Mandy Man Yee Chu

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. J. Med. Virol. 87:1022–1033, 2015.

Differentiation of aggressive and indolent subtypes of uterine sarcoma using maximum standardized uptake value

ObjectiveThe aim of the study was to elucidate the differential metabolic activities in aggressive and indolent subtypes of uterine sarcomas, which may aid in managing these heterogeneous tumours. MethodsWe retrospectively analysed the PET/computed tomography scans of consecutive patients (N=18) diagnosed with uterine sarcoma at our unit. The patients were divided into indolent (N=4) and aggressive (N=14) tumour groups, and the maximum standardized uptake values (SUVmax) of all lesions (n=134) were measured. The SUVmax of the lesions were compared between the two tumour groups using the Mann–Whitney U-test. We calculated the optimal cutoff value as determined by receiver operating characteristic analysis. A P-value less than 0.05 was considered statistically significant. ResultsThe mean SUVmax of aggressive (n=104) and indolent tumours (n=30) were significantly different (8.0±7.3 vs. 1.9±0.9 respectively; P<0.001). A cutoff of SUVmax greater than 4.0 was able to exclude indolent tumours, with 100% specificity and positive predictive value (sensitivity 72%, negative predictive value 50% and accuracy 78%; area under the curve 97%). By applying this same cutoff value on the most metabolic active lesion in each patient, we were able to correctly classify all but one patient into either the aggressive or indolent tumour group with 100% specificity and positive predictive value (sensitivity 93%, negative predictive value 80% and accuracy 94%). ConclusionAggressive and indolent uterine sarcoma subtypes have differential metabolic activities that can be used to classify them and this can aid in patient management for preoperative surgical planning and treatment stratification.

Modified symbolic play test for Oriental children

Background: Symbolic play test (SPT) is a simple test for screening preverbal language in children. This test had been validated in English‐speaking children. However, the toys may not be useful for other cultures such as Orientals like Chinese, Japanese, Koreans or Thais as they use chopsticks and bowls as eating utensils rather than spoon, fork or knife. The aim of this study was to find a set of miniature toys suitable for children of Oriental ethnic origin in order to get a reliable language test.

Cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine in the treatment of gestational trophoblastic neoplasia.

Objective The aim of this study was to evaluate the efficacy and toxicity profile of the cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine (CHAMOC) regimen in the treatment of high-risk gestational trophoblastic neoplasia (GTN). Methods We conducted a retrospective study of all patients with GTN treated with the CHAMOC regimen between 1985 and 2012 in a tertiary referral center in Hong Kong. Medical records were reviewed, and data were analyzed. Response rate and toxicity profile were assessed. Results The CHAMOC regimen was given to 79 patients from 1985 to 2012, with a total of 388 cycles administered. Among the 79 patients, CHAMOC was given to 68 as the primary treatment of high-risk GTN, whereas it was used as the salvage chemotherapy in 11 patients for failure with other chemotherapy regimens or recurrent disease. Complete remission was achieved in 58 patients (85.3%) in the primary treatment group and 8 patients (72.7%) in the salvage treatment group. Grade 3 and grade 4 neutropenia were observed in 13.0% and 3.4% of the chemotherapy cycles, respectively. Grade 3 or 4 thrombocytopenia was rare (1.3% of all treatment cycles). No secondary malignancy was observed in our patients with a mean duration of follow-up of 9.7 to 13 years, except 1 patient with advanced colon cancer diagnosed shortly after chemotherapy, which was unlikely to represent a secondary malignancy from the chemotherapy. Conclusions The CHAMOC regimen should be considered as an alternative to other chemotherapy regimens in the primary treatment of high-risk gestational trophoblastic disease, with comparable efficacy, similar short-term side-effects profile, and potentially fewer long-term complications.

The Significance of Mismatch Repair Deficiency in Young Patients With Endometrial Cancer.

The objective of this study was to identify the tumor characteristics associated with mismatch repair deficiency in young patients with endometrial carcinoma. Young patients (45 yr old or younger) with endometrial carcinoma treated by hysterectomy in our institution between July 2001 and June 2009 were identified. The clinical and pathologic data were obtained by review of clinical records. Among the 122 cases identified, paraffin sections were available in 67 cases for immunohistochemical staining and frozen tissue available in 62 cases for microsatellite instability (MSI) analysis. Both paraffin sections and frozen tissue were available in 36 cases. Among the 67 cases with immunohistochemical staining, 22 (32.8%) showed loss of expression of at least 1 mismatch repair protein. Defective MLH1 or MSH2 expression was associated with poor prognostic factors, including a higher incidence of pelvic lymph nodes metastasis (P=0.018) and higher stage (P=0.022) for MLH1, and an increased risk of lymphovascular permeation (P=0.015) for MSH2. On the contrary, defective MSH6 protein expression was associated with a lower incidence of high-grade tumors (P=0.04). Among the 62 cases with MSI analysis, 12 (19.4%) tumors were classified as microsatellite-high (MSI-H), whereas 2 (3.2%) were classified as microsatellite-low (MSI-L). There was no difference in the pathologic characteristics between MSI-stable and MSI-H tumor. We concluded that defective mismatch repair expression is important in young patients with endometrial carcinoma, with MSH6 protein being most commonly affected. The phenotype resulting from defective MSH6 expression was different from that caused by MLH1 or MSH2 loss.

Oncogenic microRNA signature for early diagnosis of cervical intraepithelial neoplasia and cancer

Cervical cancer is one of the leading causes of cancer death in women globally, despite the widespread use of cytology/human papillomavirus (HPV) screening. In the present study, we aimed to identify the potential role of microRNA (miRNA) as a diagnostic biomarker in the detection of cervical pre‐malignant lesions and cancer. In total, we recruited 582 patients with cervical diseases and 145 control individuals. The expression levels of six miRNAs (miR‐20a, miR‐92a, miR‐141, miR‐183*, miR‐210 and miR‐944) were found to be significantly up‐regulated in cervical cancer and pre‐malignant lesions compared to normal cervical samples, indicating that they are oncogenic miRNAs. Receiver operating characteristic curve analysis showed that these six miRNAs can be used to distinguish patients with cervical pre‐malignant lesions or cancer from normal individuals and they also had a good predictive performance, particularly in cervical lesions. Combined use of these six miRNAs further enhanced the diagnostic accuracy over any single miRNA marker, with an area under the curve of 0.998, 0.996 and 0.959, a diagnostic sensitivity of 97.9%, 97.2% and 91.4%, and a specificity of 98.6%, 96.6% and 87.6% for low‐grade lesions, high‐grade lesions and cancer, respectively. This six oncogenic miRNA signature may be suitable for use as diagnostic marker for cervical pre‐malignant lesions and cancer in the near future.

A Case Series of Five Patients With Pure or Mixed Gestational Epithelioid Trophoblastic Tumors and a Literature Review on Mixed Tumors.

Objectives To review the clinicopathologic features of five patients with epithelioid trophoblastic tumor (ETT). Methods Characteristics of patients diagnosed with ETT in 2000 to 2012 were reviewed. Results Among 190 patients with gestational trophoblastic neoplasia (GTN), two had pure ETT and three had mixed ETT and choriocarcinoma. The median age was 32.5 years. All the patients had localized disease in the uterus. One patient with pure ETT had a recurrence in the ureter 6 years after the initial treatment. Another patient with pure ETT had two full-term deliveries after fertility-sparing surgery. The three patients with mixed tumors had chemotherapy for GTN before their diseases were completely treated by hysterectomy. At a median follow-up of 102 months, all patients survived. Conclusions ETT is indolent. Recurrence can happen, but the risk factors are not clear. When patients with GTN fail to respond to chemotherapy, the possibility of mixed GTN should be considered.

Impact of different educational interventions on psychosocial well-being of women with a positive high-risk human papillomavirus and normal cervical cytology: a randomised trial

Abstract Introduction: The aim of this study was to compare the effect of two educational interventions on the psychosocial well-being of Hong Kong Chinese women who have a positive high-risk human papillomavirus (HPV) test and normal cervical cytology. Methods: Participants were randomised into either leaflet group, in which a written HPV factsheet was provided; or counselling group, in which a didactic HPV presentation in person in addition to the factsheet was provided. Women’s psychological conditions were assessed by self-administered questionnaires at pre, post (within one week) and 6 months after the educational interventions. Main outcome measures were psychosocial well-being (cervical cancer worry, anxiety and depression, screening-related anxieties, HPV-related shame) and knowledge of cervical screening and HPV. Results: Data from 121 women (52 in leaflet group; 69 in counselling group) were analysed. There was no significant difference in the psychosocial well-being between the two groups at alltime points. Irrespective of the two educational interventions, cervical cancer worry and anxiety decreased over time. The counselling group had a significantly higher score in knowledge of cervical screening and HPV compared with leaflet group (mean score 4.65 ± 0.19 versus 3.71 ± 0.23, p = 0.002) at post-educational intervention, but there was no significant difference (mean score 4.14 ± 0.22 versus 3.58 ± 0.24, p = 0.084) at 6 months. Discussion: Both educational interventions were comparable in relieving adverse HPV-related psychosocial effects. Combination of counselling and leaflet were more effective than leaflet only in improving women’s knowledge on cervical screening and HPV soon after educational interventions but the benefit was not apparent after 6 months.