Out-reach Colposcopy Clinics and HPV Self-Sampling Decreases Loss to Follow up in a Community based Cervical Cancer Screening Programme.

OBJECTIVE: To introduce HPV self-sampling and out-reach colposcopy clinic as interventions to improve the follow-up of HPV positive women in a community based cervical cancer screening programme. METHODS: This was a prospective observational study conducted during October 2017 to August 2019 and 2977 women underwent cervical cancer screening using CareHPV test. Follow up colposcopy for HPV positive women were conducted at the rural health center and alternatively as out-reach clinics in their own villages and default rates were compared. HPV positive women were followed up at one-year. They were given an option of either having a follow-up HPV test performed by a health care worker (HCW) or by self-sampling. Compliance to follow up in these two modalities were compared. A validated questionnaire was given to women who had given an HPV self-sample to assess their awareness about HPV and cervical cancer. RESULTS: During our initial round of cervical cancer screening using HPV as a primary screening modality, our HPV screen positive rate was 7.05% (210 out of 2977 women screened).  Our colposcopy rates following an initial invitation at the rural health centre was only 28.5%. Following this, we initiated out-reach colposcopy clinics at their own villages for HPV positive women and this increased colposcopy rates from 28.5% to 45.2%. The participation rate at one-year follow-up was increased from 40.5% to 60% by the introduction of self-sampling as a follow up option and 16.2% of women who were initially positive remained HPV positive at 12-14 months follow up. All women who were offered the option of self-sampling preferred it over a HCW collected sample. CONCLUSION: Our study showed that self-sampling could also be used effectively in the follow up of HPV positive women in the community. Outreach colposcopy clinics in their own villages enabled better follow up of HPV positive women.

Cervical Cancer Screening Coverage at Tertiary Care Institutes Across India.

OBJECTIVES: The 70% screening coverage target proposed in the global cervical cancer elimination strategy is not achieved even at tertiary centres in India. A situational analysis was done to assess the currently existing facilities and barriers in tertiary care institutes. METHODS: This cross sectional multicentric study was conducted from August to September 2021 in six tertiary care institutes across India. Women aged 30-49 years attending outpatient services (OPD) were invited for cervical screening. Women and health care professionals (HCPs) were administered structured questionnaires to assess knowledge, attitude and practices regarding cervical cancer screening services. RESULTS: Out of 6709 eligible women who attended OPD, 1666 (24.8%; range:19-57%) received screening. Availability of screening kits was limited to 10-25 Pap/HPV tests per day. Visual inspection with acetic acid (VIA) and HPV testing were offered only at certain centres. Colposcopy and treatment facilities were optimal at all centres. Knowledge, attitude and practices were analysed for 1800 women: 45.7% had heard of cervical cancer, 78.0% did not know that it is preventable, 75.8% never heard about screening. Common symptoms correctly identified included postmenopausal bleeding (4.8%), postcoital bleeding (5.7%), intermenstrual bleeding (5.8%) and vaginal discharge (12.4%). Risk factors were identified by minority: poor menstrual hygiene (6.6%), oral contraceptive pill use (6.4%), multiparity (4.4%), and HPV infection (3.0%). Out of 21, mean total knowledge score (MTKS) was 2.07± 2.67. Out of 317 HCPs, 96.5% knew that cervical cancer is caused by HPV infection, is preceded by premalignant stage, and that it is preventable by screening and treatment (80.1%). Knowledge about screening modalities was present in 87.4% for cytology, 75.1% for VIA, 68.8% for HPV test. MTKS of HCPs was 20.88±6.61 out of 32. CONCLUSION: Even at tertiary centres, limited availability of HPV tests, reluctance to implement VIA and lack of awareness among women remain the major barriers.

Immunogenicity and safety of a new quadrivalent HPV vaccine in girls and boys aged 9-14 years versus an established quadrivalent HPV vaccine in women aged 15-26 years in India: a randomised, active-controlled, multicentre, phase 2/3 trial.

BACKGROUND: To meet global cervical cancer elimination efforts, a wider range of affordable and accessible vaccines against human papillomavirus (HPV) are needed. We aimed to evaluate the immunogenicity and safety of a quadrivalent HPV vaccine (targeting HPV types 6, 11, 16, and 18), developed and manufactured by the Serum Institute of India (SIIPL). Here we report outcomes in the 9-14 years cohort. METHODS: This randomised, active-controlled, phase 2/3 trial was conducted at 12 tertiary care hospitals across India. Healthy participants aged 9-14 years or 15-26 years with no history of HPV vaccination were eligible for enrolment. Female participants were randomly assigned (1:1) with an interactive web response system, by use of a central computer-generated schedule and block randomisation (block sizes of 2, 4, 6, and 8), to receive the SIIPL quadrivalent HPV vaccine (Cervavac; SIIPL, Pune, India) or the comparator quadrivalent HPV vaccine (Gardasil; Merck Sharp & Dohme, Harleem, the Netherlands). Participants, investigators, laboratory technicians, and sponsors were masked to treatment allocation of female participants. Male participants were given the SIIPL quadrivalent HPV vaccine in an open-label manner. Study vaccines were administered intramuscularly with a two-dose schedule (at day 0 and 6 months) in the cohort aged 9-14 years, and with a three-dose schedule (at day 0, month 2, and month 6) in the cohort aged 15-26-years. Immunogenicity was assessed 30 days after the last dose by use of multiplexed ELISA. The primary outcome was the non-inferiority of immune response in terms of the geometric mean titre (GMT) of antibodies against HPV types 6, 11, 16, and 18 generated by the SIIPL quadrivalent HPV vaccine in girls and boys (aged 9-14 years) compared with the GMT generated by the comparator quadrivalent HPV vaccine in women aged 15-26 years at month 7 in the modified per-protocol population (ie, all participants who received all doses of study vaccines per assigned treatment group and had both day 0 and 1-month immunogenicity measurements after the last dose following protocol-defined window periods with no major protocol deviations). Non-inferiority was established if the lower bound of the 98·75% CI of the GMT ratio was 0·67 or higher. The co-primary outcome of occurrence of solicited adverse events (within 7 days of each dose) and unsolicited adverse events (up to 30 days after the last dose) was assessed in all participants who were enrolled and received at least one dose of study vaccine. The trial is registered with the Clinical Trials Registry - India (CTRI/2018/06/014601), and long-term follow-up is ongoing. FINDINGS: Between Sept 20, 2018, and Feb 9, 2021, 2341 individuals were screened, of whom 2307 eligible individuals were enrolled and vaccinated: 1107 (738 girls and 369 boys) in the cohort aged 9-14 years and 1200 (819 women and 381 men) in the cohort aged 15-26 years. No race or ethnicity data were collected. 350 girls and 349 boys in the SIIPL quadrivalent HPV vaccine group and 338 women in the comparator vaccine group were included in the modified per-protocol population for the primary endpoint analysis. The median follow-up for the analyses was 221 days (IQR 215-231) for girls and 222 days (217-230) for boys in the SIIPL quadrivalent HPV vaccine group, 223 days (216-232) for girls in the comparator vaccine group, and 222 days (216-230) for women in the comparator vaccine group. GMT ratios were non-inferior in girls and boys receiving the SIIPL quadrivalent HPV vaccine compared with women receiving the comparator vaccine: GMT ratios for girls were 1·97 (98·75% CI 1·67-2·32) for HPV type 6, 1·63 (1·38-1·91) for HPV type 11, 1·90 (1·60-2·25) for HPV type 16, and 2·16 (1·79-2·61) for HPV type 18. For boys the GMT ratios were 1·86 (1·57-2·21) for HPV type 6, 1·46 (1·23-1·73) for HPV type 11, 1·62 (1·36-1·94) for HPV type 16, and 1·80 (1·48-2·18) for HPV type 18. The safety population comprised all 1107 participants (369 girls and 369 boys in the SIIPL quadrivalent HPV vaccine group, and 369 girls in the comparator group). Solicited adverse events occurred in 176 (48%) of 369 girls and 124 (34%) of 369 boys in the SIIPL vaccine group and 179 (49%) of 369 girls in the comparator vaccine group. No grade 3-4 solicited adverse events occurred within 7 days of each dose. Unsolicited adverse events occurred in 143 (39%) girls and 147 (40%) boys in the SIIPL vaccine group, and 143 (39%) girls in the comparator vaccine group. The most common grade 3 unsolicited adverse event was dengue fever, in one (<1%) girl in the SIIPL vaccine group and three (1%) girls in the comparator group. There were no grade 4 or 5 adverse events. Serious adverse events occurred in three (1%) girls and three (1%) boys in the SIIPL vaccine group, and five (1%) girls in the comparator vaccine group. No vaccine-related serious adverse events were reported. There were no treatment-related deaths. INTERPRETATION: We observed a non-inferior immune response with the SIIPL quadrivalent HPV vaccine in girls and boys aged 9-14 years and an acceptable safety profile compared with the comparator vaccine. These findings support extrapolation of efficacy from the comparator vaccine to the SIIPL quadrivalent HPV vaccine in the younger population. The availability of the SIIPL quadrivalent HPV vaccine could help meet the global demand for HPV vaccines, and boost coverage for both girls and boys globally. FUNDING: Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), Government of India, and Serum Institute of India.

A Feasibility Study of Sentinel Lymph Node Biopsy in Endometrial Cancer Using Technetium 99m Nanocolloid.

To study the feasibility of sentinel node biopsy in early-stage endometrial cancer and to analyse the detection rate of sentinel lymph node (SLN) using preoperative cervical injection of Tc99m nanocolloid. Thirty-five patients with preoperative histological diagnosis of endometrial cancer without any extrauterine involvement on imaging were included in the study. Sentinel node mapping was done by cervical injection of Tc99m nanocolloid on the evening before surgery. Scintigraphic images were taken using gamma camera. Intraoperatively, nodes showing radioactivity were detected using hand-held gamma probe, dissected out separately and labelled as sentinel lymph nodes. Detection rate was calculated and analysed with respect to various parameters. Sentinel lymph node biopsy (SLNB) is feasible in endometrial cancer using cervical injection of Tc99m nanocolloid. SLN detection was done in 33 (94.3%) out of 35 patients. Bilateral detection was feasible in 19 patients (54.3%) with detection in left and right hemipelvis being 74.3%. Detection rate of SLN was 93.7% in endometrioid adenocarcinoma. Sentinel node was detected in all the patients with non-endometrioid histology. The SLNB using cervical injection of Tc99m nanocolloid is feasible in endometrial cancer. It is a safe and easily reproducible technique with good detection rate and high sensitivity. Stage of the tumour, grade and myometrial invasion do not seem to have an influence on sentinel node detection. Cervical involvement, enlarged lymph nodes and obstructed lymphatics can affect sentinel node mapping adversely.

Differences in hand movements and task completion times between laparoscopic, robotically assisted, and open surgery: an in vitro study.

Surgical dexterity depends on economy and precision of movements, and this can be objectively measured using electromagnetic motion analysis. We have assessed the differences in hand movements and task completion times between open, laparoscopic and robotically assisted surgery during an exercise performed in vitro. A standard surgical exercise was performed using open, standard laparoscopic (SL) and robotically assisted laparoscopic (RAL) approaches. The total duration of the exercise was studied along with the number and duration of movements required to complete the exercise in each surgical modality. The time taken to complete the exercise was significantly longer in both the SL and RAL approaches when compared to the open route. However, it was found that RAL had significantly decreased number of movements (mean difference = 24 movements, P < 0.006) but a longer duration of each movement when compared to SL (mean difference = 0.13 s, P < 0.001). This study shows objectively that the exercise took longer to complete using the RAL approach than the standard open approach. However, RAL had more purposeful movements and required fewer movements to complete the exercise compared to SL.

The detection of cervical intraepithelial neoplasia by electrical impedance spectroscopy: the effects of acetic acid and tissue homogeneity.

OBJECTIVE: To evaluate the efficacy of an electrical impedance probe (Epitheliometer) in the diagnosis of high grade cervical intraepithelial neoplasia (CIN) in women referred with cervical smear abnormalities and to assess the effect of acetic acid (AA) and tissue boundaries on the measurements. METHODS: A prospective observational study was undertaken in the colposcopy clinic. One hundred and sixty-five women, either with a clinical indication or abnormal cervical cytology, were recruited into the study. A pencil type probe was used to record impedance spectra from 12 points on the cervix before and after the application of 5% AA. Spectra were also recorded from tissue boundaries. Colposcopic examinations, including probe positioning, were video recorded to allow for correlations between histopathological diagnosis of colposcopically directed biopsies, colposcopic impression and the diagnosis based on impedance measurements. RESULTS: Receiver operating characteristic (ROC) curves were derived. The areas under the curves (AUCs) to discriminate original squamous from high grade CIN were 0.80 (pre AA) and 0.79 (post AA). Comparison of these curves showed no significant difference, indicating that application of AA does not produce a large change in spectra. The probe could distinguish tissue boundaries from homogeneous tissue points. CONCLUSION: The Epitheliometer has the potential to be used as an adjunct to colposcopy in the diagnosis of high grade CIN. It has the advantage of real time results, decreasing the need for diagnostic cervical biopsies, and facilitates a wider use of the 'see and treat' policy without the risk of overtreatment.

Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis.

Aberrant DNA methylation is a recognized feature of human cancers, and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also suggest that folate status is associated with the natural history of human papillomavirus (HPV) infection. A cross-sectional study was conducted to test the hypothesis that folate status and aberrant DNA methylation show a progressive change across stages of cervical pathology from normal cells to cervical cancer. Additionally, we postulated that a gene-specific hypermethylation profile might be used as a predictive biomarker of cervical cancer risk. DNA hypermethylation of seven tumor suppressor genes, global DNA hypomethylation, systemic folate status, and HPV status were measured in 308 women with a diagnosis of normal cervix (n = 58), low-grade cervical intraepithelial neoplasia (CIN1; n = 68), high-grade cervical intraepithelial neoplasia (CIN2, n = 56; and CIN3, n = 76), or invasive cervical cancer (ICC; n = 50). Lower folate status was associated with high-risk HPV infection (P = 0.031) and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (P < 0.05). Global DNA hypomethylation was greater in women with invasive cervical cancer than all other groups (P < 0.05). A cluster of three tumor suppressor genes, CDH1, DAPK, and HIC1, displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (P < 0.05). These findings are compatible with a role for folate in modulating the risk of cervical cancer, possibly through an influence over high-risk HPV infection. DAPK, CDH1, and HIC1 genes are potential biomarkers of cervical cancer risk.