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Pelvic radiotherapy is associated with gastrointestinal toxicities and deterioration of nutritional status. This study aimed to investigate the association of patient-reported outcomes (PROs) and nutritional status with body composition changes in women who underwent hysterectomy and post-operative radiotherapy for gynecologic cancer. We analyzed data of 210 patients treated with post-operative pelvic radiotherapy for gynecologic cancer between 2013 and 2018. The PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was used for gastrointestinal toxicity assessment. The Patient-Generated Subjective Global Assessment (PG-SGA) was used for nutritional assessment. Skeletal muscle index was measured from computed tomography scans at the L3 vertebral level. A reduction in skeletal muscle index ≥ 5% was classified as muscle loss. Odds ratios were calculated through logistic regression models. The PG-SGA score increased from the beginning to the end of radiotherapy (1.4 vs. 3.7, p &lt, 0.001). Patients with PRO-CTCAE scores ≥ 3 had significantly higher PG-SGA scores at the end of radiotherapy than those with PRO-CTCAE scores ≤ 2 (8.1 vs. 2.3, p &lt, 0.001). On multivariable analysis, PRO-CTCAE scores ≥ 3 and PG-SGA scores ≥ 4 at the end of radiotherapy were independently associated with increased risk of muscle loss (odds ratio: 8.81, p &lt, 0.001, odds ratio: 72.96, p &lt, 0.001, respectively). PROs and PG-SGA may be considered as markers of muscle loss after post-operative pelvic radiotherapy for gynecologic cancer.

// Zih-Yin Lai 1 , Hsin-Yueh Yeo 1 , Ya-Tse Chen 1 , Kuo-Ming Chang 2 , Tze-Chien Chen 3 , Yung-Jen Chuang 1 and Shing-Jyh Chang 4 1 Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan (R.O.C.) 2 Department of Pathology, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan (R.O.C.) 3 Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei 10449, Taiwan (R.O.C.) 4 Department of Obstetrics and Gynecology, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan (R.O.C.) Correspondence to: Yung-Jen Chuang, email: yjchuang@life.nthu.edu.tw Shing-Jyh Chang, email: justine3@ms8.hinet.net Keywords: neuroendocrine cervical carcinoma, combination therapy, genotoxic drug, PI3K inhibitor, BEZ235 Received: February 14, 2017 Accepted: April 12, 2017 Published: April 21, 2017 ABSTRACT Background: Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC. Results: The stable HM-1 cell line displayed high expression levels of the neuroendocrine marker, synaptophysin. HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin synergistically inhibited HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Taken together, the data implied the combination of etoposide and cisplatin with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis. Materials and Methods: A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 were analyzed to establish its characteristic profile. Next, HM-1 was treated with PI3K inhibitors, BKM120 and/or BEZ235, in combination with two well-known genotoxic drugs, etoposide and/or cisplatin, to evaluate which combination could serve as a more effective treatment approach. Their inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression. Conclusions: The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a potential new treatment strategy against NECC.

// Yuh-Cheng Yang 1, 4, * , Tzu-Yang Chang 3, * , Tze-Chien Chen 1 , Wen-Shan Lin 3 , Shih-Chuan Chang 3 , Yann-Jinn Lee 2, 3, 5, 6, 7 1 Department of Gynecology and Obstetrics, MacKay Memorial Hospital, Taipei City 2 Department of Pediatric Endocrinology, MacKay Children’s Hospital, Taipei City 3 Department of Medical Research, MacKay Memorial Hospital, New Taipei City 4 Department of Gynecology and Obstetrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan 5 Departments of Gynecology and Obstetrics, Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 6 Institute of Biomedical Sciences Mackay Medical College, New Taipei City, Taiwan 7 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan * These authors contributed equally to this work. Correspondence to: Yann-Jinn Lee, email: yannlee@mmh.org.tw , kylechang@mmh.org.tw Keywords: cervical cancer, HPV, immunity, ITPR3, polymorphism Received: June 15, 2016 Accepted: December 15, 2016 Published: December 28, 2016 ABSTRACT Host immunogenetic background plays an important role in human papillomavirus (HPV) infection and cervical cancer development. Inositol 1,4,5-triphosphate receptor type 3 (ITPR3) is essential for both immune activation and cancer pathogenesis. We aim to investigate if ITPR3 genetic polymorphisms are associated with the risk of cervical cancer in Taiwanese women. ITPR3 rs3748079 A/G and rs2229634 C/T polymorphisms were genotyped in a hospital-based study of 462 women with cervical squamous cell carcinoma (CSCC) and 921 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. No significant association of individual ITPR3 variants were found among controls, CSCC, and HPV-16 positive CSCC. However, we found a significant association of haplotype AT between CSCC and controls (OR = 2.28, 95% CI 1.31–3.97, P = 2.83 × 10 −3 ) and the OR increased further in CSCC patients infected with HPV-16 (OR = 2.89, 95% CI 1.55–5.37, P = 4.54 × 10 −4 ). The linkage disequilibrium analysis demonstrated that ITPR3 association with CSCC was independent of HLA-DRB1 alleles. In conclusion, these findings suggest that AT haplotype in the ITPR3 gene may serve as a potential marker for genetic susceptibility to CSCC.

Background Sarcopenia is commonly observed in patients with advanced‐stage epithelial ovarian cancer (EOC). However, the effect of body composition changes—during primary debulking surgery (PDS) and adjuvant platinum‐based chemotherapy—on outcomes of patients with advanced‐stage EOC is unknown. This study aimed to evaluate the association between body composition changes and outcomes of patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy. Methods Pre‐treatment and post‐treatment computed tomography (CT) images of 139 patients with stage III EOC were analysed. All CT images were contrast‐enhanced scans and were acquired according to a standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured using CT images obtained at the L3 vertebral level. Predictors of overall survival were identified using Cox regression models. Results The median follow‐up was 37.9 months. The median duration between pre‐treatment and post‐treatment CT was 182 days (interquartile range: 161–225 days). Patients experienced an average SMI loss of 1.8%/180 days (95% confidence interval: −3.1 to −0.4; P = 0.01) and SMD loss of 1.7%/180 days (95% confidence interval: −3.3 to −0.03; P = 0.046). SMI and SMD changes were weakly correlated with body mass index changes (Spearman ρ for SMI, 0.15, P = 0.07; ρ for SMD, 0.02, P = 0.82). The modified Glasgow prognostic score was associated with SMI loss (odds ratio: 2.42, 95% confidence interval: 1.03–5.69; P = 0.04). The median time to disease recurrence was significantly shorter in patients with SMI loss ≥5% after treatment than in those with SMI loss

Uterine sarcoma is a very aggressive and highly lethal disease. Even after a comprehensive staging surgery or en block cytoreduction surgery followed by multimodality therapy (often chemotherapy and/or radiation therapy), many patients relapse or present with distant metastases, and finally die of diseases. The worst outcome of uterine sarcomas is partly because of their rarity, unknown etiology, and highly divergent genetic aberration. Uterine sarcomas are often classified into four distinct subtypes, including uterine leiomyosarcoma, low-grade uterine endometrial stromal sarcoma, high-grade uterine endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Currently, evidence from tumor biology found that these tumors showed alternation and/or mutation of genomes and the intracellular signal pathway. In addition, some preclinical studies showed promising results for targeting receptor tyrosine kinase signaling, phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway, various kinds of growth factor pathways, Wnt/beta-catenin signaling pathway, transforming growth factor β/bone morphogenetic protein signal pathway, aurora kinase A, MDM2 proto-oncogene, histone deacetylases, sex hormone receptors, certain types of oncoproteins, and/or loss of tumor suppressor genes. The current review is attempted to summarize the recurrent advance of targeted therapy for uterine sarcomas.

// Yuh-Cheng Yang 1, 4, * , Tzu-Yang Chang 3, * , Tze-Chien Chen 1 , Wen-Shan Lin 3 , Shih-Chuan Chang 3 , Yann-Jinn Lee 2, 3, 5, 6, 7 1 Department of Gynecology and Obstetrics, MacKay Memorial Hospital, Taipei City, Taiwan 2 Department of Pediatric Endocrinology, MacKay Children’s Hospital, Taipei City, Taiwan 3 Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan 4 Department of Gynecology and Obstetrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan 5 Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan 6 Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan 7 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan * The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors Correspondence to: Yann-Jinn Lee, email: yannlee@mmh.org.tw , kylechang@mmh.org.tw Keywords: cervical cancer, HPV, immunity, P2RX7 , polymorphism Received: June 30, 2016 Accepted: September 28, 2016 Published: October 13, 2016 ABSTRACT Human papillomavirus (HPV) infection and the fate of HPV infected cervical epithelial cells are strictly associated with cervical cancer development. P2X7 receptor has been implicated in both the regulation of immune responses and apoptosis of cervical cancer cells. The study aims to investigate if polymorphisms in the P2RX7 gene are associated with the risk of cervical cancer in Taiwanese women. P2RX7 253 T/C , 835 G/A , and 1513 A/C loss-of-function polymorphisms were genotyped in a hospital-based study of 507 women with cervical squamous cell carcinoma (CSCC) and 1619 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. The frequency of 253 C/C genotype was found to increase significantly in patients with HPV-16 positive CSCC compared with controls (odds ratio = 10.2, 95% confidence interval 1.39–87.8, P c = 0.03). No significant associations were found for other 2 polymorphisms. Analysis of haplotypes also revealed no significant differences among women with CSCC, those with HPV-16 positive CSCC and controls. In conclusion, inheritance of the C/C genotype at position 253 in the P2RX7 gene may contribute to the risk of HPV-16 associated CSCC in Taiwanese women.

Endometrial stromal tumors are rare uterine tumors (

Objective: To dissect the correlated hematologic markers that reflect the clinical outcome or treatment response in patients receiving dose-dense chemotherapy with a combination of platinum (cisplatin or carboplatin) and paclitaxel. Materials and Methods: From 2009 to 2014, we enrolled 55 ovarian cancer patients (total 67 courses) including first-line, persistent, platinum-sensitive, or platinum-resistant disease in MacKay Memorial Hospital, Taipei, Taiwan. Weekly pretreatment complete blood counts and calculated ratios [platelet/neutrophil ratio, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), neutrophil/monocyte ratio, platelet/monocyte ratio, lymphocyte/monocyte ratio] during dose-dense chemotherapy were collected. By grouping these hematologic biomarkers into three different response subgroups (responsive, stable, and nonresponsive) according to CA125 trend, the data were analyzed using one-way analysis of variance, and using post hoc-Tukey test for comparing each other. A p value < 0.05 was considered to be statistically significant. Results: Absolute counts of lymphocytes and platelets, PLR, platelet/neutrophil ratio, platelet/monocyte ratio (all p < 0.001), and NLR (p=0.013) had statistically significant differences. Moreover, using box-and-whisker plot, absolute count of lymphocyte, PLR, and NLR showed most remarkable discrepancy in responsive, stable, and nonresponsive patients. Subgroup analysis for primary, platinum-sensitive, and platinum-resistant patients further revealed that PLR and NLR were significantly correlated to the outcome of dose-dense chemotherapy. Conclusion: Lower PLR or lower NLR had better treatment response for dose-dense chemotherapy and are possible markers for representing treatment response in dose-dense chemotherapy. For a clinician, this is useful for timing when to switch to another chemotherapy regimen.

Nilotinib (AMN) induces apoptosis in various cancer cells; however the effect of AMN on human ovarian cancer cells is still unclear. A reduction in cell viability associated with the occurrence of apoptotic characteristics was observed in human SKOV-3 ovarian cancer cells under AMN but not sorafenib (SORA) or imatinib (STI) stimulation. Activation of apoptotic pathway including increased caspase (Casp)-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein cleavage by AMN was detected with disrupted mitochondrial membrane potential (MMP) accompanied by decreased Bcl-2 protein and increased cytosolic cytochrome (Cyt) c/cleaved Casp-9 protein expressions was found, and AMN-induced cell death was inhibited by peptidyl Casp inhibitors, VAD, DEVD and LEHD. Increased phosphorylated c-Jun N-terminal kinase (JNK) protein expression was detected in AMN- but not SORA- or STI-treated SKOV-3 cells, and the JNK inhibitors, SP600125 and JNKI, showed slight but significant enhancement of AMN-induced cell death in SKOV-3 cells. The intracellular peroxide level was elevated by AMN and H2O2, and N-acetylcysteine (NAC) prevented H2O2- but not AMN-induced peroxide production and apoptosis in SKOV-3 cells. AMN induction of apoptosis with increased intracellular peroxide production and JNK protein phosphorylation was also identified in human A2780 ovarian cancer cells, cisplatin-resistant A2780CP cells, and clear ES-2 cells. The evidence supporting AMN effectively reducing the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis is provided.

Genetic epidemiological studies show that genetic factors contribute significantly to cervical cancer carcinogenesis. Several genome-wide association studies (GWAS) have revealed novel genetic variants associated with cervical cancer susceptibility. We aim to replicate 4 GWAS-identified single nucleotide polymorphisms (SNPs), which were associated with invasive cervical cancer in Chinese women, in a Taiwanese population. The rs13117307 C/T, rs8067378 A/G, rs4282438 G/T, and rs9277952 A/G SNPs were genotyped in 507 women with cervical squamous cell carcinoma (CSCC) and 432 age/sex matched healthy controls by using TaqMan PCR Assay. Human papillomavirus (HPV) DNA test and typing were performed in CSCC patients. Only the rs4282438 SNP was found to be significantly associated (G allele, odds ratio [OR] = 0.67, P = 1.5 × 10−5). This protective association remained in HPV-16 positive CSCC subgroup (G allele, OR = 0.60, P = 1.2 × 10−5). In conclusion, our study confirms the association of rs4282438 SNP with CSCC in a Taiwanese population. However, larger sample sets of other ethnic groups are required to confirm these findings.

Objective : To evaluate the role of surgery, radiation therapy and chemotherapy in the management of small cell carcinoma of the uterine cervix (SCCC) through a retrospective study of Taiwanese Gynecologic Oncology Group. Methods : We reviewed the medical records and histological files of 144 patients with FIGO stages IA–IIB SCCC treated in 11 main hospitals in Taiwan from 1987 to 2009. Results : There were 110 patients receiving primary surgery and 34 primary radiation therapy. Most patients in each group also received chemotherapy as part of primary treatment. A lower loco-regional failure rate was observed in patients who received primary radiation therapy than in those who had primary surgery (6% vs. 27%; P =0.009). The 5-year overall survival (OS) was 89% for 13 surgically treated patients with cervical tumor ≤2cm and no lymphovascular space involvement (LVSI) in whom recurrence was noted in 2 of 4 patients without receiving adjuvant chemotherapy and none in the 9 patients who had chemotherapy. Excluding these 13 patients, primary radiation therapy with at least 5cycles of platinum-based chemotherapy ( n =14, including 12 stages IB2–IIB) resulted in a 5-year OS of 78%, better than that of 46% by primary surgery ( n =97, including 40 stages IB2–IIB) ( P =0.046). Conclusions : None of the 9 patients with cervical tumor ≤2cm and no LVSI showed disease recurrence after primary surgery and adjuvant chemotherapy. For most patients with stages I–II, primary radiation therapy with aggressive chemotherapy was associated with better survival than surgery.

Objective Our previous work revealed that host genes ZNF582 , PTPRR , PAX1 , and SOX1 are highly methylated in cervical intraepithelial neoplasias grade 3 or worse (CIN3 + ). In this study, we used a standardized testing assay to evaluate the clinical efficacy of these biomarkers in the triage of cytological diagnoses of low-grade squamous intraepithelial lesions (LSILs), and compared the performance with human papillomavirus (HPV) testing. Methods This 2-year multicenter prospective study examined a population of 230 women from 12 medical centers who were diagnosed with LSILs on cervical cytology. Cervical scrapings were obtained prior to a colposcopy-directed biopsy for quantitative methylation analysis of ZNF582 , PTPRR , PAX1 , and SOX1 , and HPV testing. Using logistic regression and receiver operating characteristic curve analyses, the abilities of methylated genes and HPV to predict CIN3 + were assessed. Results Fifteen (6.5%) of the 230 women with a cytological diagnosis of LSIL were confirmed to have CIN3 + after a colposcopy-directed biopsy. Among the 4 methylated genes, ZNF582 was found to be the best biomarker for detecting CIN3 + . The sensitivities for methylated ZNF582 and HPV testing were 73% and 80%, and the specificities were 71% and 28%, respectively. The odds ratio for predicting CIN3 + using methylated ZNF582 was 6.8 (95% confidence interval (CI) 2.1–22.1), which was much better than HPV testing (OR=1.6, 95% CI 0.4–5.8). Conclusion This is the first study to show that ZNF582 methylation analysis of cervical swabs may be a promising choice in the positive triage of cytological diagnoses of LSILs.

Background The mere presence of human papillomavirus (HPV) is not enough for cervical cancer development and immunogenetic background may play an important role. Human leucocyte antigen (HLA)-G acts as a negative regulator of immune responses and its expression in tumour cells may enable them to avoid immune attack. We aim to study if polymorphisms in the HLA-G gene are associated with cervical cancer risk in Taiwanese women. Methods +1537 A/C , 14-bp deletion/insertion ( Del/Ins ), and +3142 G/C polymorphisms were genotyped in a hospital-based study of 317 women with cervical squamous cell carcinoma (CSCC) and 400 healthy control women frequency matched by age. The presence and genotypes of HPV in CSCC were determined. Results We found the +3142 C/C genotype and C allele were associated with increased risk for CSCC (adjusted odds ratio [OR] = 1.78, P = 0.004; adjusted OR = 1.31, P = 0.014, respectively). In subgroup analysis based on HPV type 16 positivity, significant associations with higher adjusted ORs were found in +3142 C/C genotype and C allele (adjusted OR = 2.19, P = 0.001; adjusted OR = 1.48, P = 0.003, respectively) and +1537 C/C genotype and C allele frequencies increased significantly (adjusted OR = 2.88, P = 0.004; adjusted OR = 1.69, P = 0.0005, respectively). Furthermore, the C-Del-C haplotype conferred increased risk of both CSCC and HPV-16 positive CSCC women (adjusted OR = 1.41, P = 0.009; adjusted OR = 1.94, P = 0.0001, respectively). Conclusion These findings suggest that HLA-G gene is involved in the susceptibility to CSCC.

Cervical cancer is strongly associated with infection of oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for progression to cervical cancer. It is now recognized that host immunogenetic background participates in the control of HPV infection and development of cervical cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays a central role in antitumor immunity. The aim of this study is to determine if potentially functional polymorphisms in IL-18 gene are associated with risk of HPV-induced cervical cancer in Taiwanese women. Pre-Developed TaqMan Allelic Discrimination Assay was used to genotype IL-18 − 1297 T / C , − 607 C / A , − 380 C / G , − 137 G / C , and + 105 A / C polymorphisms in a hospital-based study of 470 women with cervical squamous cell carcinoma (CSCC) and 722 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined by PCR. None of the polymorphisms or any haplotype was found to have significant differences in distribution among all subjects with CSCC, those with HPV-16 positive CSCC, and controls. Our results suggest that the IL-18 − 1297 T / C , − 607 C / A , − 380 C / G , − 137 G / C , and + 105 A / C polymorphisms are not associated with susceptibility to CSCC in Taiwanese women.

Uterine sarcomas account for 3–7% of all uterine cancers. Because of their rarity, unknown etiology, and highly divergent genetic aberration, there is a lack of consensus on risk factors for occurrence and predictive poor outcomes as well as optimal therapeutic choices. Tumor types according to the World Health Organization classification include leiomyosarcoma, endometrial stroma sarcoma, and undifferentiated sarcoma. Staging is done using the 2014 Federation International Gynecology and Obstetrics and 2010 American Joint Committee on Cancer tumor, lymph node, and metastases systems. Tumor grade can be classified based on the French Federation of Cancer Centers Sarcoma Group system or the Broder’s system that incorporates tumor differentiation, mitotic count, and tumor necrosis. This review is a series of articles discussing uterine sarcoma, and this is Part I, which focuses on one of the subtypes of uterine sarcomas—uterine leiomyosarcoma. The clinical characteristics, diagnosis, outcome, and recent advances are summarized in this article.

Cervical cancer is caused primarily by infection with oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for the progression to cervical cancer. Host immunogenetic factors may involve in the development of this disease. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is recently shown to act as a negative regulator of T-cell activation. We aim to study if polymorphisms in the ITPKC gene are associated with the risk of cervical cancer in Taiwanese women. ITPKC rs28493229 C/G, rs890934 G/T, rs2303723 C/T, and rs10420685 A/G polymorphisms were genotyped in a hospital-based study of 465 women with cervical squamous cell carcinoma (CSCC) and 800 age-matched healthy control women. The presence and genotypes of HPV in CSCC were determined. The frequency of G/G genotype and G allele of the ITPKC rs28493229 polymorphism was significantly higher in patients with CSCC compared with controls (OR = 1.81, 95 % CI 1.20–2.73, P = 0.005, P c = 0.02; OR = 1.70, 95 % CI 1.14–2.54, P = 0.008, P c = 0.03, respectively). No significant associations were found for other 3 polymorphisms. Haplotype analysis revealed the distribution of haplotype CGTA was significantly reduced in women with CSCC (OR = 0.59, 95 % CI 0.40–0.89, P = 0.01, P c = 0.04). In conclusion, we found the G/G genotype and G allele of the ITPKC rs28493229 polymorphism may contribute to the risk of CSCC in Taiwanese women. This finding provides new insights into the mechanisms of immune activation in cervical cancer.

Summary Objective To investigate the objective response rate to and tolerance of biweekly Lipo-Dox (TTY Biopharm Co. Ltd., Taipei, Taiwan) at a dosage of 20 mg/m2 in previously treated patients with recurrent cervical cancer. Materials and Methods This study was performed as a Simon's two-stage phase II clinical trial. Ten patients with recurrent cervical cancer were enrolled between April 2003 and December 2005 at the Mackay Memorial Hospital. Lipo-Dox (20 mg/m2 intravenous) diluted in 250 mL of 5% dextrose solution was administered at 2-weekly intervals. Results The mean age of the patients was 51 ± 11.1 years. The mean number of cycles of Lipo-Dox injection was 4.6 (range, 1—12 cycles). Nine patients (90%) had disease progression. Only one patient (10%) achieved a partial response, and this was also the only patient who experienced WHO grade 2 palmar-plantar erythrodysesthesia, which led to treatment delay for 2 months. The median survival time was 2 months (range, 2—6 months). The majority of patients experienced grade 1 or 2 anemia (30%), leukopenia (20%) or thrombocytopenia (20%), and others exhibited symptoms of nausea and vomiting (30%). Conclusion Salvage chemotherapy with Lipo-Dox at a dose of 20 mg/m2 administered at 2-weekly intervals produced limited responses in patients with recurrent cervical cancer. This trial will not proceed to the second stage. These results may discourage the management of recurrent cervical cancer with single-agent Lipo-Dox in future clinical trials.

Human papillomavirus (HPV) is considered to be a necessary but not sufficient cause for cervical cancer. The host immunogenetic background plays an important role in the persistence of HPV infection and subsequent development of cervical cancer. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a molecule expressed mainly on activated T cells and is important in the down-regulation of T-cell activation. The aim of this study was to determine if polymorphisms of the CTLA-4 gene are associated with HPV-induced cervical cancer in Taiwanese women. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype -318 C/T, +49 A/G and CT60 A/G polymorphisms in 144 women with cervical squamous cell carcinoma (CSCC) and 378 ethnicity-matched healthy control women. The presence and genotypes of HPV in CSCC were determined by E6-, E7-based nested polymerase chain reaction. The frequency of C/T genotype of -318 C/T polymorphism was significantly higher in patients with HPV-16-positive CSCC compared with controls (odds ratio = 1.99, 95% confidence interval = 1.16-3.42, P(c) = 0.03). No significant associations were found for +49 A/G and CT60 A/G polymorphisms. Analysis of haplotypes, computationally inferred from genotype data, also revealed no significant differences in distribution among all subjects with CSCC, those with HPV-16-positive CSCC and controls. Our results suggest that the -318 C/T variant in the promoter region of the CTLA-4 gene is associated with HPV-16-associated CSCC in Taiwanese women.

Endometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities.

Background Evodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2′3′-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism of EVO against the viability of human ovarian cancer cells is still unclear. Purpose A number of studies showed that chemotherapeutic benefits may result from targeting the endoplasmic reticular (ER) stress signaling pathway. The objective of the study is to investigate the mechanism by which ER stress protein PERK plays in EVO-induced apoptosis of human ovarian cancer cells. Methods Cell death analysis was performed by MTT assay, DNA fragmentation assay, and Giemsa staining. DiOC6 staining was used for mitochondrial membrane potential measurement. Protein levels were analyzed by Western blotting. Pharmacological studies using MAPK inhibitors and PERK inhibitor GSK2606414 were involved. Results The viability of human ovarian cancer cells A2780, A2780CP, ES-2, and SKOV-3 was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells, DNA ladders, and cleavage of caspase 3 and poly(ADP ribose) polymerase (PARP) proteins. Decreased viability of cells was reversed by adding caspase inhibitors VAD and DEVD in SKOV-3 and A2780CP cells, and incubation of cells with JNK inhibitor SP600125 (SP) and JNKI, but not other MAPK and AKT inhibitors including PD98059, SB203580, significantly prevented the apoptosis elicited by EVO in human ovarian cancer cells. Furthermore, increased expression of phospho-eIF2α (peIF2α) and phospho-PERK (pPERK) proteins was detected in EVO-treated human ovarian cancer cells, and that was inhibited by adding JNK inhibitors SP600125 and JNKI. Application of a PERK inhibitor GSK2606414 showed a significant protection of human ovarian cancer cells A2780 and A2780CP from EVO-induced apoptosis. EVO disruption of mitochondrial membrane potential (MMP) was also inhibited by adding JNK or PERK inhibitors. The structure-activity relationship study indicated that the alkyl group at position 14 in EVO is important for apoptosis induction via activation of JNK and PERK in human ovarian cancer cells. Conclusion Evidence supporting EVO induction of apoptosis via activation of JNK and PERK to disrupt MMP in human ovarian cancer cells is provided, and the alkyl at position 14 is a critical substitution for the apoptotic actions of EVO.

The present study describes 31 clinical cases of neuroendocrine cervical carcinoma (NECC) treated at Mackay Memorial Hospital between January 1, 1991 and October 31, 2003. There are two cases of atypical carcinoid tumor (ACT), four cases of large-cell neuroendocrine carcinoma (LCNEC), and 25 cases of small-cell neuroendocrine carcinoma (SCNEC). Overall survival did not differ significantly in relation to surgery, tumor histology, age, FIGO stages, chemotherapeutic regimens or lymph node involvement. The specimens available did not permit HPV (human papillomavirus)-DNA analysis in 5 cases (5/31, 9.7%). The HPV viral infection was absent in 8 cases (8/31, 26%); 17 cases of HPV-18 (17/31); and 1 case of HPV-16 (1/31). The prognosis between mixed and pure type histologic patterns is not significant. The mean survival time for all patients was 32.3 months. The 2-year and 5-year survival rates were 54.8% and 31.5% for all patients. The results of this study reaffirm the biologically aggressive nature of this rare malignancy, its low survival rate, and its very unpredictable prognostic factors. Effective treatments of neuroendocrine cervical tumor still remain inconclusive. Further efforts are still required to identify prognostic factors for this uncommon disease.

Cervical cancer is a multifactorial disease, and increasing evidence suggests that host immunogenetic background may contribute to its pathogenesis. Genetic variations in human leukocyte antigen (HLA) genes may alter the efficiency of immune response to human papillomavirus (HPV) antigens and have been implicated in the risk of cervical cancer. We investigated whether polymorphisms in the HLA-DPB1 gene were associated with cervical cancer risk in a Taiwanese population. HLA-DPB1 alleles and +550 G/A polymorphism were genotyped in a case–control study of 473 women with cervical squamous cell carcinoma (CSCC) and 676 healthy controls. The presence and genotypes of HPV in CSCC were determined. We found that the DPB1*05:01 and +550 A alleles were associated with decreased and increased risk of CSCC, respectively [odds ratio (OR) = 0.72, P c = 0.001; OR = 1.25, P c = 0.03]. In subgroup analysis based on HPV type 16 positivity, significant associations were shown in the DPB1*05:01 and *13:01 alleles (OR = 0.65, P c = 0.0007; OR = 1.83, P c = 0.004). Furthermore, the DPB1*05:01-G and *13:01-G haplotypes conferred decreased and increased risk of both CSCC and HPV-16 positive CSCC women, respectively (OR = 0.72, P c = 0.0009; OR = 0.63, P c = 0.0004 for DPB1*05:01-G; OR = 1.55, P c = 0.03; OR = 1.84, P c = 0.004 for DPB1*13:01-G). A risk haplotype DPB1*02:01-A was also observed in the HPV-16 positive CSCC women (OR = 1.51, P c = 0.05). These findings suggest that HLA-DPB1 gene is involved in the CSCC development.

The purpose of the study was to analyze negative versus positive immunoexpression of epithelial cadherin (E-cadherin) and p53 in patients with primary advanced ovarian clear cell adenocarcinoma (OCCA) and its significance in relation to clinical features, progression-free survival and overall survival (OS).Protein expression of E-cadherin and p53 was immunohistochemically evaluated in 61 OCCA patients with stages IIC to IV. The clinical factors studied included stage, age, CA-125, residual tumors, and chemotherapy regimens.Positive p53 immunoexpression was 44.8% (26/58) of OCCAs; in contrast, E-cadherin immunoexpression was observed in 75.9% (44/58) of OCCAs. The expected 5-year OS rate of OCCA treated with paclitaxel-based chemotherapy was significantly better than non-paclitaxel-based chemotherapy (40% vs 0%, P = 0.001). The expected 5-year OS rate of OCCA patients with positive E-cadherin immunoexpression (10%) was also significantly better than patients with negative E-cadherin immunoexpression (≤10%) (35% vs 0%, P = 0.02). The expected 5-year OS rate of those receiving paclitaxel-platinum chemotherapy was not significantly different from platinum-based chemotherapy for those with negative E-cadherin immunoexpression (P = 0.11). The expected 5-year OS rate of those receiving paclitaxel-based chemotherapy was better than non-paclitaxel-based chemotherapy for those with positive E-cadherin immunoexpression (43% vs 0%, P = 0.01). Paclitaxel-based chemotherapy and positive E-cadherin immunoexpression were 2 independent prognostic factors in OS of patients with OCCA (P = 0.01 and 0.04, respectively).E-cadherin is a useful prognostic marker for OCCA patients, and paclitaxel-based chemotherapy can improve survival among patients with positive E-cadherin immunoreactivity.

The present study describes the psychological impact of human papillomavirus (HPV)-related conditions or preventive interventions on Taiwanese women. Women with an HPV-related diagnosis or intervention within the past 3 months were invited to participate in a cross-sectional survey before the receipt of HPV-related diagnostic results. Participants completed a 29-item HPV impact profile (HIP), which was a questionnaire designed to represent the full spectrum of potential HPV-related impacts. The HIP assesses worries and concerns; emotional impact; sexual impact; self-image; partner issues and transmission; interactions with doctors; and control/life impact. The final sample size was 249 women from three hospitals. The mean HIP score (0-100) was normal Pap: 28.2; abnormal Pap: 44.3; CIN: 47.5; genital warts: 62.5; abnormal Pap with high-risk HPV positive: 48.8. This study indicates that significant psychological impact is found in women diagnosed with abnormal Pap, CIN, high-risk HPV test positive and genital wart compared to women with a normal Pap. Women with genital warts had the highest psychological impact scores. This is the first quantitative data that can lay the ground work for future studies that enable the comparison of the effectiveness of different interventions in alleviating the psychological burden of HPV-associated infection and preventive interventions in Taiwan.

Objective. To reassess the efficacy of the Federation of Gynecology and Obstetrics (FIGO) 2000 staging and risk factor scoring system in comparison to the original World Health Organization (WHO) prognostic scoring system (1983) in a single-institute setting. Design. Retrospective review of the medical records of 89 patients with gestational trophoblastic neoplasia. Setting. Mackay Memorial Hospital, Taipei, a regional referral center for northern Taiwan, over a 20-year period. Methods. All selected patients were classified retrospectively by the original WHO prognostic scoring system (1983) and the FIGO 2000 system. Main outcome measure. Efficacy as the correlation of risk categorization by percentage of patients between the original WHO scoring system (1983) and the FIGO 2000 system. Results. The correlation was 97%. Only two patients were classified as middle risk group in the original WHO system (1983), but as high-risk group by the FIGO 2000 system. Conclusion. There was good correlation between the original WHO (1983) and FIGO 2000 systems. Treatment outcomes by FIGO 2000 system were somewhat better than by the original WHO classification.

Extragonadal germ cell tumors are relatively rare, particularly malignant yolk sac tumors arising in the lung parenchyma. We report a case of a huge malignant yolk sac tumor in the right middle lobe. The patient was successfully treated with neoadjuvant chemotherapy followed by complete resection of the tumor.

The aim of this study is to investigate the expression of CXCR4 receptor in cervical adenocarcinoma and related mechanisms involved in pelvic lymph node metastasis. Immunohistochemistry was used to evaluate the expression of CXCR4 and the association of pelvic lymph node metastasis in archived tissue from clinical stage IB cervical adenocarcinomas (n = 37) and from benign specimens obtained at hysterectomy for other causes (n = 48). The HeLa cell (cervical adenocarcinoma-derived cell) line that expresses CXCR4 was used to study the interaction between the CXCR4 receptor and stromal cell-derived factor 1alpha (SDF-1alpha). Cell migration assays, cell numbers, flow cytometry, cell proliferation assay, and western blot were used to study the function of CXCR4 and its downstream signal transduction. The positive cases were semiquantitatively divided into three score classes according to their staining. Tumors with strong CXCR4 stainings were more likely to have pelvic lymph node metastasis than those with weak or negative stainings (87.5% vs 34.5%; P = 0.014). Only 25% of the benign specimens had weak or negative staining for CXCR4. Functioning CXCR4 receptor was expressed on HeLa cells. SDF-1alpha provoked significant signal transduction events, including chemotaxis and rescue from apoptosis. These actions were apparently mediated by the activation and phosphorylation of the extracellular signal-regulated kinase 1/2 and AKT pathways. We conclude CXCR4 expression is associated with cervical adenocarcinoma cell migration and proliferation, and primary cervical adenocarcinoma cells expressing CXCR4 are significantly more likely to metastasize to pelvic lymph nodes.

Purpose Point A, used for dose specification for intracavitary brachytherapy for cervical cancer, is the point at which the uterine artery and ureter cross. This study assessed compatibility of commonly used traditional point A (TPA) and actual anatomic point A (APA). Methods and Materials We visualized and placed radiopaque clips at the APA during pelvic and paraaortic lymphadenectomy in 11 patients with cervical carcinoma. Orthogonal and oblique radiographs were obtained after insertion of brachytherapy applicators. We measured the distance between the TPA and APA and estimated the brachytherapy dose to each of the two points. Results A total of 64 brachytherapy treatments were performed. The mean distances between the TPA and APA were 5.2 ± 1.0 cm on the right and 5.4 ± 1.1 cm on the left. The estimated brachytherapy doses delivered to the APA as a percentage of the presumed 500-cGy fraction size to the TPA were 35.2% (176.6 ± 59.0 cGy) on the right and 30.0% (150.2 ± 42.9 cGy) on the left. The marked discrepancy in the position of the two points was not related to individual kinetic variations during brachytherapy treatment, tumor size, or bladder filling. Conclusions The conventional TPA does not provide an accurate estimate of the APA determined during lymphadenectomy, indicating a need to reevaluate the current practice for determining the brachytherapy prescription for cervical cancer. ( ClinicalTrials.gov Identifier, NCT00319462)

Purpose. To evaluate the relation between tumor response, treatment toxicity, and serum cytokine profiles in patients with cervical cancer receiving cisplatin-based chemoradiation. Patients and Methods. Forty-two patients with cervical carcinoma receiving chemoradiation were recruited. Hemogram, biochemistry profile, cytokine levels, tumor size, and toxicity were assessed weekly. Results. The absolute neutrophil count decreased accompanied by an increase in serum levels of G-CSF during chemoradiation. The sudden elevation of serum TGF-β 1 and VEGF levels after the first fraction of brachytherapy accompanied with the development of greater radiation therapy (RT) morbidity. Lower pretreatment TGF-β 1 and VEGF levels are associated with tumor response to chemoradiation. Conclusion. The serial changes in serum cytokines during chemoradiation may correlate with tumor regression and treatment morbidity.

Nontyphoidal Salmonella infection in a patient with systemic lupus erythematosus (SLE) is rare.A 24-year-old woman with a 9-year history of SLE, on corticosteroids, presented with severe abdominal pain, fever, vomiting and diarrhea for 1 day. Transabdominal sonography and abdominal computed tomography showed a right-sided well-defined pelvic mass. Laboratory study revealed leukocytosis. An emergency laparotomy revealed a right ovarian mass with purulent exudate. A right partial oophorectomy was performed. Pathologic examination revealed a hemorrhagic ovarian cyst with focal abscess. Culture of the ovarian mass grew Salmonella typhimurium. Postoperatively the patient did well and was discharged 5 days later.Patients with SLE are at risk of Salmonella infection. Gynecologists should be aware of the possibility of an ovarian abscess caused by Salmonella in such patients presenting with a pelvic mass and fever.

Objective . The aim was to compare survival in pure and mixed-type advanced clear cell ovarian carcinoma and to determine the benefits among patients with pure advanced clear cell ovarian carcinoma treated in paclitaxel-platinum-based chemotherapy in comparison with those treated in conventional platinum-based chemotherapy after primary surgery. Methods . Between 1994 and 2001, 31 women with stage III and IV pure clear cell ovarian carcinoma and nine patients with stage III and IV mixed-type clear cell carcinoma were identified from the tumor registry of six institutions. All patients underwent cytoreductive surgery followed by conventional platinum-based chemotherapy or paclitaxel and platinum-based chemotherapy. Results . The median survival of women with pure clear cell carcinoma was 11 months, compared to 48+ months for those with mixed-type clear cell carcinoma ( P = 0.003). Overall, for women with pure clear cell carcinoma, 35% had clinically complete responses to chemotherapy. For women with pure clear cell carcinoma treated with paclitaxel-platinum-based chemotherapy, the median survival was significantly longer than for those treated with conventional platinum-based chemotherapy (16.26 vs. 10.75 months, P = 0.045; with optimal cytoreduction, 40.95 vs. 9.02 months, P = 0.028). Univariate analysis showed paclitaxel-platinum-based treatment was the only favorable prognostic factor for women with advanced pure clear cell ovarian carcinoma ( P = 0.05). Conclusions . Patients with advanced pure clear cell ovarian carcinoma have poorer prognoses than those with the mixed type. Paclitaxel-platinum-based chemotherapy improved survival among our patients with advanced pure clear cell carcinoma, especially for those with optimal cytoreduction.

Objective. A retrospective study was undertaken to evaluate the accuracy of frozen section diagnosis in gynecological surgery. Methods. We compared the results of 792 consecutive gynecological frozen section diagnoses with their final diagnoses from January 1991 to June 1996. Slides for which the frozen section diagnosis was uncertain or incompatible with the final diagnosis were reviewed by an attending pathologist to determine the possible causes. Results. A total of 299 ovarian, 390 lymph node, 56 uterine lesions, and 77 other tissue samples were obtained. The frozen section diagnosis was compatible with the final diagnosis in 97.5% of cases. The sensitivity for nonbenign lesions was 90.9%, and the specificity was 99.5%. There were no false positives or overestimated cases; 1.3% of cases were falsely negative, 0.4% underestimated the degree of malignancy, and 0.9% were uncertain. Possible causes for incompatible or uncertain frozen section diagnoses were analyzed. The accuracy of frozen section diagnoses for ovarian, lymph node, uterine, and other tissues was also evaluated. Frozen section was found to identify correctly 13 of 17 ovarian malignancies metastaic from other organs, 14 of 15 germ cell malignancies, and 3 of 4 dysgerminomas. The low sensitivity in ovarian borderline malignancy was due to the even lower sensitivity in its mucinous subgroup. The relationship between section numbers and accuracy of frozen section diagnosis in mucinous ovarian tumors was assessed. Conclusion. Frozen section diagnosis in gynecology is sufficiently accurate for clinical use, with a low false negative rate and an even lower false positive rate. Most incompatible frozen section diagnoses occurred in ovarian lesions, especially in mucinous ovarian tumors. Performing multiple sections (at least one section for every 10 cm in diameter) is recommended in the frozen section diagnosis of mucinous ovarian tumors.

Heavy menstrual bleeding, or menorrhagia, is subjectively defined as a “complaint of a large amount of bleeding during menstrual cycles that occurs over several consecutive cycles” and is objectively defined as menstrual blood loss of more than 80 mL per cycle that is associated with an anemia status (defined as a hemoglobin level of