Combined HPV 16 E2 and L1 methylation predict response to treatment with cidofovir and imiquimod in patients with vulval intraepithelial neoplasia.

BACKGROUND: Topical cidofovir and imiquimod can effectively treat approximately 55% of patients with vulval intraepithelial neoplasia (VIN), thus avoiding the need for surgery. Human papillomavirus (HPV) E⁢2 gene methylation predicts response to treatment but a methylation measurement is only obtainable in approximately 50% of patients. OBJECTIVE: This work aimed to determine if the applicability and predictive power of the E⁢2 methylation assay could be improved by combining it with the components of a host and viral DNA methylation panel (S5) that has been found to predict disease progression in patients with cervical intraepithelial neoplasia. METHODS: HPV E2 methylation and S5 classifier score were measured in fresh tissue samples collected pre-treatment from 132 patients with biopsy-proven VIN grade 3 who participated in a multicentre clinical trial and were randomised to treatment with cidofovir or imiquimod. RESULTS: Combining HPV16 E⁢2 and HPV16 L⁢1 methylation provides a biomarker that is both predictive of response to topical treatment and that can produce a clinically applicable result for all patients. Patients with HPV 16 L⁢1^high and HPV 16 E⁢2^high (36/132 (27.3%)) were more likely to respond to treatment with cidofovir (12/15 (80.0%)) than imiquimod (9/21 (42.9%)) (p= 0.026). Patients with HPV 16 L⁢1^low or HPV 16 E⁢2^low (including those with no HPV/unassessable methylation) were more likely to respond to imiquimod: 23/50 (46.0%) vs 31/46 (67.4%) (p= 0.035). CONCLUSIONS: Combined HPV E⁢2 and L⁢1 methylation is a potential predictive marker in treatment for all patients with VIN. These findings justify validation in a prospective trial.

International Gynaecological Cancer Society (IGCS) 2020 Annual Global Meeting: Twitter activity analysis.

OBJECTIVES: Twitter is the most frequently used social media platform by healthcare practitioners, at medical conferences. This study aimed to analyze Twitter conversations during the virtual International Gynecological Cancer Society 2020 conference to understand the interactions between Twitter users related to the conference. METHODS: Tweets using the hashtag '#IGCS2020' were searched using the Twitter Search Application Programming Interface (API) during the period 10-13 September 2020. NodeXL Pro was used to retrieve data. The Clauset-Newman-Moore cluster algorithm clustered users into different groups or 'clusters' based on how users interacted. RESULTS: There were 2009 registrants for the virtual IGCS 2020 conference. The total number of users within the network was 168, and there were 880 edges connecting users. Five types of edges were identified as follows: 'replies to' (n=18), 'mentions' (n=221), 'mentions in retweets' (n=375), retweets (n=198), and tweets (n=68). The most influential account was that of the IGCS account itself (@IGCSociety). The overall network shape resembled a community where distinct groups formed within the network. Our current analyses demonstrated that less than 10% of the total members interacted on Twitter. CONCLUSION: This study identified the most influential Twitter users within the '#IGCS2020' community. he results also confirmed the community network shape of the #IGCS2020 hashtag and found that the most frequent co-related words were 'ovarian' and 'cancer' (n=39).

Technique for inguino-femoral lymph node dissection in vulvar cancer: an international survey.

BACKGROUND: Vulvar cancer is a rare disease and despite broad adoption of sentinel lymph node mapping to assess groin metastases, inguino-femoral lymph node dissection still plays a role in the management of this disease. Inguino-femoral lymph node dissection is associated with high morbidity, and limited research exists to guide the best surgical approach. OBJECTIVE: To determine international practice patterns in key aspects of the inguino-femoral lymph node dissection technique and provide data to guide future research. METHODS: A survey addressing six key domains of practice patterns in performing inguino-femoral lymph node dissection was distributed internationally to gynecologic oncology surgeons between April and October 2020. The survey was distributed using the British Gynecological Cancer Society, the Society of Gynecologic Oncology, authors' direct links, the UK Audit and Research in Gynecology Oncology group, and Twitter. RESULTS: A total of 259 responses were received from 18 countries. The majority (236/259, 91.1%) of respondents reported performing a modified oblique incision, routinely dissecting the superficial and deep inguino-femoral lymph nodes (137/185, 74.1%) with sparing of the saphenous vein (227/258, 88%). Most respondents did not routinely use compression dressings/underwear (169/252 (67.1%), used prophylactic antibiotics at the time of surgery only (167/257, 65%), and closed the skin with sutures (192 74.4%). Also, a drain is placed at the time of surgery by 243/259 (93.8%) surgeons, with most practitioners (144/243, 59.3%) waiting for drainage to be less than 30-50 mL in 24 hours before removal; most respondents (66.3%) routinely discharge patients with drain(s) in situ. CONCLUSION: Our study showed that most surgeons perform a modified oblique incision, dissect the superficial and deep inguino-femoral lymph nodes, and spare the saphenous vein when performing groin lymphadenectomy. This survey has demonstrated significant variability in inguino-femoral lymph node dissection in cases of vulvar cancer among gynecologic oncology surgeons internationally.

Are trainees working in obstetrics and gynecology confident and competent in the care of frail gynecological oncology patients?

INTRODUCTION: Older patients undergoing cancer surgery are at increased risk of post-operative complications, prolonged hospital stay, and mortality. Identification of frailty can help predict patients at high risk of peri-operative complications and allow a collaborative, multidisciplinary team approach to their care. A survey was conducted to assess the confidence and knowledge of trainees in obstetrics and gynecology regarding identification and management of peri-operative issues encountered in frail gynecological oncology patients. METHODS: A web-based survey was distributed via the Audit and Research in Gynaecological Oncology (ARGO) collaborative and UK Audit and Research Collaborative in Obstetrics and Gynaecology (UKARCOG) . The survey on the management of frail peri-operative patients was disseminated to doctors-in-training (trainees) working in obstetrics and gynecology in the United Kingdom (UK) and Ireland. Specialty (ST1-7), subspecialty, and general practice trainees, non-training grade doctors, and foundation year doctors currently working in obstetrics and gynecology were eligible. Consultants were excluded. Study data were collected using REDCAP software hosted at the University of Manchester. Responses were collected over a 6-week period between January and February 2020. RESULTS: Of the 666 trainees who participated, 67% (425/666) reported inadequate training in peri-operative management of frail patients. Validated frailty assessment tools were used by only 9% (59/638) of trainees and less than 1% (4/613) were able to correctly identify all the diagnostic features of frailty. Common misconceptions included the use of chronological age and gender in frailty assessments. The majority of trainees (76.5%, 448/586) correctly answered a series of questions relating to mental capacity; however, only 6% (36/606) were able to correctly identify all three diagnostic features of delirium. A total of 87% (495/571) of trainees supported closer collaboration with geriatricians and a multidisciplinary approach. CONCLUSIONS: Obstetrics and gynecology trainees reported inadequate training in the peri-operative care of frail gynecological oncology patients, and overwhelmingly favored input from geriatricians. Routine use of validated frailty assessment tools may aid diagnosis of frailty in the peri-operative setting. There is an unmet need for formal education in the management of frail surgical patients within the UK and Irish obstetrics and gynecology curriculum.

Complication rates and lymph node count between two different skin incisions at time of inguino-femoral lymph node dissection in vulvar cancer.

INTRODUCTION: Inguino-femoral lymph node dissection plays a crucial role in the management of vulvar cancer. The procedure is associated with high complication rates, including infection, lymphocysts/lymphoedema and wound dehiscence. Several skin incision techniques exist and practice among gynecology oncologists is variable. Little evidence exists to guide surgeons regarding the optimal surgical approach. This study aimed to determine the difference in 30-day complication rates, number of lymph nodes and length of stay between patients undergoing the modified oblique and classical 'lazy S' skin incision. METHODS: A retrospective review between January 2014 and September 2018 was performed in the University Hospital of Wales, Cardiff. All cases of inguino-femoral lymph node dissection performed for vulvar cancer were included in the study without exclusion. Data collected included age, body mass index (BMI), incision type, suture material, length of hospital stay, complication rates, cancer stage, lymph node count, lymph node positivity rate and recurrence rates. Data were analyzed using SPSS software and clinical significance was set as p<0.05. RESULTS: Thirty-five cases of classical 'lazy S' and 14 cases of modified oblique were included in the analysis. The mean patient age was 65 years (range 41-86) in the classical 'lazy S' group and 58 years (range 19-81) in the modified oblique group. The mean BMI was 28 kg/m2 (range 18-45) in the classical 'lazy S' group and 29 kg/m2 (range 20-36) in the modified oblique group. In the classical 'lazy S' group, the stage classification was as follows: stage IB (18), II (2), IIIA (3), IIIB (4), IIIC (8). In the modified oblique group, the stage classification was: stage IB (8), II (4), IIIA (2). Grade 3-4 complications were statistically significantly more common after the classical 'lazy S' versus the modified oblique operation (20/35, 57.1% vs 2/14, 14.3%, p<0.02). Mean number of nodes harvested was statistically significantly higher in the classical 'lazy S' group compared with the modified oblique group (11.1 nodes, range 6-17 vs 7 nodes, range 4-11, p<0.001). Node positivity rate was higher in the classical 'lazy S' group compared with the modified oblique group (28.6% vs 10%, p=0.08). Mean hospital stay was statistically significantly longer in patients undergoing classical 'lazy S' versus modified oblique (10.7 vs 4.5 days, p=0.02). One case of groin node recurrence occurred and this patient was in the classical 'lazy S' arm. CONCLUSION: The rate of overall and serious complications was lower after modified oblique skin incision compared with classical 'lazy S'. However, the absolute lymph node count and lymph node positivity rate were higher in the 'lazy S' group.

Human Papillomavirus DNA Methylation Predicts Response to Treatment Using Cidofovir and Imiquimod in Vulval Intraepithelial Neoplasia 3.

Purpose: Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting.Experimental Design: DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing.Results: Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n = 30), median E2 methylation was significantly higher in patients who responded (P ≤ 0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n = 33), median E2 methylation was lower in patients who responded to treatment (P = 0.03; not significant after Bonferroni correction); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity.Conclusions: These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial. Clin Cancer Res; 23(18); 5460-8. ©2017 AACR.

Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT³VIN): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Vulval intraepithelial neoplasia is a skin disorder affecting the vulva that, if left untreated, can become cancerous. Currently, the standard treatment for patients with vulval intraepithelial neoplasia is surgery, but this approach does not guarantee cure and can be disfiguring, causing physical and psychological problems, particularly in women of reproductive age. We aimed to assess the activity, safety, and feasibility of two topical treatments--cidofovir and imiquimod--as an alternative to surgery in female patients with vulval intraepithelial neoplasia. METHODS: We recruited female patients (age 16 years or older) from 32 centres to an open-label, randomised, phase 2 trial. Eligibility criteria were biopsy-proven vulval intraepithelial neoplasia grade 3 and at least one lesion that could be measured accurately. We randomly allocated patients to topical treatment with either 1% cidofovir (supplied as a gel in a 10 g tube, to last 6 weeks) or 5% imiquimod (one 250 mg sachet for every application), to be self-applied three times a week for a maximum of 24 weeks. Randomisation (1:1) was done by stratified minimisation via a central computerised system, with stratification by hospital, disease focality, and presentation stage. The primary endpoint was a histologically confirmed complete response at the post-treatment assessment visit 6 weeks after the end of treatment (a maximum of 30 weeks after treatment started). Analysis of the primary endpoint was by intention to treat. Secondary outcomes were toxic effects (to assess safety) and adherence to treatment (to assess feasibility). We present results after all patients had reached the primary endpoint assessment point at 6 weeks; 2-year follow-up of complete responders continues. This trial is registered with Current Controlled Trials, ISRCTN 34420460. FINDINGS: Between Oct 21, 2009, and Jan 11, 2013, 180 participants were enrolled to the study; 89 patients were randomly allocated cidofovir and 91 were assigned imiquimod. At the post-treatment assessment visit, a complete response had been achieved by 41 (46%; 90% CI 37·0-55·3) patients allocated cidofovir and by 42 (46%; 37·2-55·3) patients assigned imiquimod. After 6 weeks of treatment, 156 (87%) patients (78 in each group) had adhered to the treatment regimen. Five patients in the cidofovir group and seven in the imiquimod group either withdrew or were lost to follow-up before the first 6-week safety assessment. Adverse events of grade 3 or higher were reported in 31 (37%) of 84 patients allocated cidofovir and 39 (46%) of 84 patients assigned imiquimod; the most frequent grade 3 and 4 events were pain in the vulva, pruritus, fatigue, and headache. INTERPRETATION: Cidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease. FUNDING: Cancer Research UK.

Increased methylation of Human Papillomavirus type 16 DNA correlates with viral integration in Vulval Intraepithelial Neoplasia.

BACKGROUND: Methylation of HPV16 DNA is a promising biomarker for triage of HPV positive cervical screening samples but the biological basis for the association between HPV-associated neoplasia and increased methylation is unclear. OBJECTIVES: To determine whether HPV16 DNA methylation was associated with viral integration, and investigate the relationships between viral DNA methylation, integration and gene expression. STUDY DESIGN: HPV16 DNA methylation, integration and gene expression were assessed using pyrosequencing, ligation-mediated PCR and QPCR, in biopsies from 25 patients attending a specialist vulval neoplasia clinic and in short-term clonal cell lines derived from vulval and vaginal neoplasia. RESULTS: Increased methylation of the HPV16 L1/L2 and E2 regions was associated with integration of viral DNA into the host genome. This relationship was observed both in vivo and in vitro. Increased methylation of E2 binding sites did not appear to be associated with greater expression of viral early genes. Expression of HPV E6 and E7 did not correlate with either integration state or increased L1/L2 methylation. CONCLUSIONS: The data suggest that increased HPV DNA methylation may be partly attributable to viral integration, and provide a biological rationale for quantification of L1/L2 methylation in triage of HPV positive cervical screening samples.

Bringing interdisciplinary and multicultural team building to health care education: the downstate team-building initiative.

PURPOSE: To evaluate the impact of the Downstate Team-Building Initiative (DTBI), a model multicultural and interdisciplinary health care team-building program for health professions students. METHOD: A total of 65 students representing seven health disciplines participated in DTBI's first three years (one cohort per year since implementation). During the 18-session curriculum, students self-evaluated their group's progress through Tuckman's four team-development stages (FORMING, STORMING, NORMING, PERFORMING) on an 11-point scale. Students completed matched pre- and postintervention program evaluations assessing five variables: interdisciplinary understanding, interdisciplinary attitudes, teamwork skills, multicultural skills, and team atmosphere. After participation, students completed narrative follow-up questionnaires investigating impact one and two years after program completion. RESULTS: Each year's team development curve followed a similar logarithmic trajectory. Cohort 1 remained in team development stage 3 (NORMING) while Cohorts 2 and 3 advanced into the final stage-PERFORMING. A total of 34 matched pre- and postintervention evaluations showed significant change in all major variables: Team atmosphere and group teamwork skills improved most (48% and 44%, respectively). Interdisciplinary understanding improved 42%. Individual multicultural skills (defined by ability to address racism, homophobia, and sexism) started at the highest baseline and improved the least (13%). Group multicultural skills improved 36%. Of 23 responses to the follow-up surveys, 22 (96%) stated DTBI was a meaningful educational experience applicable to their current clinical surroundings. CONCLUSIONS: DTBI successfully united students across health discipline, ethnicity, socioeconomic class, gender, and sexual orientation into functioning teams. The model represents an effective approach to teaching health care team building and demonstrates benefits in both preclinical and clinical years of training.