioma patients, making possible the early diagnosis of OCCC.

Protective effect of eicosapentaenoic acid on insulin resistance in hyperlipidemic patients and on the postoperative course of cardiac surgery patients: the possible involvement of adiponectin.

Accumulated studies have shown that ω-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have protective roles against inflammatory responses such as hyperlipidemia, diabetes mellitus (DM) and cardiovascular diseases. Here we examined the effects of administering EPA to hyperlipidemic patients and other patients undergoing cardiac surgery to determine whether this treatment would increase plasma EPA levels and to clarify the association between EPA treatment and adiponectin production in hyperlipidemic patients. We also assessed the effect of preoperative EPA administration on postoperative adverse events such as postoperative atrial fibrillation (POAF) and postoperative infection in the cardiac surgery patients. The EPA administration significantly increased the serum EPA concentrations in both patient populations (p＜0.001). In the hyperlipidemic patients, the EPA administration significantly increased plasma adiponectin levels (p＜0.05), accompanied by a decrease in insulin resistance designated by the HOMA-IR (homeostasis model assessment of insulin resistance) score (p＜0.05) and Hs-CRP (high sensitivity C-reactive protein) value (p＜0.05). In the cardiac surgery patients, no significant effect of EPA on cardiac adverse events such as POAF was observed. However, our results clearly demonstrated that both the neutrophil-to-lymphocyte ratio and the 2nd-line antibiotic requirement in the EPA group were significantly decreased compared to the untreated control group (p＜0.05). We suggest that EPA administration may exert anti-inflammatory effects in patients with hyperlipidemia and in those undergoing cardiac surgery, possibly through an increase in plasma adiponectin levels.

Alterations of hypoxia-induced factor signaling pathway due to mammalian target of rapamycin (mTOR) suppression in ovarian clear cell adenocarcinoma: in vivo and in vitro explorations for clinical trial.

OBJECTIVES: Before setting into the clinical trial using a combination of mammalian target of rapamycin (mTOR) inhibitors (rapamycin and everolimus) and other anticancer drugs, this study was conducted to confirm the efficacy of the new therapeutic strategy for ovarian clear cell adenocarcinoma (CCA), which targeted mTOR-hypoxia-induced factor (HIF) signal transduction system. MATERIALS AND METHODS: Using the cultured cells of CCA and animal models, alteration of mTOR-HIF cofactors and cell proliferation under the mTOR inhibitor-treated condition were analyzed. RESULTS: Mammalian target of rapamycin-HIF cofactors were inhibited dependent on concentration by mTOR inhibitor, resulting in suppression of the cultured CCA proliferation. However, von Hippel-Lindau was up-regulated at the messenger RNA level. In the nude mice with subcutaneously implanted CCA cells, apoptosis and necrosis were detected especially around the center of the tumors in the mTOR inhibitor-treated group more conspicuously than in the nontreated group. In the assessment of combination therapy with other antitumor agents, a combined treatment with mTOR inhibitor and chemotherapeutic agents caused a significant decrease in tumor size compared to the chemotherapeutic agents-only group. CONCLUSIONS: Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.

Enhanced expression of sulfatide, a sulfated glycolipid, in well-differentiated endometrial adenocarcinoma.

OBJECTIVES: It is well known that a poorly differentiated endometrial adenocarcinoma shows more rapid progression and a worse response to therapy than a well-differentiated endometrial adenocarcinoma. Qualitative and quantitative changes of cell surface glycolipids occur during neoplastic transformation. Sulfatide is one of the sulfated glycolipids in the cell membrane that may have an important role in various functions such as cell adhesion. To examine the molecular background of the morphological and biological features of well-differentiated and poorly differentiated cancer, we measured the levels of lipids, especially glycolipids, in tumor tissues from patients with endometrial carcinoma. MATERIALS AND METHODS: We determined the composition of lipids and glycolipids in tumor tissues, investigated glycosyltransferase messenger RNA expression by the reverse transcription-polymerase chain reaction, and assessed the localization of galactosylceramide sulfotransferase (an enzyme involved in sulfatide biosynthesis) by immunohistochemical staining. RESULTS: No significant differences were observed between well-differentiated and poorly differentiated cancer with respect to the levels of cholesterol ester, cholesterol, phospholipids, cholesterol sulfate, ceramides, neutral glycolipids of the globo series, and GM3 ganglioside. However, the amount of sulfatides in well-differentiated tumors was significantly greater than that in poorly differentiated tumors, which was confirmed by thin-layer chromatography and immunostaining with a monoclonal antisulfatide antibody. Altered expression of sulfatide was found to be secondary to a change of galactosylceramide sulfotransferase messenger RNA expression. Immunohistochemical staining revealed that galactosylceramide sulfotransferase expression was characteristically observed in glandular areas but not in solid areas. CONCLUSION: These findings suggest that sulfatide contributes to the well-differentiated phenotype of endometrial adenocarcinoma and that it is being expressed in normal uterine endometrium at sites of gland formation during the luteal phase, as we have previously reported.

Long Term Prognostic Implications of Expression of Glucose Transporter-1 and Hexokinase II in Patients with Stage I Uterine Leiomyosarcoma.

Many malignant epithelial tumors show increased expression of glucose transporter-1 (GLUT-1) and hexokinase II (HK-II), both of which are involved in glucose metabolism. GLUT-1 levels are often correlated with prognosis in these tumors. The current retrospective study was conducted to evaluate the importance of GLUT-1 and HK-II expression in leiomyosarcoma (LMS), a malignant uterine non-epithelial tumor with a poor prognosis. The subjects were 23 patients with stage I LMS. Expression of GLUT-1 and HK-II was evaluated immunohistochemically in samples removed surgically, and the MIB-1 index was evaluated as a measure of cell proliferation. The association of these results with prognosis was examined. Twenty samples of leiomyoma (LOM), a benign non-epithelial tumor, were used as controls. Immunohistochemical expression was defined as negative staining (-), weak to sporadic staining (1+), and strong staining (2+) per microscopic field, respectively. Malignancy was evaluated in 2000 cells and the MIB-1 index was calculated. Overall survival for LMS was estimated using the Kaplan-Meier method. Of the LMS cases, 12 were GLUT-1-positive (52.2%; 2+: 2, 1+: 10) and 15 were HK-II-positive (65.2%; 2+: 1, 1+: 14). GLUT-1 expression in LMS was significantly correlated with the MIB1 index. The 10-year survival rates were 90.9% and 58.3% in GLUT-1-negative and GLUT-1-positive cases, respectively, and 75.0% and 73.3% in HK-II-positive and HK-II-negative cases, respectively. GLUT-1 expression was significantly correlated with prognosis. Cases of stage I LMS showed a significant correlation between the expression level of GLUT-1 and the MIB-1 index, an indicator of malignancy. GLUT-1-negative cases had a better prognosis than GLUT-1-positive cases, suggesting that GLUT-1 expression is an effective prognostic marker.

Association of circulating levels of leptin and adiponectin with metabolic syndrome and coronary heart disease in patients with various coronary risk factors.

The aim of this study was to investigate the associations of adiponectin and leptin with metabolic syndrome (MetS) and coronary heart disease (CHD) in patients with various coronary risk factors. We determined serum adiponectin, leptin, and metabolic syndrome components in 104 patients (59 men and 45 women; aged 40-86 years) with various coronary risk factors at a cardiovascular out-patient clinic. Natural logarithmic transformed (ln) leptin was lower in men and smokers, and positively correlated with body mass index (BMI) (r = 0.59, P < 0.0001), waist circumference (r = 0.60, P < 0.0001), and homeostasis model assessment of insulin resistance (HOMA-IR) levels (r = 0.24, P < 0.02). Ln adiponectin was higher in women and nonsmokers, and was correlated with age and high-density lipoprotein cholesterol (HDL-C). Patients with MetS (n = 69) had significantly higher BMI, HOMA-IR, and ln leptin and lower ln adiponectin than those without Mets (Ln leptin, 2.14 ± 0.08 versus 1.30 ± 0.11; Ln adiponectin, 2.29 ± 0.06 versus 2.54 ± 0.09). In contrast, patients with coronary heart disease (CHD: n = 40) had significantly lower serum ln adiponectin concentrations than non-CHD patients (n = 64) (1.79 ± 0.12 versus 1.91 ± 0.10) as well as lower HDL-C and a higher smoking percentage. Consistent results were obtained by multivariate analyses. In conclusion, this study disclosed factors associated with the increase in serum leptin and adiponectin. Serum levels of leptin may be associated positively with MetS, whereas adiponectin levels are associated negatively with MetS and CHD, even in patients with various coronary risk factors.

Pyogenic Spondylitis in Multidisciplinary Therapies of Gynecologic Malignancies: Three Cases Reports.

Both during and after cancer treatment, pyogenic spondylitis is an uncommon but serious complication. Because pyogenic spondylitis is often recognized as a complication of a distant process causing bacteremia, it initially may be misdiagnosed the primary infection such as urinary tract infection. Consequently, a considerable delay in diagnosis frequently occurs. In addition, estrogen deprivation caused by cancer treatments including RT/CCRT, CT and surgical therapy promotes changes of the immune system. We report two cases of pyogenic spondylitis in a patient with vaginal cancer that occurred delay of the diagnosis, and in a patient with endometrial cancer that had chronic steroid use, and one case of suppurative osteomyelitis in a patient with vulvar cancer that had diabetes mellitus with obesity. Gynecologic oncologists must consider the diagnosis of pyogenic spondylitis based on clinical symptoms such as localized lumbago and medical history. Estrogen deprivation, repeated cancer treatment, diabetes mellitus with obesity, immunosuppression by chronic steroid use are risk factors of pyogenic spondylitis. To prevent delay in diagnosis of pyogenic spondylitis, it is necessary that we must have careful management and follow-up considering all of information such as clinical features and medical history on patients during and after treating for gynecologic malignancies.

Association of menopause, aging and treatment procedures with positive margins after therapeutic cervical conization for CIN 3: a retrospective study of 8,856 patients by the Japan Society of Obstetrics and Gynecology.

OBJECTIVE: The Japan Society of Obstetrics and Gynecology conducted a retrospective multi-institutional survey of patients who underwent cervical conization in Japan. This study aimed to determine the predictive factors for positive surgical margins in cervical intraepithelial neoplasia grade 3 (CIN 3) patients after therapeutic cervical conization and those for positive margins in patients who did not experience recurrence and did not undergo additional treatment. METHODS: In 2009 and 2013, 14,832 patients underwent cervical conization at 205 institutions in Japan. Of these, 8856 patients who underwent therapeutic conization fulfilled the inclusion criteria. Their histologic findings and clinical outcomes were evaluated based on standard statistical procedures and clinical and demographic characteristics. RESULTS: Negative and positive margins were observed in 7,585 and 1,271 (14.4%) patients, respectively. The predictors of positive margins were menopausal status (p<0.001), loop electrosurgical excision procedure (p<0.001), and Shimodaira-Taniguchi (S-T) conization (p<0.001). Of 1,271 patients with positive margins, 1,060 underwent no additional treatment; among those 1,060 patients, 129 (12.2%) experienced recurrence. The predictors of positive margins in patients who did not undergo additional treatment and did not experience recurrence were age, parity, gravidity, S-T conization, and laser scalpel conization. CONCLUSION: Menopausal status and treatment procedures were associated with positive margins after therapeutic conization of CIN 3. It is important to understand the characteristics of treatment procedures and select an appropriate procedure for each case. For elderly or menopausal patients with positive margins, immediate additional treatment is recommended.

The trend and outcome of postsurgical therapy for high-risk early-stage cervical cancer with lymph node metastasis in Japan: a report from the Japan Society of Gynecologic Oncology (JSGO) guidelines evaluation committee.

OBJECTIVE: The Japan Society of Gynecologic Oncology published the first guidelines for the treatment of cervical cancer in 2007. The aim of this research was to evaluate the influence of the introduction of the first guideline on clinical trends and outcomes of patients with early-stage cervical cancer who underwent surgery. METHODS: This analysis included 9,756 patients who were diagnosed based on the pathological Tumor-Node-Metastasis (pTNM) classification (i.e., pT1b1, pT1b2, pT2b and pN0, pN1, pNX) and received surgery as a primary treatment between 2004 and 2009. Data of these patients were retrospectively reviewed, and clinicopathological trends were assessed. The influence of the introduction of the guideline on survival was determined by using a competing risk model. RESULTS: For surgery cases, the estimated subdistribution hazard ratio (HR) by the competing risk model for the influence of the guideline adjusted for age, year of registration, pT classification, pN classification, histological type, and treatment methods was 1.024 (p=0.864). Following the introduction of the first guideline in 2007, for patients with lymph node metastasis, the use of chemotherapy (CT) as a postsurgical therapy increased, whereas that of concurrent chemoradiotherapy (CCRT)/radiotherapy (RT) decreased (p<0.010). For pN1 cases, the estimated subdistribution HR by the competing risk model for the influence of the guideline was 1.094 (p=0.634). There was no significance in the postsurgical therapy between CT and CCRT/RT (p=0.078). CONCLUSIONS: Survival of surgical cases was not improved by the introduction of the guidelines. It is necessary to consider more effective postsurgical therapy for high-risk early-stage cervical cancer.

Analysis of pathological and clinical characteristics of cervical conization according to age group in Japan.

OBJECTIVE: With increased screening, more patients with precancerous or early cervical cancer are now being identified. Age at pregnancy, and thus number of patients requiring fertility preservation, have also increased, resulting in more diagnostic and therapeutic cervical conization (conization) procedures. We here investigated the pathological and clinical characteristics of patients undergoing conization, with a focus on age. The objectives of our study were to identify the risk factors potentially involved in cervical intraepithelial neoplasia (CIN) recurrence or persistence, additional treatment after conization, the effects of conization on pregnancy, and the actual status of conization in Japan. STUDY DESIGN: A "Subcommittee for Investigation of Cervical Conization" within the Gynecologic Oncology Committee in the Japan Society of Obstetrics and Gynecology investigated pathological and clinical characteristics of conization at 205 institutions in Japan. We analyzed pathological and clinical characteristics according to age ≤50 and >50 years. RESULTS: Patients aged 20-40 years accounted for 12904 (87%) of the 14,832 study patients (median: 37 years, range: 16-88 years). However, 1838 (12.4%) were aged >50 years. The commonest post-operative diagnosis was CIN grade 3 in all age groups. Rates of invasive cancer, post-operative detection of more advanced lesions, positive surgical margins, additional treatment, and recurrence were significantly higher in patients aged ≥50 years than those aged <50 years (all p < 0.01), whereas rates of post-operative complications did not differ significantly between age groups. The relationship between cerclage and the incidence of amniorrhexis or premature birth did not differ significantly in any age group. CONCLUSION: Post-conization management of patients aged ≥50 years requires considering the high rates of detection of more advanced lesions post-operatively, positive surgical margins, and recurrence. Cerclage should not be performed post-conization without careful consideration.

Utility of Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA) for the Detection of Early Stage Epithelial Ovarian Cancer.

Comprehensive serum glycopeptide spectra analysis (CSGSA) evaluates >10,000 serum glycopeptides and identifies unique glycopeptide peaks and patterns via supervised orthogonal partial least-squares discriminant modeling. CSGSA was more accurate than cancer antigen 125 (CA125) or human epididymis protein 4 (HE4) for detecting early stage epithelial ovarian cancer. Combined CSGSA, CA125, and HE4 had improved diagnostic performance. Thus, CSGSA may be a useful screening tool for detecting early stage epithelial ovarian cancer.

Comprehensive Serum Glycopeptide Spectra Analysis Combined with Artificial Intelligence (CSGSA-AI) to Diagnose Early-Stage Ovarian Cancer.

Ovarian cancer is a leading cause of deaths among gynecological cancers, and a method to detect early-stage epithelial ovarian cancer (EOC) is urgently needed. We aimed to develop an artificial intelligence (AI)-based comprehensive serum glycopeptide spectra analysis (CSGSA-AI) method in combination with convolutional neural network (CNN) to detect aberrant glycans in serum samples of patients with EOC. We converted serum glycopeptide expression patterns into two-dimensional (2D) barcodes to let CNN learn and distinguish between EOC and non-EOC. CNN was trained using 60% samples and validated using 40% samples. We observed that principal component analysis-based alignment of glycopeptides to generate 2D barcodes significantly increased the diagnostic accuracy (88%) of the method. When CNN was trained with 2D barcodes colored on the basis of serum levels of CA125 and HE4, a diagnostic accuracy of 95% was achieved. We believe that this simple and low-cost method will increase the detection of EOC.

Small Cell Neuroendocrine Carcinoma of the Endometrium with Difficulty Identifying the Original Site in the Uterus.

Diagnosis of malignant uterine tumor with continuous lesions from the uterine body to the cervix, i.e., endometrial or cervical cancer, depends on the main site of the lesions. However, it may be difficult to differentiate advanced cancer that is widespread in the uterus. We experienced a patient who was diagnosed with small cell neuroendocrine carcinoma (SCNEC) based on histopathological characteristics of SCNEC in the endometrium. This tumor frequently coexists with endometrioid carcinoma, but we had difficulty finding the original site of SCNEC in the endometrium. The patient was a 59-year-old, two-parous woman who underwent hysterectomy after diagnosis of malignant uterine tumor. Preoperative cervical and endometrial histology permitted diagnosis of SCNEC. Imaging showed that most of the anterior uterine wall from the uterine body to cervix was replaced by tumors. Histopathologic findings for the resected uterus showed that most of these tumors were SCNEC, but components of endometrioid carcinoma had developed from the endometrium just beneath the fundus to the lower uterine body. The growth pattern of endometrioid carcinoma was endophytic. Based on this finding, the patient was diagnosed with endometrial SCNEC associated with endometrioid carcinoma. The patient initially responded well after postoperative chemotherapy, but early recurrence led to death at three months after the first treatment. This case shows that SCNEC in the uterine body is likely to coexist with endometrioid carcinoma. These findings are useful to determine the original site in postoperative pathological diagnosis of highly advanced tumors. SCNEC is a rapidly progressive and aggressive tumor in clinical practice, but some cases have a relatively good initial response to chemotherapy and it is important to start treatment early.