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Abstract Background Although immune cell therapy has long been used for treating solid cancer, its efficacy remains limited. Interferon (IFN)-producing killer dendritic cells (IKDCs) exhibit cytotoxicity and present antigens to relevant cells; thus, they can selectively induce tumor-associated antigen (TAA)-specific CD8 T cells and may be useful in cancer treatment. Various protocols have been used to amplify human IKDCs from peripheral sources, but the complexity of the process has prevented their widespread clinical application. Additionally, the induction of TAA-specific CD8 T cells through the adoptive transfer of IKDCs to immunocompromised patients with cancer may be insufficient. Therefore, we developed a method for generating an immune cell-based regimen, Phyduxon-T, comprising a human IKDC counterpart (Phyduxon) and expanded TAA-specific CD8 T cells. Methods Peripheral blood mononuclear cells from ovarian cancer patients were cultured with human interleukin (hIL)-15, hIL-12, and hIL-18 to generate Phyduxon-T. Then, its phenotype, cytotoxicity, and antigen-presenting function were evaluated through flow cytometry using specific monoclonal antibodies. Results Phyduxon exhibited the characteristics of both natural killer and dendritic cells. This regimen also exhibited cytotoxicity against primary ovarian cancer cells and presented TAAs, thereby inducing TAA-specific CD8 T cells, as evidenced by the expression of 4-1BB and IFN-γ. Notably, the Phyduxon-T manufacturing protocol effectively expanded IFN-γ-producing 4-1BB+ TAA-specific CD8 T cells from peripheral sources; these cells exhibited cytotoxic activities against ovarian cancer cells. Conclusions Phyduxon-T, which is a combination of natural killer cells, dendritic cells, and TAA-specific CD8 T cells, may enhance the efficacy of cancer immunotherapy.

Background/Purpose: Efforts were made to explore the influence of diagnostic timing for cancer-associated thromboembolic events on survival of ovarian cancer patients. Methods: We reviewed the medical records of 75 ovarian cancer patients with thromboembolism and evaluated the prognostic factors affecting disease-free survival and overall survival. Results: These 75 patients were classified into two categories by the diagnostic timing of the thromboembolism, during (33 cases) and after (42 cases) initial diagnosis of ovarian cancer groups. The diagnostic timing of thromboembolism was not related to disease-free survival or overall survival of the studied population. Advanced disease stage, clear cell histology, interval debulking surgery, no recurrence/persistence of ovarian cancer, and patients treated with anticoagulant(s) treatment >3 months were associated with the disease-free survival. Advanced disease stage, clear cell histology, body mass index (BMI) ≥24 kg/m2 at the diagnosis of ovarian cancer, and no recurrence/persistence of ovarian cancer influenced the overall survival. In the subgroup analysis, compared to the after initial ovarian cancer diagnosis group, patients with stage I/II disease, BMI

Abstract Background Fertility‐sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early‐stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. Methods A total of 1297 patients aged between 20 and 44 years with newly diagnosed early‐stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site‐specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer‐specific survival (CSS) was evaluated using Kaplan–Meier method with log‐rank test and Cox regression model. Results There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high‐grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66–1.77, p = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06–0.82, p = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. Conclusion FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.

Since government-provided annual cervical cytology testing for all Taiwanese women aged 30 years or older became available in 1995, both cervical cancer incidence and death have decreased significantly. However, with the 2018 introduction of the national immunization program for human papillomavirus (HPV) vaccination in all schoolgirls aged 13–15 years old, the positive predictive value of cytology testing is expected to decrease with rising vaccination rates, and therefore a transition to more sensitive HPV-based testing may be needed. This position paper, derived from discussions by a panel of experts in cervical cancer screening, provides short-, medium-, and long-term policy recommendations to manage the transition between cervical screening methods for Taiwan. The recommendations include concrete suggestions regarding testing procedures, standards, accreditation, monitoring, promotion, and implementation. It is hoped that comprehensive preparation and management of this transition will enable Taiwan to repeat the previous successes of the cervical cytology testing program.

Abstract Background We investigated risk factors influencing the outcome of unexpected ovarian carcinomas. Methods We reviewed the ovarian carcinoma patients treated at atertiary medical institution between 2000 and 2017 and analyze the clinico‐pathological characteristics, treatment strategies, recurrence status, and outcome. Results A total of 112 women (65 primary laparoscopic surgery [LSC] and 47 laparotomic surgery [LAPA]) were included in the analysis. The LSC group had smaller ovarian tumors (10.5 ± 7.3 cm vs. 16.6 ± 8.7 cm, p = 0.031) and higher incidence of subsequent staging surgery (56.9% vs. 25.5%, p = 0.0001) compared to the LAPA group. There were 98/112 (86.6%) of early stages (I/II) diseases. The difference between the recurrent rate (27.7% vs. 31.9%), disease‐free survival (DFS), and overall survival (OS) were not significant among surgical groups. In the multivariate analysis, FIGO stage (stage II hazard ratio [HR] 6.61, p = 0.007; stage III HR 8.40, p = 0.002) was the only prognostic factor for DFS. FIGO stage (stage II HR 20.78, p = 0.0001; stage III HR 7.99, p = 0.017), histological type (mucinous HR 12.49, p = 0.036), and tumor grade (grade 3 HR 35.01, p = 0.003) were independent prognostic factors for OS, while women with latency >28 days from primary to staging surgery had significantly poorer OS (p = 0.008). Women with latency >28 days between primary surgery and adjuvant chemotherapy had similar DFS (p = 0.31) and a trend of poorer OS (p = 0.064). Conclusions The prognosis of unexpected ovarian cancer is independent from the primary surgical procedure and comprehensive staging surgery should be performed at close proximity after the diagnosis of unexpected ovarian malignancy.

Abstract To evaluate the uterine corpus cancer incidence rates, age-specific trends, and birth cohort patterns by different histologic types. We conducted a retrospective cohort study of uterine cancer patients (n = 28,769) of all ages from the National Cancer Registry of Taiwan between 1998 and 2017. We estimated the incidence trends, average annual percent changes (AAPCs), and cancer-specific survival (CSS) rate for the two main subtypes (endometrioid and nonendometrioid) of uterine cancer in Taiwan. During the study period, uterine corpus cancer incidence rates increased over time from 5.3 to 15.21 per 100,000 women. Incidence trends for endometrioid carcinoma increased in all age groups (positive AAPCs > 5% for each age group), and the rise was steeper among women aged 50 years and younger. For nonendometrioid carcinomas, incidence rates increased among women over 50 years. The CSS rate improved among women with stage I (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49–0.81) and stage III (HR 0.72, 95% CI 0.58–0.90) endometrioid carcinomas after 2013 compared with those during 2009–2012. However, the CSS rate remained unchanged for nonendometrioid carcinomas. Age, diagnostic period, stage and histologic types were significant factors associated with the 5-year CSS rate. We found that the incidences of both endometrioid and nonendometrioid carcinomas continued to increase among contemporary birth cohorts. Etiologic research is needed to explain the causes of these trends.

Background Expression of immune checkpoints in the tumor microenvironment is one mechanism underlying paclitaxel (PTX) chemoresistance. This study aimed to investigate whether the addition of checkpoint blockade to PTX can improve the therapeutic efficacy against apparently disseminated intraperitoneal tumors.Methods We analyzed the in vivo expression of various immune checkpoints in CD3+CD8+ cytotoxic T cells from tumor-bearing mice treated with or without PTX and validated the tumor-killing activities of selected checkpoint-expressing T-cell subpopulations ex vivo. The regulation of selected checkpoints was investigated in vitro. The therapeutic effects of inhibition of a targeted checkpoint pathway with antibodies added to PTX therapy were examined.Results CD3+CD8+ T cells expressed with herpes virus entry mediator (HVEM), programmed cell death 1 (PD-1), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) in tumor-bearing hosts treated with PTX had effective tumoricidal activities. In addition to PTX and cytokines, B and T lymphocyte attenuator (BTLA) or homologous to lymphotoxin, exhibits inducible expression and competes with herpes simplex virus (HSV) glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes (LIGHT) interacting with HVEM can regulate the expression of PD-1 on CD3+CD8+ T cells. Interleukin (IL)-15 increased the percentage of HVEMhighgranzyme B (GZMB)+ cells among CD3+CD8+ T cells, which was suppressed by the BTLA/HVEM signal. LIGHT induced the percentage of HVEM+GZMB+ cells but not HVEMhighGZMB+ cells among CD3+CD8+ T cells. Expression of IL-15, BTLA, or LIGHT was detected in CD19+ B cells and regulated by damage-associated molecular patterns/Toll-like receptor interactions. In the tumor-bearing hosts treated with PTX, certain proportions of BTLA+ B or PD-1+ T lymphocytes were still noted. When dual inhibition of BTLA and PD-1 was added to PTX, the antitumor effects on intraperitoneally disseminated tumors can be significantly improved.Conclusions Dual blockade of BTLA on B cells and PD-1 on cytotoxic T cells may have clinical potential for enhancing the efficacy of PTX in the treatment of tumors with intraperitoneal spread, including epithelial ovarian carcinomas.

Abstract Background Ovarian cancer (OC) is the most lethal gynecological cancer due to the recurrence of drug-resistance. Cancer initiating cells (CICs) are proposed to be responsible for the aggressiveness of OC. The rarity and difficulty of in vitro long-term cultivation of CICs challenge the development of CIC-targeting therapeutics. Reprogramming cancer cells into induced cancer initiating cell (iCICs) could be an approach to solve these. Several inducible CICs have been acquired by activating the expression of stemness genes in different cancer cells. However, few reports have demonstrated the feasibility in OC. Methods Patients with primary OC receiving surgery were enrolled. Tumor tissue were collected, and OCT4, SOX2, and NANOG expressions were assessed by immunohistochemistry (IHC) staining to investigate the association of stemness markers with overall survival (OS). An high-grade serous ovarian cancer (HGSOC) cell line, OVCAR-3 was reprogrammed by transducing Yamanaka four factors OCT4, SOX2, KLF4 and MYC (OSKM) to establish an iOCIC model, iOVCAR-3-OSKM. CIC characteristics of iOVCAR-3-OSKM were evaluated by RT-PCR, sphere formation assay and animal experiments. Drug-resistance and migration ability were accessed by dye-efflux activity assay, MTT assay and migration assay. Gene profile was presented through RNA-sequencing. Lineage differentiation ability and organoid culture were determined by in vitro differentiation assays. Results In OC patients, the co-expression of multiple stem-related transcription factors (OCT4, SOX2, and NANOG) was associated with worse OS. iOVCAR-3-OSKM cells generated by reprogramming successfully exhibited stemness characteristics with strong sphere-forming and tumorigenesis ability. iOVCAR-3-OSKM cells also showed malignant potential with higher drug resistance to chemodrug, Paclitaxel (PTX) and migration ability. iOVCAR-3-OSKM was maintainable and expandable on feeder-dependent culture condition, it also preserved ovarian lineage differentiation abilities, which could well differentiate into OC cells with CK-7 and CA125 expressions and develop into an organoid mimic poor prognostic OC histological feature. Conclusions The establishment of iOVCAR-3-OSKM not only allows us to fill the gap in the information on induced CICs in OC but also provides a potential strategy to develop personalized CICs and organoid models for treating OC in the near future.

ABSTRACT Background We investigated the agreement and accuracy of preoperative magnetic resonance imaging (MRI) with postoperative pathological characteristics and stages of endometrial endometrioid carcinoma (EEC). Methods We recruited 527 women with EEC who underwent staging surgery at a single medical institution. The preoperative MRI, stages, and clinical and pathological parameters, including myometrial invasion (MI), cervical invasion (CI), adnexal metastasis (AM), intra‐abdominal metastasis, and pelvic and/or para‐aortic nodal metastasis, were recorded and analyzed. The agreement and accuracy between the preoperative MRI findings and these parameters and stages were assessed. Results The rate of the preoperative MRI‐based clinical stage matching the postoperative surgical stage was 85.2% in International Federation of Gynecology and Obstetrics stage IA, 51.9% in stage IB, 35.5% in stage II, 5.3% in stage IIIA, 33.3% in stage IIIB, 28.6% in stage IIIC1, 64.3% in stage IIIC2, and 93.8% in stage IVB. The consistency between radiologists and pathologists was 80.5% for deep MI, 91.5% for cervical invasion, 92.2% for adnexal metastasis, 98.9% for intra‐abdominal metastasis, and 87.5% and 92.2% for pelvic and para‐aortic nodal metastases, respectively. The negative predictive value of intra‐abdominal metastasis was the highest with 99.8%. Conclusions Preoperative MRI could be an excellent tool for routine preoperative assessment to predict pathological parameters and stages of EEC, especially in excluding intra‐abdominal metastatic disease.

Abstract Background Women with endometrial cancer (EC) have favorable prognoses, leaving them vulnerable to the development of second primary cancers (SPCs). We investigated the SPC risk and survival outcomes among EC patients treated with surgery alone in order to exclude the impact of adjuvant treatment on the results. Methods Data from the Taiwan Cancer Registry from 1995 to 2013 were analyzed. Standardized incidence ratios (SIRs) of SPCs among EC survivors were calculated. Results Among 7725 women enrolled, 478 developed an SPC. The overall SIR for SPCs in EC survivors was 2.84 (95% confidence interval [CI] 2.59–3.10) compared with the general female population. Women diagnosed with EC at age

Objective: To report two cases of for primary peritoneal serous carcinoma (PPSC) to present with gastrointestinal manifestations that mimic colorectal cancer. Case report: There were two patients with initial presentations of fatigue with iron deficiency anemia, and tenesmus with bloody stool. Tumors of the ascending colon and rectum were detected by colonofiberoscope, and pathologic reports of tumor biopsies revealed adenocarcinoma of suspected gynecologic origin. Both patients underwent optimal debulking surgery without macroscopic residual tumor, and then received adjuvant carboplatin and paclitaxel chemotherapy with bevacizumab. Conclusions: PPSC can clinically present like primary colorectal carcinoma. The differential diagnosis requires special staining of several markers for tumor tissues.

Abstract Background The optimal adjuvant treatment for stage III endometrial cancer in the era of modern radiotherapy remains undefined. We investigated the benefit of adjuvant radiotherapy for women who underwent optimal resection for stage III endometrial cancer in the era of modern radiotherapy. Methods We retrospectively reviewed patients with endometrial cancer who were treated between 2010 and 2018. Adjuvant treatment included radiotherapy by modern radiotherapy techniques (intensity-modulated or volumetric modulated arc radiotherapy), chemotherapy, or both. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed via multivariate Cox proportional hazards models. Results One hundred sixty-one patients were initially included (52, 9, and 100 with stages IIIA, IIIB, and IIIC cancer, respectively); 154 patients (96%) received adjuvant therapy. Such adjuvant treatment was associated with improved RFS (p = 0.014) and OS (p = 0.044) over surgery alone. Adjuvant radiotherapy by modern radiotherapy techniques led to low incidence of acute (25%) and chronic (7%) grade ≥ 2 gastrointestinal toxicity. On univariate analysis, non-endometrioid histology and grade 3 status were associated with higher risks of tumor recurrence and death, whereas adjuvant radiotherapy alone or in combination chemotherapy reduced their risks. On multivariate analysis, non-endometrioid histology was associated with increased recurrence (hazard ratio [HR], 2.95; p = 0.009), whereas adjuvant radiotherapy alone or with chemotherapy was associated with lower recurrence (HR, 0.62; p = 0.042). Patients > 60 years of age (p = 0.038) as well as those with endometrioid histology (p = 0.045), lymphovascular space invasion (p = 0.031), and ≥ 2 positive lymph nodes (p = 0.044) benefited most from adjuvant radiotherapy. Conclusions Modern adjuvant radiotherapy (intensity-modulated or volumetric modulated arc radiotherapy) alone or with chemotherapy should be considered for women with optimally resected stage III endometrial cancer. Trial registration ClinicalTrials.gov, NCT04251676 . Registered 24 January 2020. Retrospectively registered.

Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of BRCA mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p=0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p=0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p=0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p

AimTo retrospectively investigate the pre-operative clinical factors and ultrasonographic features that influence the accuracy of the intraoperative frozen section (IFS) of ovarian tumors.Patients and methodsWomen with ovarian tumors that underwent IFS in one tertiary medical center were recruited from January 2010 to December 2018. Demographic and clinical data of these women were retrieved from medical records in the hospital’s centralized database.ResultsA total of 903 ovarian tumors were enrolled, including 237 (26.2%) benign, 150 (16.6%) borderline tumor, and 516 (57.2%) malignant. The overall accuracy of IFS among all specimens was 89.9%. The sensitivities of IFS in diagnosing borderline tumors (82.0%) and malignant tumors (88.2%) were lower than in diagnosing benign tumors (98.7%, p

Abstract Background The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/paclitaxel-based chemotherapy, but the overall survival rate is poor. The purpose of this study was to investigate the therapeutic potential of chemotherapy combined with inhibition of B and T lymphocyte attenuator (BTLA) for clinical use to treat EOC. Methods Initially, we evaluated the potential application of chemotherapy combined with anti-BTLA antibody in an animal model. We then analyzed the distribution and regulation of BTLA expression on immunocytes in vitro. Finally, we examined the correlation between BTLA expression levels in cancerous tissues and prognosis in 254 EOC cases. Results The combination of chemotherapy and anti-BTLA antibody for inhibiting BTLA significantly reduced peritoneal tumor volume and extended survival in tumor-bearing mice. In addition, BTLA could be identified mostly on B lymphocytes, especially on CD19hi B cells, rather than on T lymphocytes and natural killer cells. Under regulation of interleukins 6 and 10, more BTLA+CD19hi B lymphocytes could be induced through AKT and STAT3 signaling pathways. Detectable BTLA expression in ovarian cancerous tissues was associated with worse disease-free and overall survivals of EOC patients. Conclusions BTLA detected in cancerous tissues can predict poor outcome of EOC patients. Inhibition of BTLA combined with chemotherapy can elevate immune activation and generate potent anti-tumor effects. Thus, the combination of chemotherapy and anti-BTLA antibody may hold potential clinical application for the treatment of EOC patients. Trial registration The Trial Registration Number was NCT00854399.

Objective: To evaluate the clinical presentations, diagnosis, management, and outcomes of torsion of the pedunculated subserous uterine leiomyoma. Materials and methods: We retrospectively reviewed medical records of patients with subserous uterine leiomyomas undergoing surgeries at National Taiwan University Hospital from January 2001 to December 2015. Results: Five cases of torsion of pedunculated subserous uterine leiomyoma were identified. All presented with sudden onset abdominal pain. Two patients received emergent surgeries, the other three cases received scheduled surgeries. The postoperative courses of these five women were uneventful without sequelae. Conclusions: Torsion of pedunculated subserous uterine leiomyoma is rare. Accurately diagnosing it prior to surgery is a major challenge. It should be one of the differential diagnosis in patients with uterine leiomyoma presenting with acute abdomen. Keywords: Abdominal pain, Emergency, Myomectomy, Subserous leiomyoma, Torsion

Objective: To report a case and review published cases of large cell neuroendocrine carcinoma (LCNEC) of the endometrium. Case report: A 51-year-old female presented with postmenopausal bleeding and a palpable pelvic mass. An endometrial biopsy showed a malignant mixed Mullerian tumor (MMMT). Suboptimal debulking surgery was performed. The final pathology revealed stage IVB endometrial LCNEC. Post-operative adjuvant chemotherapy with cisplatin and etoposide was administered. Two months after discontinuing adjuvant chemotherapy, salvage chemotherapy with cisplatin and ifosfamide was administered due to tumor progression; however, obstructive ileus was noted 2 months later. A segmental small bowel resection and palliative colostomy were performed. She died secondary to a post-operative infection 8 days after the operation. Conclusion: Endometrial LCNEC is a rare but aggressive disease. If diagnosed, combined therapies, including staging surgery, following by adjuvant radiotherapy and chemotherapy, should be performed.

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.

Objective: To evaluate the influence of age, screening interval, and histologic type on the effect of Pap smears in cervical cancer screening. Materials and methods: Data were retrieved from the Taiwan National Cancer Registry and Cervical Cancer Screening Registration System for the period from 2002 to 2010. Age, Pap smear interval, FIGO stage, and histology were further analyzed. Results: A total of 12,294 women with cervical cancer were enrolled, including 10,040 with squamous cell carcinoma (SCC), 1720 with adenocarcinoma (ADC), 401 with adenosquamous carcinoma (ASC), and 133 with small cell neuroendocrine carcinoma (SMC). Women who had a Pap smear at an interval of

In this retrospective study, we investigated adverse events and outcomes in patients treated with bevacizumab for ovarian, fallopian tube, or primary peritoneal cancers at a single hospital. We determined the cumulative incidences of various bevacizumab-related adverse events and the correlation between dose and adverse event incidences. We analyzed data from 154 patients that received 251 rounds of bevacizumab as first-line, first salvage, >2 salvage treatments. Adverse events of any grade were observed in 121 (78.6%) patients; at least one grade 3 or 4 adverse event occurred in 32 (20.8%) patients. The two most common events were proteinuria (38.3%) and hypertension (33.8%). The first-line treatment group displayed significantly higher frequencies of hypertension (52.7% vs. 18.9% vs. 15.5%, p < 0.001), wound complications (9.1% vs. 0% vs. 1.2%, p = 0.010), arthralgia (29.1% vs. 11.3% vs. 8.3%, p = 0.003), and reduced range of joint motion (14.5% vs. 5.7% vs. 3.6%, p = 0.046), compared to those in the first and >2 lines salvage groups, respectively (Kruskal–Wallis test). The cumulative incidences of all grades and grades 3/4 of hypertension cumulative incidence plateaued at around 30% for all grades and 10% for grades 3 and 4, at bevacizumab doses above 8080 and 3510 mg, respectively. The proteinuria cumulative incidence plateaued at around 35% for all grades and 3% for grades 3 and 4, at bevacizumab doses above 11,190 and 4530 mg, respectively. We concluded that, in this realistic clinical population, different kinds and higher cumulative incidences of adverse events were observed compared to those reported in previous clinical trials. Moreover, bevacizumab doses showed cumulative toxicity and plateau effects on hypertension and proteinuria.

We aimed to identify factors predicting parametrial invasion in early-stage cervical cancer patients undergoing radical hysterectomy. We recruited women with invasive cervical cancer who underwent radical hysterectomy at a single medical institute from 2000-2011. The clinical and pathological characteristics and outcomes were retrospectively recorded, and the risk factors for parametrial invasion were analyzed. We enrolled 339 patients, including 7 with stage IA1 carcinomas, 10 with stage IA2, 266 with stage IB1, 39 with stage IB2, 14 with stage IIA1, and 3 with stage IIA2. The majority (237/339, 69.9%) had squamous cell carcinoma, while 32 (12.4%) had parametrial invasion. The 16 patients with stage IB1 tumors and parametrial invasion were older (55.9±9.5vs. 49.0±9.9 years, p = 0.005, Mann-Whitney U test), and had deeper cervical stromal invasion (9.59±4.87 vs. 7.47±5.48 mm, p = 0.048, Mann-Whitney U test), larger tumor size (2.32±1.15 vs. 1.74±1.14cm, p = 0.043, Mann-Whitney U test), higher incidences of lymphovascular space invasion (87.5% vs. 28.8%, p2 cm,10% had parametrial invasion and 24.2% had lymph node metastasis compared with only 4% and 9.4% of stage IB1 patients with a tumor size

The overall survival (OS) of patients with ovarian cancer is poor while epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The aim of the present study was to evaluate the clinico-pathologic characteristics, especially the prognostic factors, for patients with epithelial ovarian cancer (EOC) in Taiwan. Information about newly diagnosed patients with EOC from 2009 to 2012 was retrieved from the database of the Taiwan Cancer Registry. Data from 2009 to 2013 for the respective cases from the claims database of Taiwan's National Health Insurance and National Death Registry were then retrieved. Potential prognostic factors were analyzed. The mean age at diagnosis of the 2,498 patients was 52.8 years. Serous carcinoma and clear cell carcinoma were diagnosed in 43.3% and 22.8% of the total patients, respectively. For patients with early-stage disease, taxane-based adjuvant chemotherapy, stage I, and younger age at diagnosis led to better overall survival (p = 0.030, p = 0.002, p

We evaluated the prevalence of and risk factors for hypersensitivity reactions related to carboplatin, which is commonly used to treat gynecological malignancies. All women with pathologically documented ovarian, fallopian tube, or primary peritoneal cancer treated with carboplatin alone or a carboplatin-based combination chemotherapy regimen at a single hospital between January 2006 and December 2013 were retrospectively recruited. We analyzed the incidence, characteristics, risk factors, management, and outcomes of carboplatin-related hypersensitivity reactions among these patients. Among 735 eligible women, 75 (10.2%) experienced a total of 215 carboplatin-related hypersensitivity reaction events. The annual incidence of carboplatin-related hypersensitivity reactions gradually increased from 0.88% in 2006 to 5.42% in 2013. The incidence of carboplatin-related hypersensitivity was higher in patients with advanced stage disease (P < 0.001, Kruskal-Wallis test), serous and mixed histological types (P = 0.003, Kruskal-Wallis test), malignant ascites (P = 0.009, chi-square test), and history of other drug allergy (P < 0.001, chi-square test). Compared to women without hypersensitivity reactions, women who experienced hypersensitivity reactions had a significantly greater median cycle number (12 vs. 6, P < 0.001, independent sample t-test) and dose (6,816 vs. 3,844 mg, P < 0.001, independent sample t-test). The cumulative incidence of carboplatin-related hypersensitivity reactions dramatically increased with >8 cycles or dose >3,500 mg. Therefore, disease severity, histological type, malignant ascites, past drug allergies, and cumulative carboplatin dose are risk factors for carboplatin-related hypersensitivity reactions. Such reactions could potentially be reduced or prevented by slowing the infusion rate and using a desensitization protocol involving anti-allergy medications.

We analyzed the management and risk of subsequent cervical intraepithelial neoplasm 3 (CIN3) and invasive cervical cancer in women with low-grade squamous intraepithelial lesion (LSIL) cytology. A total of 53,293 women with a new diagnosis of cytologic LSIL were identified in Taiwan's national cervical screening registration database. Based on the retrieved clinical management data, the incidence of subsequent CIN3+ lesions was determined, and the hazard ratios (HRs) were estimated using a Cox proportional hazards model. The average follow-up was 5.02 years. A total of 988 women developed CIN3+ lesions during this period, with an overall incidence of 369.3 women per 100,000 person-years. Cryotherapy and conization/loop electrosurgical excision procedure (LEEP) decreased the subsequent risk of CIN3+ lesions in women younger than 50 years (HR 0.49, 95% confidence interval [CI] 0.37-0.64, p

Objective: To report a case of isolated omental peritoneal carcinoma without peritoneal carcinomatosis. Case report: A 60-year-old female with abdominal distention was found to have a pelvic mass. Under the impression of ovarian cancer, laparotomy was performed only to show one isolated mass over omentum. Serial examination and pathology study including immunochemical staining indicated primary peritoneal serous carcinoma. Conclusion: Isolated omental peritoneal carcinoma without peritoneal carcinomatosis and ascites is rare, and whether this represented a unique entity with different chemotherapy response and treatment outcome from the disseminated form of primary peritoneal carcinoma needs to be reviewed in the future.

Objective: To investigate the various genotypes of human papillomavirus (HPV) in Taiwanese women patients with abnormal cervical cytology and analyze the associations between HPV types, cervical preinvasive lesions, and the medical characteristics of these patients. Materials and Methods: We performed HPV genotyping GeneChip procedures and colposcopies for 784 women with abnormal Papanicolaou smears. The characteristics of the patients and the status of the HPV infection were correlated. Results: A total of 706 (90.1%) of the 784 women were positive for HPV infection, including 641 patients with high-risk HPV (HR-HPV). Among the patients with high-grade squamous intraepithelial lesions (HSILs), the average age of the 273 patients with other HR-HPV types (48.6 ± 13.8 years) was significantly older than the 222 patients infected with HPV 16/18 (39.8 ± 11.8 years) (p

Objective: Signal transducer and activator of transcription (STAT)1 is a key tumor suppressor, which is always methylated in a variety of human cancers. However, nonspecific primers for the detection of specific promoter hypermethylation of STAT1 gene can lead to false-positive or false-negative results for gene methylation. Materials and Methods: We designed new primers for the detection of STAT1 methylation and compared the sensitivities and specificities of these new primers with prior published primers by methylation-specific polymerase chain reaction (PCR) from ovarian clear cell carcinomas. The mRNA expression levels of STAT1 in these cancerous tissues were also evaluated by reverse-transcriptase PCR and correlated with the results of promoter methylation of STAT1 gene. Results: Nine (39%) of the 23 samples detected by the new primers and 13 samples (56%) detected by prior published primers showed STAT1 methylation. A direct DNA sequencing test revealed that four of the 13 samples (30.8%) showed false positivity for STAT1 methylation using the prior published primers. In contrast, none of the nine samples was false-positive for the detection of STAT1 methylation using the new primers. The new primers for the detection of STAT1 methylation showed 100% specificity and 100% sensitivity without false positivity. Conclusion: Specific primers for methylation-specific PCR are mandatory for the accurate detection of STAT1 gene methylation. Besides, specific primers can generate correct interpretation of STAT1 gene methylation, and its correlation with the clinicopathological characteristics and outcome of cancer patients.

Endometrial hyperplasia is considered a precursor of endometrial carcinoma, but concurrent endometrial carcinoma in patients with endometrial hyperplasia is seen frequently. Our aim was to examine the risk factors for coexisting endometrial carcinoma in patients with endometrial hyperplasia. Methods: Between January 1996 and September 2006, 77 patients who underwent hysterectomy for endometrial hyperplasia were enrolled retrospectively. We divided the patients into non-endometrial carcinoma and endometrial carcinoma groups, depending on the final pathology of hysterectomy and analyzed the clinical variables of these patients. Results: The prevalence rate of concurrent endometrial carcinoma in patients with endometrial hyperplasia was 26%. Those with atypical endometrial hyperplasia had a higher rate of coexisting endometrial carcinoma (54%). In addition to cytologic atypia, body mass index (BMI) was another risk factor. All the patients with concomitant endometrial carcinoma had at least one risk factor, but almost 50% of the cases in the non-endometrial group had no risk factors. Half of the women with cytological atypia and BMI > 25 had coexisting endometrial carcinoma. Conclusion: When patients are diagnosed with endometrial hyperplasia, surgical intervention should be performed in those with cytological atypia and higher BMI because of the possibility of coexisting endometrial carcinoma.

The formation of pseudoaneurysms in patients with gynecologic malignancies is rare. We describe a patient with locally advanced cervical cancer who had life-threatening rectal bleeding due to a ruptured pseudoaneurysm of the right external iliac artery, which was successfully treated by emergent endovascular covered stent placement. This 56-year-old woman had received concurrent chemoradiation, salvage hysterectomy and systemic chemotherapy for advanced cervical cancer. About 25 months after her diagnosis of cervical cancer, she suffered from acute life-threatening rectal bleeding. Angiography revealed active extravasation from a pseudoaneurysm of the right external iliac artery. A covered stent was placed across the pseudoaneurysm via an endovascular approach to stop the bleeding. The patient recovered well without any sequelae. We believe that this technique might also be useful in other irradiated gynecologic cancer patients, especially when direct surgical repair is difficult to perform due to pelvic irradiation or tumor recurrence.

Globally, cervical cancer is one of the most common cancers in women, representing up to 25% of all female cancers, and is the most common cancer in developing countries. It kills around 250,000 women every year worldwide and around 1,000 in Taiwan. Cervical cancer is largely preventable through screening programs to diagnose cervical lesions that may progress to invasive cancer. It has recently been definitively linked to genital human papillomavirus (HPV) infections. HPV fulfills the criteria for a carcinogenic agent defined by the International Agency for Research on Cancer. More than 200 types of HPV have been identified by DNA sequence data, and 85 HPV genotypes have been well characterized to date. HPV can infect the basal epithelial cells of the skin or inner tissue linings and is, accordingly, categorized as either cutaneous or mucosal. Genital HPV infections are now recognized as a major risk factor in at least 95% of cervical cancers. Thirty different HPV genotypes have been identified as causative of sexually transmitted diseases, most of which induce lesions in the cervix, vagina, vulva, penis, and anus. The main aim of this review is to evaluate the current literature regarding the relationship between HPV and cervical neoplasm, host immune responses to HPV, and the current status of preventive and therapeutic HPV vaccines.

Objective: Mature cystic teratoma with gliomatosis peritonei is an uncommon condition, with the implantation of nodules of mature glial tissue within the peritoneal cavity, which may be mistaken for peritoneal carcinomatosis or peritoneal tuberculosis. Here, we present a case of mature cystic teratoma with mature gliomatosis peritonei. Case Report: A 36-year-old woman had been suffering from progressive abdominal distension for 2 months. Sonography revealed a heterogeneous echo-complex mass measuring 15 × 12.7 × 10 cm in the pelvis. Computed tomography scan revealed a pelvic mass with calcification in the peritoneal cavity. A right ovarian tumor was found at laparotomy, and right salpingo-oophorectomy was performed. Miliary tumors were also noted on the omentum and peritoneal surfaces. Omentectomy and peritoneal biopsy were performed. The pathology report showed a mature cystic teratoma with mature gliomatosis peritonei. The patient was followed-up for 1 year, with no evidence of recurrence up to the time of writing. Conclusion: Gliomatosis peritonei is considered to be a benign lesion accompanying cystic teratoma. Extensive sampling is essential to exclude the presence of immature elements, which may imply a poor prognosis and require aggressive therapy.

BACKGROUND: Associations of obesity and obesity-related metabolic factors (adiposity factors) with uterine corpus cancer (UCC) and ovarian cancer (OVC) risk have been described. Still, a cause-effect relationship and the underlying mediators remain unclear, particularly for low-incidence populations. We aimed to prospectively determine whether adiposity factors could predict the development of UCC and OVC in Taiwanese women. To explore the biological mediators linking adiposity factors to cancer risk, we examined the association of two adipokines, leptin and adiponectin, with the gynecological cancers. METHODS: Totally, 11,258 women, aged 30-65, were recruited into the Community-Based Cancer Screening Program (CBCSP) study during 1991-1993, and were followed for UCC and OVC cases until December 31, 2011. Cox proportional hazard models were used to estimate hazard ratios (HRs). Adiposity factors and risk covariates were assessed at recruitment. Newly-developed cancer cases were determined from data in the government's National Cancer Registry and Death Certification System. For adipokienes study, a nested case-control study was conducted within the cohort. Baseline plasma samples of 40 incident gynecological cancer cases and 240 age-menopause-matched controls were assayed for adipokines levels. FINDINGS: There were 38 and 30 incident cases of UCC and OVC, respectively, diagnosed during a median 19.9 years of follow-up. Multivariate analysis showed that alcohol intake (HR = 16.00, 95% = 4.83-53.00), high triglyceride levels (HR = 2.58, 95% = 1.28-5.17), and years of endogenous estrogen exposure per 5-year increment (HR = 1.91, 95% = 1.08-3.38) were associated with increased UCC risk. High body mass index (BMI ≥ 27 kg/m(2), HR = 2.90, 95% = 1.30-6.46) was associated with increased OVC risk. Analysis further showed an independent effect of adipokines on UCC and OVC risk after adjustment of the risk covariates. CONCLUSION: We provided evidence that alcohol intake, high triglyceride levels and long endogenous estrogen exposure increase UCC risk, whereas obesity positively predicts OVC risk. Circulating adipokines may mediate the link of adiposity factors to gynecological cancer risk.

Objective: Inversion of the uterus is indeed a rarity for a gynecologist. The puerperal variety is associated with pregnancy, including term pregnancy and abortion. The nonpuerperal condition may be tumor-induced or idiopathic. We present a nonpuerperal uterine inversion and discuss a reasonable plan for its management Case Report: A 42-year-old, unmarried woman without sexual experience and any systemic diseases noted a mass outside of the vaginal introitus combined with massive vaginal bleeding and abdominal pain of sudden onset after taking laxative agents for colonoscopic preparation. Then she had voiding difficulty with distended bladder. A suprapubic urinary catheter was inserted and 800 mL urine was drained out. The patient received emergency tumor resection and subtotal hysterectomy. The diagnosis of uterine inversion was confirmed during operation. The postoperative course was uneventful and she was discharged without complication. Conclusion: Nonpuerperal inversion of the uterus is rarely encountered by gynecologists. Diagnosis of uterine inversion is often not easy and imaging studies might be helpful. Surgical treatment is the method of choice in nonpuerperal uterine inversion.

Objective: Laminaria placement is seldom thought to be associated with postabortal sepsis Case Report: A nulliparous woman presented with high fever, low blood pressure, and signs of infection during artificial legal abortion with laminaria placement for cervical dilatation. Broad-spectrum antibiotics were given. Cultures of blood, placenta, and arterial line all yielded Enterobacter cloacae. The patient responded to antibiotics and supportive care. Conclusion: The use of laminaria still places patients at risk for infection because there is a certain risk of ascending colonization with potentially pathogenic microorganisms from the vaginal and cervical microflora, as in our patient. Surgical disinfection, prophylactic antibiotics, and shortened duration of laminaria placement are helpful to prevent infectious insult. Once signs of infection are noted, physicians should take action as soon as possible, such as initiating broad-spectrum antibiotics and intensive care.

INTRODUCTION: Human papillomavirus (HPV) has been consistently implicated in causing several kinds of malignancies, and two HPV oncogenes, E6 and E7, represent two potential target antigens for cancer vaccines. We developed two fusion protein vaccines, PE(ΔIII)/E6 and PE(ΔIII)/E7 by targeting these two tumor antigens to test whether a combination of two fusion proteins can generate more potent anti-tumor effects than a single fusion protein. MATERIALS AND METHODS: In vivo antitumor effects including preventive, therapeutic, and antibody depletion experiments were performed. In vitro assays including intracellular cytokine staining and ELISA for Ab responses were also performed. RESULTS: PE(ΔIII)/E6+PE(ΔIII)/E7 generated both stronger E6 and E7-specific immunity. Only 60% of the tumor protective effect was observed in the PE(ΔIII)/E6 group compared to 100% in the PE(ΔIII)/E7 and PE(ΔIII)/E6+PE(ΔIII)/E7 groups. Mice vaccinated with the PE(ΔIII)/E6+PE(ΔIII)/E7 fusion proteins had a smaller subcutaneous tumor size than those vaccinated with PE(ΔIII)/E6 or PE(ΔIII)/E7 fusion proteins alone. CONCLUSION: Fusion protein vaccines targeting both E6 and E7 tumor antigens generated more potent immunotherapeutic effects than E6 or E7 tumor antigens alone. This novel strategy of targeting two tumor antigens together can promote the development of cancer vaccines and immunotherapy in HPV-related malignancies.

INTRODUCTION: Uterine cancer was the most rapidly increasing malignancy and the second most common gynecologic malignancy in Taiwan. METHODS: We analyzed the secular trend of uterine cancer incidence and compare the survival of women with uterine carcinomas and uterine sarcomas in Taiwan. Data on women diagnosed with uterine cancer between 1979 and 2008 were obtained from the Taiwan cancer registry. Survival data were analyzed by using Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: Records of 11,558 women with uterine carcinomas and 1,226 women with uterine sarcomas were analyzed. The age-adjusted incidence rate of endometrioid adenocarcinoma increased from 0.83 per 100,000 women per year between 1979 and 1983 to 7.50 per 100,000 women per year between 2004 and 2008. The 5-year survival rate of women with endometrioid adenocarcinoma (83.2%) was higher than that for women with clear cell carcinoma (58.3%), serous carcinoma (54.4%), and carcinosarcoma (35.2%) (p

BACKGROUND: The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. MATERIALS AND METHODS: Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. RESULTS: The cytokines, including IL-4 (p=0.017) and TNF-α (p=0.046), significantly decreased while others such as TGF-β (p=0.013), IL-6 (p=0.016), and IL-10 (p=0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8(+) T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37 ± 0.64 vs. early 14.25 ± 3.11, p=0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20 ± 0.03 g) than the sequential high-dose (0.69 ± 0.06 g) and sequential low-dose (0.67 ± 0.07 g) CD25 Ab deletion groups (p=0.001) after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-γ-secreting, mesothelin-specific T lymphocytes compared to the other groups (p

Objective: In early-stage endometrial cancer, aggressive histologic types (grade 3 endometrioid, serous, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types) are associated with an increased risk of distant metastases and worse survival. However, the optimal adjuvant treatment for these patients remains controversial. The present study investigated the outcomes of different adjuvant treatments in patients with 2023 FIGO stage IIC endometrial cancer. Methods: We retrospectively identified patients with 2023 FIGO stage IIC endometrial cancer who underwent surgery followed by either adjuvant treatment or observation from 2000 to 2020 at two tertiary centers in Korea and Taiwan. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models. We also analyzed recurrence patterns after different adjuvant treatments. Results: A total of 272 patients were identified; 204 received adjuvant treatment postoperatively, whereas 68 only underwent observation. Adjuvant treatment was not associated with improved RFS or OS. Non-endometrioid histologic types (p=0.003) and presence of lymphovascular space invasion (LVSI, p=0.002) were associated with worse RFS, whereas only non-endometrioid histologic types impacted OS (p=0.004). In subgroup analyses, adjuvant treatment improved OS in patients with LVSI (p=0.020) and in patients with both LVSI and grade 3 endometrioid histologic type (p=0.007). We found no difference in locoregional and distant recurrence between patients undergoing adjuvant treatment or observation. Conclusion: In this study, the addition of adjuvant treatment was associated with an OS benefit for patients with LVSI, especially those with grade 3 endometrioid tumors. [ABSTRACT FROM AUTHOR]