竹井 裕二

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.

The patient was an unmarried nulliparous 21-year-old female who was referred to our hospital with an abdominal mass. Bilateral ovarian tumors with a solid component were detected and both were suspected to be ovarian cancer. Since the patient strongly wished to preserve fertility, we performed left salpingo-oophorectomy, right cystectomy, and omentectomy. A postoperative histopathological examination revealed that the bilateral ovarian tumors were mucinous borderline tumors. The patient selected oocyte cryopreservation. Oocyte retrieval from the right ovary was performed 2 years after surgery, and six oocytes were obtained. The puncture of a small cyst revealed mucinous fluid, not normal follicular fluid; therefore, puncture fluid cytology was performed. A recurrent mucinous borderline ovarian tumor was suspected. Right salpingo-oophorectomy was performed and a recurrent mucinous borderline ovarian tumor was diagnosed. Puncture fluid properties need to be considered when there is an opportunity for oocyte retrieval after fertility-sparing surgery.

The persistence of antitumor effects has been reported after the completion of treatment with immune checkpoint inhibitors (ICIs) for various types of carcinoma, such as malignant melanoma, exhibiting a durable response. A durable response has also been noted after the discontinuation of treatment at an early stage due to adverse events, including in renal pelvic cancer, pancreatic cancer and intrahepatic cholangiocarcinoma; however, to the best of our knowledge, a similar case report has not yet been published in the malignant gynecological tumor field. The present study described a patient with refractory advanced endometrial cancer in whom the administration of pembrolizumab was discontinued after the completion of the 7th course due to renal dysfunction; however, persistent tumor-reducing effects and decreases in the levels of tumor markers were noted for more than 18 months after the cessation of treatment. Pembrolizumab may be continuously administered to some patients for a long period, whereas a durable response is achieved by others even after its discontinuation at an early stage; therefore, difficulties are associated with selecting an appropriate duration of administration. Further studies are required to search for biomarkers that facilitate high-accuracy effect predictions, and to establish an optimal administration period in consideration of specific adverse reactions to ICIs and cost-effectiveness.

PURPOSE: Although neutrophil extracellular traps (NETs) are present in various tumors, their roles in tumor biology have not been clarified yet. In this study, we examined how NETs affect the pharmacokinetics and effects of doxorubicin (DOX). METHODS: NETs were generated by neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS). DOX was added to NETs and their distribution was observed under fluorescein microscopy, and the diffusion of DOX through 3 μM pores from lower to upper chambers was evaluated with a fluorescence-based assay. Ovarian cancer cells, KOC-2S and SKOV3, were embedded in collagen gel droplets and cultured in 3D way and their apoptosis was examined with flow cytometry. RESULTS: DOX was mostly co-localized with NETs. The transfer of DOX to upper chambers increased over time, which was significantly decreased by the presence of neutrophils stimulated with PMA or LPS in the lower chamber. DOX outside of the gel increased the rates of annexin V (+) apoptotic cells, which were significantly reduced by the addition of LPS-stimulated neutrophils in media both in KOC-2S and SKOV3. The reduced diffusion and apoptosis were mostly restored by the destruction of the NETs structure with 1000 u/ml DNAse I. CONCLUSION: NETs efficiently trap and inhibit the diffusion of DOX which may attenuate its ability to induce apoptosis of ovarian cancer cells. Degradation of NETs with DNAse I may augment the response of ovarian cancer to DOX.

This study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate-risk stage I and II or high-risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel-epirubicin-carboplatin (TEC), paclitaxel-anthracycline (doxorubicin)-carboplatin (TAC), or dose-dense paclitaxel-carboplatin (ddTC). The primary end-point was the completion rate (CRate) of six cycles of treatment. The secondary end-points were progression-free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P = .005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2-year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911).

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12-16 years, and catch-up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2-3 (CIN2-3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12-15 years (n = 36), 16-18 years (n = 23), 19-22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P < .001). This finding was supported by age at first sexual intercourse; among women with CIN2-3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12-16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994-1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1-3 (CIN1-3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among "unvaccinated" cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged <40 years, newly diagnosed with CIN/AIS during 2012-2021 for time trends. Declining trends in HPV16/18 prevalence over 9 years were observed in CIN1 (36.0-10.0%, Ptrend = 0.03) and CIN2-3/AIS (62.5-36.4%, Ptrend = 0.07) among women aged <25 years. HPV16/18 prevalence in CIN1 and CIN2-3/AIS diagnosed at age 20-24 years was lower in 1994-1999 birth cohorts compared with 1988-1993 birth cohorts (4.5% vs. 25.7% for CIN1 and 40.0% vs. 58.1% for CIN2-3/AIS, both p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2-3/AIS suggests herd effects of HPV vaccination in Japan.

It has remained elusive whether standard chemotherapy regimens are safe for patients with ovarian cancer and poor general condition. The purpose of the present study was to assess the response to and toxicity of weekly paclitaxel and carboplatin (W-PC) in patients with ovarian cancer and poor general condition. The subjects were patients with ovarian cancer who received W-PC at Jichi Medical University Hospital (Shimotsuke, Japan) between January 2008 and December 2016. Patients who were ≥80 years old and/or had a performance status ≥3 and/or severe complications/underlying diseases were selected. Patients received paclitaxel (60 mg/m2) and carboplatin (area under the curve 2 mg/ml/min) on days 1, 8, and 15 of a 28-day cycle. Their medical records were retrospectively reviewed. A total of 31 patients were included in the study. Grade 3/4 neutropenia, anemia and thrombocytopenia developed in 18 (58%), 5 (16%) and 1 (3%) patients, respectively. Furthermore, three (10%) patients had a complete response (CR), 12 (39%) had a partial response (PR), 5 (16%) had stable disease and 11 (35%) had progressive disease. The overall response rate was 48% (15/31) and the disease control rate was 65% (20/31). The 5-year progression-free survival was 15% and the 5-year overall survival was 15%. A total of 9 patients survived for >40 months, one of whom survived without recurrence for 122 months. Performance status <3, a tumor response of CR or PR and >5 chemotherapy cycles were indicators of favorable prognosis. Only >5 chemotherapy cycles (vs. ≤5; P=0.002) was an independent good prognostic factor according to multivariate analysis. In conclusion, W-PC was tolerable and slightly effective in patients with ovarian cancer and poor general condition. W-PC may be one option for patients who are unable to receive standard chemotherapy regimens.

A previous study by our group reported that removing a larger number of lymph nodes in patients with stage I ovarian clear cell carcinoma (OCCC) improved progression-free survival (PFS). The present study investigated whether clinical conditions, particularly the number of removed lymph nodes, are independent predictors of progression for stage II or higher OCCC and whether the significance of the number of removed lymph nodes differs according to FIGO stage for OCCC. A total of 113 patients with OCCC who had undergone surgery between January 1993 and December 2015 were retrospectively enrolled and the clinicopathological data were obtained from their medical records. Among patients with stage II or higher OCCC, PFS of those with no residual tumor or no lymph node metastasis was significantly better than that of those with residual tumor (P=0.023) or lymph node metastasis (P=0.035). Multivariate analysis revealed that no residual tumor was the only independent predictor for improved PFS of patients with stage II or higher. Regarding the number of removed lymph nodes, it did not significantly affect the PFS of patients with stage II or higher OCCC, whereas it improved the PFS of those with stage I, being an independent predictor of progression of stage I OCCC. In summary, although the number of removed lymph nodes was an independent predictor of progression for stage I OCCC, it was not for stage II or higher OCCC. The prognostic significance of the number of removed lymph nodes in OCCC may differ depending on the FIGO stage.

AIM: To clarify incidence and clinical features of treatment-related leukemia (TRL) due to taxane/platinum therapy in gynecological cancer patients. METHODS: We conducted a retrospective study of gynecological cancer patients who were diagnosed at facilities participating in the Gynecologic Oncology Trial and Investigation Consortium and started only taxane/platinum therapy as chemotherapy between 2002 and 2006. RESULTS: The site of the primary lesion was the ovary in 124, endometrium in 37, and uterine cervix in 4. The regimen of chemotherapy was paclitaxel (T) + carboplatin (C) therapy in 134 and others in 31 patients. The cumulative incidence was 2.4% (4/165), and the incidence was 2.9/1,000 person-years. All four cases were acute myeloid leukemia. The average total doses of T and C in patients without TRL were 1,693 (SD 1,050) and 4,170 (SD 2,423) mg. For TRL patients, the total T and C doses were, respectively, 1,555 and 3,540 mg, 1,620 and 4,200 mg, 2,130 and 4,700 mg, 3,220 mg and 8,310 mg. The fourth patient received additional 2,415 mg of docetaxel and 2,155 mg of nedaplatin. The intervals from the primary chemotherapy to the onset of TRL were 27, 34, 67, and 114 months. Three patients had no evidence of ovarian cancer. Three patients died of TRL at 4 days, 5 months, and 11 months, one patient remained in remission at 25 months after diagnosis of TRL. CONCLUSION: Patients receiving taxane/platinum therapy should undergo long-term follow-up with attention to the development of TRL, even if the gynecologic malignant cancer is in remission.

Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor, and vasohibin-2 (VASH2), its homolog, exhibits proangiogenic activity. VASH2 is expressed by various cancer cells and accelerates tumor angiogenesis and progression. VASH2 was recently shown to exhibit tubulin carboxypeptidase (TCP) activity related to microtubule functions. Paclitaxel (PTX), an effective chemotherapeutic agent that is widely used to treat ovarian cancer, inhibits microtubule depolymerization and may interact with VASH2. We herein established several VASH2 knockout ovarian cancer cell lines using the CRISPR/Cas9 genome editing system to examine the intracellular tubulin detyrosination status and PTX chemosensitivity. The knockout of VASH2 did not affect the proliferation or sphere-forming activity of ovarian cancer cells in vitro. A Western blot analysis of VASH2 knockout cells revealed the weak expression of detyrosinated tubulin and upregulated expression of cyclin B1. The knockout of VASH2 significantly increased chemosensitivity to PTX, but not to cisplatin in ovarian cancer cell lines. The knockout of VASH2 reduced TCP activity and increased cyclin B1 expression, resulting in increased PTX chemosensitivity in ovarian cancer cells. The inhibition of angiogenesis and regulation of microtubule activity may be achieved in ovarian cancer treatment strategies targeting VASH2.

AIM: Pegylated liposomal doxorubicin (PLD) is one of the second-line chemotherapy regimens for platinum-resistant recurrent ovarian cancer, but in clinical practice, it is also used for third or subsequent lines of chemotherapy. There is no report on the efficacy and toxicity of PLD in relation to the number of previous chemotherapy regimens. The purpose of this study was to clarify these points and compare with the results of gemcitabine (GEM) therapy we reported previously. METHODS: We retrospectively reviewed the medical records of patients with platinum-resistant recurrent ovarian cancer who underwent two or more cycles of PLD therapy between July 2009 and March 2017 at our institution. We used our reported data of GEM for comparison analysis. RESULTS: Seventy-eight patients were enrolled in this study. The overall response rate was 19.2% and the disease control rate (DCR) was 53.8%. The DCR with 1, 2, 3, and 4 or more previous regimens was 53.8%, 48.6%, 63.6% and 66.7%, respectively. Grade 3/4 neutropenia and anemia developed in 59.0% and 12.8%, respectively. Grade 2 or higher hand -foot syndrome, stomatitis, and liver dysfunction developed in 25.6%, 25.6% and 2.6%, respectively. When the number of previous regimens was 3 or higher, the DCR of PLD was significantly higher than that of GEM (64.7% vs 30.8%, P = 0.037). CONCLUSION: The DCR did not decrease with a greater number of previous regimens. When the number of previous regimens was 3 or higher, PLD therapy had a superior DCR to GEM therapy. Toxicity was tolerable in PLD therapy.

Objectives: The purpose of this study was the perinatal outcomes of patients who became pregnant after adenomyomectomy.Study design: The retrospective cohort study was performed involving pregnant women with a history of adenomyomectomy between 1 January 2011 and 31 December 2018. At 24-26 weeks, the patients were admitted even without symptoms or signs. When regular uterine contractions were observed, tocolysis was performed.Results: Ten patients were included. Elective and emergent cesarean section (CS) was performed in seven and three patients, respectively. Emergent CS was performed due to onset of labor (tocolytic failure) at 28, 24, and 32 weeks. Although no patients suffered uterine rupture, myometrial thinning was observed at the site corresponding to that of adenomyomectomy in three patients. Of these three patients, two required emergent CS due to tocolytic failure with cervical length (CL) shortening. In contrast, CLs were stable in the other seven patients with elective CS.Conclusions: Three patients after adenomyomectomy showed preterm delivery, and three had a very thin uterus to the extent that the fetus could be observed through the uterine wall. A short CL should be paid special attention in pregnant women with a history of adenomyomectomy.

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012-2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2-3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type-specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type-specific RCs between CIN1 and CIN2-3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type-specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2-3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2-3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01-4.98), followed by HPV31 (2.51, 1.54-5.24), HPV18 (2.43, 1.59-4.32), HPV35 (1.56, 0.43-8.36), HPV33 (1.01, 0.49-3.31), HPV52 (0.99, 0.76-1.33), and HPV58 (0.97, 0.75-1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71-2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14-0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9-valent vaccine contributed to 89.7% (95% CI, 88.7-90.7) of CIN2-3/AIS and 93.8% (95% CI, 92.4-95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9-valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.

Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, Ptrend  < .0001) and CIN2-3/AIS (83.3% to 45.0%, Ptrend  = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch-up vaccination (P = .04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government's suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.

PURPOSE: To compare the efficacy, safety, and tolerability profiles of pegylated liposomal doxorubicin and carboplatin (PLDC) with those of gemcitabine and carboplatin (GC) for the treatment of patients with platinum-sensitive recurrent ovarian cancer. METHODS: Ovarian cancer patients with recurrence > 6 months after first-line platinum and taxane-based therapies were randomly assigned to PLDC [pegylated liposomal doxorubicin 30 mg/m2 plus carboplatin area under the curve (AUC) 5 mg/mL/min on day 1] every 4 weeks or GC (gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 4 mg/mL/min on day 1) every 3 weeks for at least 6 cycles. The primary endpoint was progression-free survival, and overall response rate, overall survival, toxicity, and dose administration were secondary endpoints. RESULTS: One-hundred patients (49 PLDC; 51 GC) were randomly assigned. Over a median follow-up of 24 months, the median progression-free survival was 12.0 months (95% CI 9.2-15.0) for PLDC and 9.8 months (8.9-12.3) for GC [HR 0.69 (0.455-1.047)] with a difference of 2.2 months. The response rate was 57.1% (41.0-72.3) for PLDC and 56.4% (39.6-72.2) for GC. No obvious differences in toxicity (G3/4) were noted between arms. The median relative dose intensity of planned dose per week was 88.9% for pegylated liposomal doxorubicin and 53.1% for gemcitabine (p < 0.0001). CONCLUSIONS: PLDC and GC are both good treatment candidates for platinum-sensitive recurrent ovarian cancer patients; however, the dose intensity was lower for GC than for PLDC. PLDC had a more favorable risk-benefit profile than that of GC for patients.

OBJECTIVE: To examine predictors of pathological parametrial invasion in clinical stage IIB cervical cancer, and to examine prognostic factors in pathological stage IIB disease. METHODS: This study is an ancillary analysis of a nation-wide retrospective cohort examining 6,003 clinical stage IB-IIB cervical cancers. Women with clinical stage IIB disease who underwent primary radical hysterectomy with lymphadenectomy were examined (n = 714). Multivariate analysis was performed to identify independent clinico-pathological factors for pathological parametrial invasion and to identify independent prognostic factors in pathological stage IIB disease. RESULTS: Parametrial invasion was identified on the surgical specimen in 400 cases (56.0%, 95% confidence interval 52.4-59.7). On multivariate analysis, deep stromal invasion (DSI, adjusted-OR 3.922), multiple pelvic nodal metastases (adjusted-OR 3.266), lympho-vascular space invasion (adjusted-OR 2.333), and uterine corpus invasion (adjusted-OR 1.656) remained independent tumor factors for pathological parametrial invasion. In classification-tree models, tumors with DSI and multiple pelvic nodal metastases had the highest incidence of pathological parametrial invasion (75.0-87.7%); contrary, tumors without DSI had the lowest incidence (21.9%). Among patients with pathological stage IIB disease, the absolute difference in 5-year disease-free survival rates was 57.2%, ranging between 80.9% in those with squamous histology with none/single pelvic nodal metastasis and 23.7% in those with non-squamous histology with multiple pelvic nodal metastases. CONCLUSION: In clinical stage IIB cervical cancer, accuracy for pathological parametrial invasion is low-modest. With absence of DSI, only one in five clinical stage IIB diseases has pathological stage IIB disease. Survival of pathological stage IIB varies widely and is largely dependent on nodal factors.

OBJECTIVE: To establish new criteria for the omission of lymphadenectomy in patients with endometrioid carcinoma. METHODS: We retrospectively reviewed 185 cases of histologically confirmed endometrioid carcinoma by hysterectomy at Jichi Medical University Hospital between January 2006 and December 2011. We reviewed patient medical records to detect risk factors for lymph node metastasis to identify the optimum criteria for lymphadenectomy omission. RESULTS: Univariate analysis revealed risk factors for lymph node metastasis to be a large tumor size (volume index ≥40 cm³) (p<0.0001), tumor diameter >2 cm (p=0.0003), myometrial invasion ≥50% based on pre-operative MRI (p=0.0366), elevated serum CA125 (pre-menopausal value ≥70 U/mL, post-menopausal value ≥25 U/mL) (p=0.0004), and lymphadenopathy on pre-operative CT scans (p=0.0002). Multivariate analysis indicated that tumor volume index, tumor diameter, elevated serum CA125, and CT scans positive for lymphadenopathy were independent risk factors for lymph node metastasis. Thus, we set tumor diameter >2 cm, elevated serum CA125, and CT scans positive for lymphadenopathy as risk factors. In cases with no risk factors, the rate of lymph node metastasis was 2.1%, which rose to 8.9%, 30.4%, and 58.3% for those with one, two, and three risk factors, respectively. The rate of para-aortic lymph node metastasis rose from 0% to 2.5%, 10.9%, and 41.7% among those with zero, one, two, and three risk factors, respectively. CONCLUSIONS: We propose that lymphadenectomy can be omitted in cases of endometrioid carcinoma that do not have any of the following risk factors: tumor diameter >2 cm, elevated serum CA125, and a CT scan positive for lymphadenopathy. We believe that these new criteria will limit inter-institutional differences as they are all objective factors. Further, they are useful in predicting lymph node metastasis, including para-aortic lymph node metastasis, based on the number of risk factors present.

Hysteroscopic transcervical resection (TCR) is often performed as fertility sparing treatment for atypical polypoid adenomyoma (APA) patients. However, TCR has the risk of uterine wall perforation, especially when the tumor extends deeply into the uterine muscle layer. We report an APA patient in whom it was impossible to completely resect the tumor by TCR, but laparotomy tumor resection followed by levonorgestrel-releasing intrauterine system (LNG-IUS) was successful. The patient was a 35-year-old nulligravida woman. We performed laparotomy tumor resection and inserted the LNG-IUS into uterine cavity just after surgery. Microscopic residual tumor was suspected based on histopathological findings. However, the patient has not relapsed for 26 months, even though the LNG-IUS was removed after 6 months. Laparotomy tumor resection may be one fertility sparing treatment option for APA patients. Furthermore, it may be effective to use the LNG-IUS after surgery for two purposes that are adhesion prevention and tumor disappearance.

BACKGROUND: Although there have been several reports regarding the significance of staging lymphadenectomy for early stage ovarian clear cell carcinoma (CCC) patients, there have been few reports focusing on the number of removed lymph nodes. The aim of this study was to evaluate the impact of the number of removed lymph nodes on recurrence-free survival (RFS) in stage I ovarian CCC. METHODS: The subjects were patients with ovarian CCC who underwent surgery between January 1988 and December 2013. Clinicopathological variables were obtained from the medical records retrospectively. Statistical analysis using Kaplan-Meier method, log-rank test, and Cox proportional hazards model was performed. RESULTS: A total of 68 patients were entered into this study. The median number of removed lymph nodes was 56.5 (21-135). We calculated that the cutoff value of the number of removed lymph nodes for predicting recurrence was 35. RFS of the group with ≥ 35 removed lymph nodes was significantly better than that of the group with < 35 removed lymph nodes (p = 0.001). Similarly, RFS of stage IA and PS 0 or 1 was significantly better than that of stage IC (p = 0.029) and PS 2 or 3 (p = 0.001), respectively. Multivariate analysis revealed that the number of removed lymph nodes, stage, and PS was independent predictors for RFS. CONCLUSIONS: This study showed that the number of removed lymph nodes ≥ 35 was an independent predictor for improved RFS for stage I ovarian CCC. Sufficient lymphadenectomy may improve prognosis for stage I ovarian CCC.

OBJECTIVE: This multicenter phase II Japanese Gynecologic Oncology Group study (JGOG1067) was designed to evaluate the efficacy and safety of postoperative chemotherapy in patients with node-positive cervical cancer. METHODS: Patients with stage IB-IIA squamous cervical cancer who underwent radical hysterectomy and were confirmed to have pelvic lymph node metastasis were eligible for this study. The patients postoperatively received irinotecan (CPT-11; 60mg/m2 intravenously on days 1 and 8) and nedaplatin (NDP; 80mg/m2 intravenously on day 1). Chemotherapy administration commenced within 6weeks after surgery and was repeated every 28days for up to 5cycles. The primary endpoint of this study was the 2-year recurrence-free survival (RFS) rate. The secondary endpoints were the 5-year overall survival (OS) rate, 5-year RFS rate, and adverse events such as complications of chemotherapy and lower-limb edema. RESULTS: Sixty-two patients were analyzed according to our protocol, among whom 55 (88.7%) completed 5cycles of scheduled treatment. The median follow-up period was 66.1months (range, 16.8-96.6months). The 2-year and 5-year RFS rates were 87.1% (95% confidence interval [CI]: 75.9-99.3) and 77.2% (95% CI: 64.5-85.8), respectively. Fourteen patients (22.5%) experienced recurrence during the follow-up period, 8 of whom died of the disease. The 5-year OS rate in this study was 86.5% (95% CI: 74.8-93.0). Only 9.7% of the patients experienced lymphedema in their legs. CONCLUSION: Postoperative chemotherapy without radiotherapy was found to be very effective in high-risk patients with node-positive cervical cancer.

The purpose of this phase II trial was to assess the efficacy and toxicity of paclitaxel and nedaplatin (TN) as the initial postoperative adjuvant chemotherapy for uterine cervical cancer with lymph node metastases (LNM). Patients with FIGO stage IB1-IIA2 squamous cell carcinoma of the uterine cervix were enrolled. Histological confirmation of LNM was mandatory. Intravenous paclitaxel at 175 mg/m2 and nedaplatin at 80 mg/m2 were administered every 28-day cycle, of which there were 5 cycles after radical hysterectomy. Sixty-two patients were enrolled in the study from November 2011 to July 2015. Their median age was 48.5 years (range 28-64). The median tumor diameter was 37 mm (5-64). Overall, 30 patients (48.4%) had 1 metastatic lymph node, 11 (17.7%) had 2, 3 (4.8%) had 3, 5 (8.1%) had 4, and 13 (21.0%) had 5 or more. With a median follow-up of 45.7 months (range 23.4-69.5), the 2-year relapse-free survival and 2-year overall survival rates were 79.0% (90% CI, 69.0%-86.2%) and 93.5% (95% CI, 83.7%-97.5%), respectively. Almost all adverse events were relatively mild. Grade 3-4 adverse events (NCI-CTC ver. 4.0) that occurred in 5% or more of patients were neutropenia (60.7%) and infection (6.6%). The proportion of patients who completed 5 cycles of treatment was 90.3%. Postoperative adjuvant chemotherapy with TN for cervical cancer with LNM was demonstrated to be an effective and feasible treatment. A phase III trial is warranted to compare this with concurrent chemoradiotherapy.

AIM: Gemcitabine is used not only as a second-line, but also as a third-line or higher regimen for taxane/platinum-resistant recurrent ovarian cancer. The purpose of this study was to clarify the response to and toxicity of gemcitabine for recurrent ovarian cancer according to the number of previous chemotherapy regimens. METHODS: The subjects were patients with taxane/platinum-resistant recurrent ovarian cancer on gemcitabine treatment at the present hospital between June 2007 and September 2013. We retrospectively reviewed the medical records. Response and adverse events were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. and the Common Terminology Criteria for Adverse Events v4.0, respectively. RESULTS: The subjects consisted of 65 patients. The median number of previous chemotherapy regimens was 3 (range, 1-7). Overall response rate was 4.6%, and disease control rate (DCR) was 40.0%. DCR versus one, two, three, and ≥four previous chemotherapy regimens was 83.3%, 45.0%, 36.4%, and 23.5%, respectively. Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 52.3%, 9.2%, and 9.2% of patients, respectively. Prevalence of grade 3/4 neutropenia according to one, two, three, and ≥four previous chemotherapy regimens was 66.7%, 55.0%, 54.5%, and 41.2%, respectively. Prevalence of anemia, thrombocytopenia, and almost all the non-hematological toxicities also did not increase with an increase in the number of previous chemotherapy regimens. CONCLUSIONS: Although DCR decreased as the number of previous chemotherapy regimens increased, the toxicities did not increase. Gemcitabine may be relatively safe in heavily pretreated ovarian cancer patients.

AIM: During routine follow-up for postoperative endometrial cancer, we have encountered patients with and without symptoms at recurrence. In this study, we investigated whether or not there is a difference in the prognosis between patients with and without symptoms at recurrence. METHODS: We reviewed endometrial cancer patients who had been treated in our hospital between 1998 and 2007. Routine follow-up was conducted by our facility criteria. We investigated recurrence-free survival (RFS), presence or absence of symptoms at recurrence, overall survival from recurrence (OSFR), and overall survival (OS). RESULTS: The subjects were 293 patients. Recurrence was detected in 46 patients. The median RFS was 15 (1-103) months. At the time of recurrence, symptoms were present in 14 patients and absent in 32 patients. In groups with and without symptoms at recurrence, the median OSFR were 36 (2-100) and 45 (2-139) months, respectively. The median OS were 55 (6-163) and 100 (11-178) months, respectively. There were no significant differences in either parameter. Independent prognostic factors for OSFR and OS were histopathologic types other than endometrioid carcinoma (vs endometrioid carcinoma, hazard ratio = 3.102 and 3.008, respectively) and RFS of 14 months or shorter (vs 15 months or longer, hazard ratio = 2.378 and 3.739, respectively). CONCLUSION: There was no difference in the prognosis between the groups with and without symptoms at recurrence. Independent prognostic factors of recurrent patients were histopathologic types and RFS. A large-scale study should be conducted to examine the necessity of routine follow-up for detecting recurrence in the absence of symptoms.

Hyponatremia is often caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Hypersecretion of vasopressin frommalignant tumors can be considered a cause of SIADH. Most of these ectopic productions of vasopressin are complications of small cell lung cancer. Cases concomitant with ovarian tumors are very rare, and a specific causative substance from the ovary is often unknown. A 16-year-old woman was diagnosed with an ovarian tumor. She developed hyponatremia that was resistant to medical treatment, but immediately improved after surgical resection of the tumor. Her diagnosis was SIADH caused by an ovarian tumor; however, her serum vasopressin level was normal. It is possible that a vasopressin-like substance causing SIADH was secreted by either nervous system tissue within an immature teratoma or small cell lung cancer. We should be cautious when SIADH is a complication of an ovarian tumor.

Ovarian non-gestational choriocarcinomas co-existing with adenocarcinoma are extremely rare and have been reported as epithelial ovarian carcinomas of a "non-germ cell origin" with "choriocarcinomatous differentiation". Although the cellular origin of non-gestational choriocarcinoma may be post-meiotic ovarian germ cells or the dedifferentiation of epithelial ovarian carcinoma, detailed genetic evidence has not yet been obtained to support this. We herein present a case of ovarian non-gestational choriocarcinoma co-existing with adenocarcinoma in a 29-year-old woman. The tumor rapidly increased in size and lung metastases appeared soon after parturition. We genetically demonstrated that the cellular origin of ovarian non-gestational choriocarcinoma was a post-meiotic germ cell derivation using a short tandem repeat analysis. The co-existing adenocarcinoma component was also shown to be of the same germ cell origin. These tumors showed the same homozygous pattern. A molecular genetic approach may be important for understanding the clinicopathological features of such tumors.

BACKGROUND: There are no definitive criteria for identifying which patients with The International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical cancer will benefit from adjuvant therapy after radical hysterectomy. The aims of this study were to clarify the efficacy of adjuvant therapy and assess complications after radical hysterectomy in patients with FIGO stage IB1 cervical cancer with intermediate risk factors. METHODS: Between January 2005 and December 2009, the medical records of 75 stage IB1 patients' intermediate risk factors (i.e., tumor size 2-4 cm, lymphovascular involvement, and/or deep stromal invasion >1/2) who underwent radical hysterectomy at six institutions were collected, and these patients were enrolled in this nonrandomized retrospective study. We simplified the criteria of intermediate risk factors as much as possible, as the criteria adopted in some clinical studies are complicated in practice. RESULTS: The patients were grouped according to the receipt of adjuvant therapy as follows: 46 patients, no further treatment; 19 patients, external beam radiation treatment, including 9 patients who received brachytherapy; 5 patients, concurrent chemoradiotherapy (CCRT); and 5 patients, chemotherapy (CT). The clinical outcomes and complications in each group were analyzed. After an average follow-up of 82.6 months (range, 24-135 months), only one patient with all three risk factors who received radiotherapy (RT) experienced recurrence. Excluding this patient, the remaining patients who received RT, CCRT, or CT had two or three risk factors. Lymphedema was significantly more common among patients who received RT or CCRT, whereas the incidence of ileus and ureteral obstruction was not different among the treatment groups. However, an unsutured peritoneum increased the risk of ileus. CONCLUSIONS: The findings of this study suggest that RT and CCRT after radical hysterectomy are not beneficial in patients with intermediate risk factors. In particular, RT and CCRT appeared to increase the incidence of lymphedema. A prospective randomized study is needed to verify the findings of this study.