HPV 16 E2 binding sites 1 and 2 become more methylated than E2 binding site 4 during cervical carcinogenesis.

E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16/18 genome may exert either transcriptional activation/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter-proximal), and 4 (promoter-distal) were assessed by pyrosequencing and compared among HPV 16/18-positive cervical cancer, high-grade, and low-grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&2 methylation increased from high-grade lesions to cervical cancer (P < 0.001). HPV 16 E2BS4 methylation increased from low-grade to high-grade premalignant lesions (P = 0.041). Both HPV 18 E2BS1&2 and E2BS4 methylation increased from low-grade to high-grade Cervical Intraepithelial Neoplasia (P = 0.019 and 0.001 respectively) and further increased form high-grade lesions to cervical cancer (P < 0.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&2 (for transcriptional repression of E6/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low-grade to high-grade cervical premalignant lesions and from high-grade lesions to cervical cancer.

Expert consensus on improving iron deficiency anemia management in obstetrics and gynecology in Asia.

Iron deficiency anemia (IDA) is a major health burden among women in Asia. Key issues in IDA management in Asia are under-diagnosis and under-treatment. The lack of Asia-specific guidelines, and suboptimal utilization of treatment compounds the management of IDA. To address these gaps, a panel of 12 experts in obstetrics, gynecology, and hematology from six regions in Asia convened to review current practices and clinical evidence and provide practical guidance on IDA diagnosis and management in Asian women. The Delphi approach was used to obtain objective opinions and attain consensus on statements pertaining to awareness, diagnosis, and management of IDA. In total, 79 statements attained consensus and are summarized to provide guidance on raising awareness of IDA and approaches for improved diagnosis and treatment of IDA among women in various settings: pregnancy, postpartum, heavy menstrual bleeding, gynecologic cancers, and perioperative care. This clinician-led consensus integrates appropriate recommendations based on clinical evidence and best practices and is intended to guide decision making in the management of iron deficiency/IDA in women. The expert panel raises a call for timely diagnosis and utilization of appropriate treatment, including use of high-dose intravenous iron, stringent blood management, and interdisciplinary collaboration, for optimization of IDA management among women in Asia.

A combination of electroacupuncture and auricular acupuncture for postoperative pain after abdominal surgery for gynaecological diseases: A randomized controlled trial.

BACKGROUND: Postoperative pain following laparotomy for gynaecological diseases is a common problem that requires effective management to ensure patient satisfaction and recovery. Despite the wide use of acupuncture for pain management, knowledge of its efficacy in managing postoperative pain is limited. Previous literature used either acupuncture or auricular acupuncture alone. However, the combined use of acupuncture and auricular acupuncture have not been studied yet. PURPOSE: This study examined the efficacy and feasibility of combined electroacupuncture and auricular acupuncture compared to a sham control in reducing pain during 5 days after a laparotomy for gynaecological diseases. This combined therapy was hypothesized to provide greater pain reduction than previous studies with less frequent treatment. STUDY DESIGN: Randomized sham-controlled, patient- and- assessor-blinded trial. METHODS: This trial recruited 72 patients scheduled for laparotomy in Hong Kong. Either acupuncture (n = 36) or non-invasive sham acupuncture (n = 36) was performed on the patients preoperatively (1 session) and postoperatively (once a day, up to 6 sessions). The primary outcome was pain at rest, measured using a numerical rating scale from postoperative days 0-5. Secondary outcomes such as analgesics consumption were also assessed. A data and safety monitoring board (DSMB) was established. RESULTS: All 72 randomized patients were included in the analysis. The acupuncture group had a smaller pain score at rest at 22 hrs (mean = 2.6) than the sham control group (mean = 4.0) (Post hoc intention to treat analysis, Linear regression, mean difference = -1.4, 95% confidence interval = [-0.2] -2.7, p = 0.029). No statistically significant between-group difference was found in other outcomes. No serious adverse event was observed. CONCLUSION: Perioperative acupuncture treatments are safe and feasible, but the efficacy of acupuncture is inconclusive.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

Expression of deltaNp73 and TAp73alpha independently associated with radiosensitivities and prognoses in cervical squamous cell carcinoma.

PURPOSE: The p73 gene produces different protein isoforms using alternative promoters and splicing, which have different biological characteristics. This study was to investigate the expression patterns of two distinct p73 isoforms (deltaNp73 and TAp73alpha) in cervical squamous cell carcinomas (SCC) and the relationship between their expressions and prognostic significance in cervical SCC patients. EXPERIMENTAL DESIGN: We investigated the protein expressions of deltaNp73 and TAp73alpha in 117 cervical SCC and 113 normal cervical tissues using immunohistochemistry. The expression levels were analyzed with clinical variables and patients' survival. RESULTS: DeltaNp73and TAp73alpha were significantly overexpressed in cervical SCC compared with those in normal cervical epithelium (P < 0.001). However, their expressions were inversely correlated (P < 0.001, R = -0.368) and associated with differential tumor radiosensitivity. Overexpression of deltaNp73 was significantly found in SCC resistant to irradiation (P < 0.001), whereas increase of TAp73alpha expression was observed in the majority of SCC sensitive to irradiation (P < 0.001). Multivariate and survival analyses indicated that the expressions of deltaNp73 and TAp73alpha were independently associated with prognosis: deltaNp73 was associated with recurrence of the disease [P = 0.001; odds ratio (OR), 4.857] and an adverse outcome (P = 0.012; OR, 4.676), whereas TAp73alpha predicted a better survival of cervical SCC patients (P = 0.018; OR, 0.065). CONCLUSIONS: The p73 gene might be an important determinant of cellular response to irradiation. The expressions of the two main isoforms (deltaNp73 and TAp73alpha) might be potential markers for predicting the prognosis and sensitivity to radiotherapy in patients with cervical SCC.

Enhancement of the radiosensitivity of cervical cancer cells by overexpressing p73alpha.

Radiation therapy is the most effective therapy for cervical cancer in advanced stages. p53 plays a critical role in the cellular response to radiation-induced DNA damage. However, p53 function is often impaired in the presence of the oncoprotein E6 from human papillomavirus, which is often associated with the development of cervical cancer. p73, a p53 family member, is highly similar to p53, but is resistant to the degradation by human papillomavirus E6. In this study, we investigated the role of p73alpha in relation to cellular radiosensitivity in the p53-impaired cervical cancer cells. Radiosensitivity and irradiation-induced apoptotic cell death were examined in the exogenous overexpressed p73alpha- and p53-impaired cells. Our results showed that the endogenous p73alpha expressed only in the radiosensitive cervical cancer C4-1 cells, but not in the radioresistant SiHa, Caski, and HeLa cells. Overexpression of exogenous p73alpha by transfection in the radioresistant cells resulted in a significant increase of cellular sensitivity to radiation. Enhanced radiosensitivity in p73alpha-transfected cells was attributed by increase of cellular apoptosis. Coactivation of p21 was also observed in the p73alpha-transfected cells upon radiation treatment. In summary, our findings suggested that p73alpha is an important determinant of cellular radiosensitivity in the p53-impaired cervical cancer cells.

Randomized non-invasive sham-controlled pilot trial of electroacupuncture for postpartum depression.

BACKGROUND: Postpartum depression affects 10-15% of mothers. Although acupuncture was efficacious for major depressive disorder in pregnancy and in women outside the perinatal period, there has been no randomized controlled study on the feasibility, tolerability, and efficacy of acupuncture for postpartum depression. METHODS: This was a randomized, subject- and assessor-blind, parallel-group, sham-controlled trial. Twenty women within six months postpartum with DSM-IV-diagnosed major depressive disorder of mild severity, defined as a 17-item Hamilton Depression Rating Scale (HDRS(17)) score of 12 to 19, were randomly assigned to either electroacupuncture or non-invasive sham acupuncture two sessions weekly for four weeks. RESULTS: There was significant reduction in HDRS(17) score from baseline to 4-week posttreatment in both groups, with an effect size 1.4 and 1.8 for electroacupuncture and sham acupuncture, respectively. Improvement was observed as early as two weeks after commencing acupuncture. The response and remission rate in the electroacupuncture group at 4-week posttreatment was 33% and 44%, respectively; for the sham acupuncture group, it was 60% and 50%, respectively. There was no significant between-group difference in all outcome measures, including the HDRS(17), Edinburgh Postnatal Depression Scale, Hospital Anxiety and Depression Scale, Clinical Global Impression, and Sheehan Disability Scale. Treatment credibility, success of blinding, and adverse events were similar between groups. LIMITATION: Small sample size and high attrition rate. No waiting list observation group. CONCLUSION: Both electroacupuncture and non-invasive sham acupuncture were effective for postpartum depression. Further studies utilizing larger sample size, better recruitment strategies, and home-based acupuncture treatment are warranted. CLINICAL TRIAL INFORMATION: Pilot Study on the Use of Acupuncture for Postpartum Depression; ClinicalTrials.gov Registration #NCT01178008; URL - http://clinicaltrials.gov/ct2/show/NCT01178008?term=postpartum+acupuncture&rank=1.

Relationship between bone mineral density changes in pregnancy and maternal and pregnancy characteristics: a longitudinal study.

OBJECTIVE: The study aims to verify whether a progressive fall in bone mineral density (BMD) values can be demonstrated using quantitative ultrasound measurements of the os calcis. The BMD change during the pregnancy was then correlated with other maternal and pregnancy characteristics to identify any high-risk factors for bone loss in pregnancy. METHODS: Consecutive patients were recruited from a low-risk obstetric clinic over a period of 9 months. BMD measurements were performed at the os calcis before 18 weeks, between 28 and 32 weeks, and at 36-38 weeks using a Hologic Sahara Clinical Bone Sonometer system. A computer-derived BMD value was obtained with each measurement. Body fat composition was also measured using a Tanita 501 bioimpedance assay system. RESULTS: In a cohort of 780 patients, a mean fall in BMD of 0.040 g/cm2 was demonstrable across the trimesters. The difference in BMD across the three serial measurements was highly significant (p < 0.001). Univariate analysis showed that those with a low initial BMD, glucose intolerance and high body fat accumulation weight gain during the pregnancy had lower BMD loss, while gestational hypertension and obesity had no impact on the degree of BMD loss. Entering these parameters in a logistic regression analysis showed that the impact of glucose intolerance was lost, but that the other factors remained significant. A linear regression model of quantitative variables showed that only fat accumulation (p = 0.03) and early pregnancy BMD values (p < 0.001) remained significant factors associated with BMD loss. CONCLUSION: A gradual fall in BMD was demonstrable using ultrasound measurement of the os calcis from early to late pregnancy. Of the various parameters identified as significant factors affecting BMD loss in pregnancy, a low initial BMD in early pregnancy and high body fat accumulation during pregnancy appeared to be related to lower BMD loss.

Proliferation to apoptosis ratio as a prognostic marker in adenocarcinoma of uterine cervix.

OBJECTIVES: To determine the Mitotic Index (MI), Apoptotic Index (AI), the ratio of the two indices (MI/AI) in normal endocervical glands, adenocarcinoma in situ (AIS) and invasive adenocarcinoma of cervix, and to evaluate the relationship among these indices with various clinicopathological features. METHODS: The MI, AI and MI/AI ratio in cervical adenocarcinoma were evaluated based on: (1) cell morphology in hematoxylin and eosin-stained sections; (2) immunohistochemical study for Ki67 antigen and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL). Eighty cases of invasive adenocarcinoma and eighteen cases of adenocarcinoma in situ (AIS) adjacent to invasive adenocarcinoma were included. Adjacent normal endocervical epithelium in 26 cases of adenocarcinoma was included as control. RESULTS: The MI, AI and MI/AI in normal endocervical glands, AIS and invasive carcinomas showed statistically significant differences (P<0.001). A significant positive correlation was found between AI and MI, as assessed by morphological features (P<0.001) and immunohistochemistry (P=0.006). The MI/AI ratio, determined by morphology, significantly correlated with staging (P=0.023) and survival (P=0.0045). Multivariate survival analysis showed that both MI/AI ratio determined by morphology (P<0.001) and stage of tumor (P=0.03) had independent prognostic value in invasive adenocarcinoma. CONCLUSIONS: Tumor proliferation significantly correlated with apoptotic activity in cervical adenocarcinoma. The MI/AI ratio was an independent prognostic factor associated with patient survival. Histological determination of MI/AI ratio proved to be an economical and potentially useful adjunct in predicting clinical outcome of patients with cervical adenocarcinoma.