The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

An important role of genetic factors in the development of breast cancer (BC) or ovarian cancer (OC) in Taiwanese (ethnic Chinese) patients has been suggested. However, other than germline BRCA1 or BRCA2 mutations, which are related to hereditary breast-ovarian cancer (HBOC), cancer-predisposition genes have not been well studied in this population. The aim of the present study was to more accurately summarize the prevalence of genetic mutations in HBOC patients using various gene panels ranging in size from BRCA1/2 alone to multi-gene panels. Among 272 HBOC patients analyzed, the prevalence of BRCA1, BRCA2 and non-BRCA1/2 pathogenic mutations was 7.7% (21/272), 6.8% (16/236) and 8.2% (13/159), respectively. The total mutation rate was 18.4% (50/272). Although no founder mutations were identified in this study, two recurrent mutations, BRCA1 (c.3607C>T) and BRCA2 (c.5164_5165 delAG), were found. The main pathogenic/likely pathogenic mutations in non-BRCA1/2 genes included ATM, BRIP1, FANCI, MSH2, MUYTH, RAD50, RAD51C and TP53. The prevalence rate of gene mutations in HBOC patients did not differ with respect to whether BC or OC was the first diagnosis or they presented a family history of the disease or their age at diagnosis. HBOC patients with both BC and OC exhibited a higher prevalence rate of mutations (50.0%) than patients with OC (25.0%) or BC (8.6%) alone. In conclusion, evaluation of hereditary cancer risk in Taiwan HBOC patients, particularly individuals with double cancer, is strongly encouraged. Panel testing can yield additional genomic information, and widespread and well-designed panel testing will help in assessing more accurate mutational prevalence of risk genes.

Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma.

The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics.

Comparison of single-incision mini-slings (Ajust) and standard transobturator midurethral slings (Align) in the management of female stress urinary incontinence: A 1-year follow-up.

OBJECTIVE: To investigate the effectiveness and safety of a new single-incision mini-sling (SIMS)-Ajust-compared with the standard transobturator midurethral sling (SMUS)-Align-for the treatment of female stress urinary incontinence (SUI). MATERIALS AND METHODS: A retrospective cohort study was conducted between January 1, 2010 and August 31, 2012. Women with SUI who underwent either SMUS-Align or SIMS-Ajust were recruited. The primary outcomes included operation time, estimated operative blood loss, postoperative pain, and complications. The secondary outcomes included subjective and objective success, defined as an International Consultation on Incontinence Questionnaire (ICIQ) score of 0 or improvement as felt by the patient and a long-term complication, such as dyspareunia and mesh erosion after 6 months and 12 months of follow-up. RESULTS: A total of 136 patients were enrolled, including 76 receiving SMUS-Align and 60 receiving SIMS-Ajust. Baseline characteristics of the patients in both groups were similar, without a statistically significant difference. Primary outcomes between both groups were similar, except that women treated with SIMS-Ajust had statistically significantly shorter operation time (p = 0.003), less intent to treat (p < 0.05), and earlier postoperative discharge (p = 0.001) than women treated with SMUS-Align. Secondary outcomes were similar without a significant difference between the two groups (93% vs. 88% success rate in each group). CONCLUSION: Our results showed that SIMS-Ajust was not inferior to SMUS-Align with respect to success rate, and might have a slight advantage in early discharge. A long-term follow-up or prospective study is needed to confirm the above findings.

Noninvasive prenatal testing for fetal trisomy in a mixed risk factors pregnancy population.

OBJECTIVE: This study assesses the performance of noninvasive prenatal testing (NIPT) for fetal aneuploidies in a mixed risk factors pregnancy population. MATERIALS AND METHODS: Data review of 169 pregnant women undergoing prenatal aneuploidy screening in a single tertiary medical center was conducted. Indications included maternal anxiety, advanced maternal age, abnormal nuchal translucency, and high/moderate risk of first trimester Down syndrome screening. Multifetal pregnancies and patients receiving in vitro fertilization were also enrolled for analysis. RESULTS: A total of 169 patients were enrolled in this study during a time period from July 2012 to June 2014. For patients' ≥ 34 years, anxiety about amniocentesis was the most common reason for patients selecting NIPT for fetal aneuploidy screening, with 107 (88.4%) patients choosing NIPT for this reason. Among the total patient population, two patients showed a positive result from NIPT. One patient displayed 47, XXY, which was confirmed to be a false-positive result. The other patient displayed trisomy 18, which was confirmed by an amniotic cell culture. The sensitivity for NIPT is 100% with the specificity 99.4%. CONCLUSIONS: NIPT for fetal aneuploidy in a mixed risk factors pregnancy population showed high accuracy. NIPT applied to the low risk population might reassure the anxious family.

Robotic-assisted laparoscopic complex myomectomy: a single medical center's experience.

OBJECTIVE: Conventional laparoscopic myomectomy (LM) has inherent limitations due to its rigid structure. The robotic system is a newly developed technology equipped with a flexible EndoWrist that offers good performance in delicate motions. Our objective was to share our clinical experience in the management of complex myomectomy using this robotic system. MATERIALS AND METHODS: From October 2010 to March 2012, 21 patients with symptomatic complex uterine myomas were evaluated. Complex myomectomy was defined as surgery involving more than two fibroids, large fibroids, or preexisting pelvic adhesions. We recorded and analyzed the preoperative characteristics of the patients and the fibroids, the detailed surgical time, and several postoperative outcomes to evaluate the feasibility and efficacy of robotic-assisted LM (RALM) for complex fibroids. RESULTS: A total of 21 patients were enrolled in this study. The mean age of the patients was 40.1 ± 4.5 years and the mean size of the largest fibroid was 7.3 ± 3.5 cm. RALM achieved satisfactory results, including a short postoperative hospital stay (3.1 ± 0.9 days), a low conversion rate (none of our patients required conversion to either a minilaparotomy or conventional open surgery), and a low complication rate (1 case in 21 patients, 4.8%). The average estimated blood loss was 235.7 ± 283.3 mL. CONCLUSION: Our study results demonstrated that RALM is a safe and effective method for handling complex fibroids.

Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B.

Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Here we reveal a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late-state ovarian tumours, as compared with normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer.

Outcome of patients with bulky IB (≥ 6 cm) cervical squamous cell carcinoma with and without cisplatin-based neoadjuvant chemotherapy.

OBJECTIVE: To study the surgical morbidity and outcomes of patients with markedly bulky cervical squamous cell carcinoma (≥ 6 cm Cx-SCC) who underwent radical hysterectomy (RH) with and without neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: This retrospective study enrolled patients with International Federation of Gynecology and Obstetrics (FIGO) IB markedly bulky Cx-SCC who were treated with either three courses of weekly single agent cisplatin NACT (50 mg/m2) and subsequent radical hysterectomy (NACT-RH) or direct radical hysterectomy (RH) between 1996 and 2001. A total of 60 patients fulfilled the criteria, including 35 and 25 patients with NsACT-RH and RH, respectively. RESULTS: There was no statistically significant difference in basic characteristics between the two groups, except the smaller pathological tumor size, less blood loss, and lower immediate complication rate in the NACT-RH group. Median survival was 143.8 months in the NACT-RH group and 129.8 months in the RH group, respectively, without a statistically significant difference. Multivariate analysis showed that large pathological tumor size [hazard ratio (HR) 10.66, 95% confidence interval (CI) 2.93-38.80], the presence of para-aortic lymph node metastases and an immediate complication (HR 8.33 and 4.55, 95% CI 1.66-41.75 and 1.35-15.27, respectively) contributed to a worse outcome. CONCLUSION: Weekly single agent cisplatin NACT indeed reduced the pathological tumor size and immediate complication rate during the RH, supporting the feasibility of subsequent RH in the management of patients with bulky Cx-SCC.

Measurement of fetal maxillary and mandibular angles for first-trimester prenatal screening among Taiwanese women.

BACKGROUND: Early fetal structure evaluation is crucial. Fetal abnormalities might indicate chromosomal anomalies or abnormal fetal growth. The aim of this study was to establish the appropriate reference range of maxillary and mandibular angles among the Taiwanese population at 11(+0)-13(+6) weeks of gestation in normal singleton pregnancy as reference values for prenatal ultrasonographic examinations. METHODS: Fetal ultrasonographic data on maxillary angles and mandibular angles at a gestational age ranging from 11(+0) weeks to 13(+6) weeks were recorded in this study. Maternal background and pregnancy outcome were obtained from hospital records. RESULTS: A total of 87 patients were included in this study. Maxillary and mandibular angles were successfully recorded in 87 (100%) and 84 (96.6%) patients, respectively. The mean maternal age was 31 (range, 19-41) years, with a corresponding gestational age of 12(+4) (range, 11(+0)-13(+6)) weeks. The maxillary and mandibular angles were 79.9° ± 15.6° and 71.0° ± 12.8°, respectively. First-degree correlation was not found to exist between gestational age and maxillary and mandibular angles. CONCLUSION: Normative data for ultrasonographic measurements of maxillary and mandibular angles among the Taiwanese population are presented. Our results may serve as reference values in congenital anomaly screening during prenatal examination.

Umbilical artery Doppler velocimetry in normal pregnancies from 11(+0) to 13(+6) gestational weeks: a Taiwanese study.

OBJECTIVE: The aim of this study is to investigate the relationship between umbilical artery flow and gestational age (GA) at 11-13(+6) weeks in normal pregnancy in the Taiwanese population. MATERIALS AND METHODS: Two hundred and fifty-three normal singleton pregnancies with GA ranging from 11 to 13(+6) weeks were included in this study. The velocity of systolic, diastolic, and pulsatility index (PI) of the umbilical artery, and the mean velocity of the umbilical vein were recorded. RESULTS: One hundred and eighty-seven participants fulfilling the inclusion and exclusion criteria were analyzed. The mean maternal age was 31 (range 19-45) years, with a corresponding GA of 12(+4) (range 11-13(+6)) weeks. The absence of end-diastolic velocity of the umbilical artery was observed in most of our cases (90.1%). No significant change was found in the vascular indices with GA for the mean velocity of the umbilical vein (mean velocity = 0.923 × GA - 1.594, r = 0.1497, p = 0.115). The systolic velocity of the umbilical artery and PI, however, behaved differently from the other variables. There was a significant increase in systolic velocity with GA [systolic wave (S wave) velocity = 0.237 × GA + 2.267; r = 0.149, p = 0.041]. By contrast, the PI showed a significant decrease in relation to the GA (PI = -0.016 × GA + 4.068; r = 0.196, p = 0.007). CONCLUSION: The S-wave velocity of the umbilical artery increased with GA. By contrast, the PI of the umbilical artery showed a decreasing trend with GA. This may ensure optimal placental perfusion, which is necessary to accommodate the increased blood flow to the developing fetus. Furthermore, an absence of end-diastolic velocity in the first trimester and early second trimester was usually seen.

Clinicopathological features and survival in young Taiwanese women with endometrial carcinoma.

OBJECTIVE: The aim of this study is to compare the clinicopathological features and survival of young women with endometrial cancer (aged <50 years) with those of older women with endometrial cancer (aged ≥50 years). METHODS: We conducted a retrospective cohort study of patients with histologically confirmed endometrial cancer treated at the Taipei Veterans General Hospital from 2001 to 2010. RESULTS: One hundred forty-six patients (28.5%) were aged younger than 50 years at diagnosis. The median follow-up was 36.5 months (range, 0.9-121.7 months). Low body mass index (P < 0.001), nulliparity (P < 0.001), less medical illness (P < 0.001), synchronous primary ovarian cancer (P = 0.001), endometrioid type (P = 0.005), low tumor grade (P < 0.001), no para-aortic lymph node involvement (P < 0.047), less myometrial invasion (P < 0.001), and no vascular space invasion (P = 0.001) were common among the younger women compared with the older women. There were significant differences in the disease-free survival (P = 0.006) and overall survival (P = 0.004) between the 2 groups. In the multivariate Cox model, advanced stage had an effect on both disease-free survival (P = 0.004) and overall survival (P = 0.050). CONCLUSIONS: Nulliparity, body mass index less than or equal to 23 kg/m, endometrioid type, low-grade tumor, synchronous primary ovarian cancer, and favorable survival were common among the younger women.

Impact of ovarian preservation in women with endometrial cancer.

BACKGROUND: Bilateral salpingo-oophorectomy (BSO) is standardly performed in the treatment of endometrial cancer. The purpose of this study was to evaluate the impact of ovarian preservation on the outcome of patients with endometrial cancer. METHODS: A retrospective cohort study was performed using the 2000-2010 database of endometrial cancer patients who were treated at Taipei Veterans General Hospital. Information regarding patient age, pathologic reports, and follow-up results was abstracted from medical records. RESULTS: Five hundred and twenty-nine patients were reviewed in this study. Mean age and follow-up duration were 55.7 ± 11.4 years and 37.5 ± 30.1 months, respectively. The median disease-free survival was 31.2 months (range 0.2-126.9 months). There were no significant differences in disease-free survival between stage I patients with ovarian preservation versus those with oophorectomy (p = 0.473). In a multivariate Cox model, ovarian preservation had no effect on disease-free survival [hazard ratio (HR) = 2.72; 95% confidence interval (CI), 0.48-15.59]; however, it was not significantly related to stage and para-aortic lymph node involvement. CONCLUSION: Ovarian preservation may be considered in premenopausal women with early-stage low-risk endometrial cancer.

Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells.

Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen-associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial-mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug-VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2-Slug-VEGF pathway.

Hormone therapy for patients with advanced or recurrent endometrial cancer.

The "gold standard" treatment for endometrial cancer is completely staged surgery, followed by radiation or chemotherapy, based on the final pathological surgical stage and requirements. In the primary treatment of endometrial cancers, hormones are rarely taken into consideration after primary surgery. Primary treatment with hormones to preserve fertility in younger women with endometrial cancer is an attractive option, and many successful cases have been reported, although the majority of them finally received definite therapy, including total hysterectomy. The role of hormone therapy is often delayed in recurrent disease; response rates to progestins and tamoxifen or aromatase inhibitors in advanced/recurrent endometrial cancers are approximately 15-20% and nearly ≤ 10%, respectively. This review is focused on updated information and recent knowledge on the use of hormones in the management of women with advanced or recurrent endometrial cancers.

Fetal maxillary and mandibular length in normal pregnancies from 11 weeks' to 13(+6) weeks' gestation: a Taiwanese study.

OBJECTIVES: This study aims to establish the normal range of maxillary and mandibular lengths within the Taiwanese population at 11(+0) weeks to 13(+6) weeks of gestation in normal singleton pregnancy as a reference value for prenatal ultrasonographic examinations. MATERIALS AND METHODS: We examined nuchal translucency in 269 normal singleton pregnancies, with the gestational age ranging from 11 weeks to 13(+6) weeks in this study. Fetal biometric measurements, with an emphasis on maxillary and mandibular lengths, were obtained from the patients during consecutive routine prenatal ultrasonographic examinations. RESULTS: Maxillary and mandibular lengths were recorded successfully in 191 patients and 179 patients, respectively. The mean maternal age was 31 years (range 19-45 years), with a corresponding gestational age of 12 + 4 weeks (range, 11(+0)-13(+6) weeks). A first-degree correlation was found to exist between the gestational age and maxillary length (r = 0.596; p < 0.0001; y = 1.491 × GA - 10.523) as well as mandibular length (r = 0.465; p < 0.0001; y = 1.050 × GA - 6.50). CONCLUSION: Normative data for ultrasonographic measurements of maxillary and mandibular lengths within the Taiwanese population were presented. Our data can serve as a reference value in congenital anomaly screening during prenatal examination.

Global distribution pattern of histological subtypes of epithelial ovarian cancer: a database analysis and systematic review.

BACKGROUND: Epithelial ovarian cancer is basically a heterogeneous disease with different chemosensitivity and distinct molecular alternations for each histological subtype. In order to assess whether the results of clinical trials can be extrapolated to a new country, it is critical to first examine whether the relative frequencies is homogenous across countries. METHODS: Cancer registry database from a single institution in Taiwan combined with systematic review of the global literature on the relative frequencies of histological subtypes between 2003 and 2012 was provided. RESULTS: Of 175 titles identified, 41 studies met inclusion/exclusion criteria. Globally, for each subtype, the median value of relative frequencies for serous subtype was 45.0%, with the Philippines (16.0%), Indonesia (22.7%), and Brazil (30.1%) as the three lowest countries and South Africa (68.0%), Greece (71.5%), and India (86.7%) as the three highest countries; for mucinous subtype, 11.4%, Italy (3.0%), Australia (3.4%), and Japan (5.4%) were the three lowest countries, while Indonesia (29.1%), Singapore (30.3%), and South Korea (38.6%) were the three highest countries; for endometrioid subtype, 12.6%, India (1.6%), Greece (5.7%), and Portugal (7.6%) were the three lowest countries, while Taiwan (24.8%), Egypt (25.0%), and Austria (25.5%) were the three highest countries; and for clear cell subtype, 5.3%, Pakistan (1.0%), Iran (2.0%), and Brazil (2.1%) were the three lowest countries while Thailand (16.0%), Taiwan (16.8%), and Spain (18.8%) were the three highest countries. CONCLUSIONS: Relative frequencies of subtypes were not homogenous across countries. This diversity may reflect the geographical and ethnic variations. Globally, epithelial ovarian cancer is a heterogeneous disease with a heterogeneous distribution pattern.

Clinical presentation and outcome of adult-type granulosa cell tumors: a retrospective study of 30 patients in a single institute.

BACKGROUND: Ovarian adult-type granulosa cell tumors (GCTs) are characterized as low-malignant and late-recurrent ovarian tumors. Although some clinical and pathological prognostic factors have been reported, other factors have yet to be sufficiently investigated for necessary confirmation. The aim of this study was to test the correlation between clinical factors and outcome, based on patients seen in a single institute. METHODS: Thirty patients with pathologically confirmed adult-type GCTs between 1984 and 2010 were reviewed retrospectively. Among them, eight (26.7%) had recurrence, which subsequently contributed to two mortalities. RESULTS: In a comparison of the clinical characteristics of the premenopausal and postmenopausal women with GCT, all of the postmenopausal women had symptoms (100% vs. 63.6%, p = 0.01). With regard to disease recurrence, only abnormal preoperative serum cancer antigen 125 level (≥ 35 U/mL) was significant (50% vs. 11%, p = 0.03), and residual tumor showed a borderline trend (100% vs. 21.4%, p = 0.06). Other factors, including International Federation of Gynecology and Obstetrics stage, tumor size, tumor rupture prior to or during operation, body mass index, parity, serum estrogen level, and adjuvant therapy, were not statistically significant. CONCLUSION: Physicians should be alert to the difference in the symptom presentation of GCTs between pre- and postmenopausal women, giving particular attention to the usefulness of the preoperative serum level of cancer antigen 125 in patients with GCTs. More evidence is needed to confirm this observation.