Perceived barriers to self-collected HPV testing for cervical cancer screening, and knowledge of HPV: a survey of primary healthcare smear-takers across Aotearoa New Zealand.

AIMS: Cervical cancer remains a burden within Aotearoa New Zealand, with 2022 screening rates sitting 12.7% below target. The National Cervical Screening Programme has changed to primary human papillomavirus (HPV) testing for all screen-eligible people, with the aim for home self-testing. Little is known about the readiness of primary care for the change to self-testing and its associated challenges. A pilot HPV cervical cancer screening programme is being conducted in 17 practice centres. The aim of this study is to explore smear-taker knowledge at these centres about the use of primary HPV testing for cervical cancer screening. METHODS: This is an ethically approved questionnaire study, with data from a structured web-based questionnaire sent to all smear-takers at the pilot centres. RESULTS: We achieved a total completion rate of 57.8%. The average score for "Knowledge of HPV" was 56.5% (range=20-100%). The challenges to patient home HPV self-testing were felt to be overall "not at all" to "mildly challenging". Up to 73.3% of participants identified ongoing needs for further education. CONCLUSIONS: The findings indicate knowledge deficits regarding HPV testing for cervical cancer screening and a desire for the provision of further education. Overall, respondents felt that no major barriers to implementing HPV self-testing would occur.

Direct oral anticoagulants (DOACs) use for prolonged venous thromboembolism prophylaxis following surgery for gynaecological malignancies in Australia and New Zealand - A clinician survey.

BACKGROUND: Current international guidelines recommend 28 days of enoxaparin as venous thromboembolism (VTE) prophylaxis after surgery for gynaecologic cancer. Direct oral anticoagulants (DOACs) have been investigated as an alternative to enoxaparin for post-operative VTE prophylaxis. High-quality evidence to demonstrate safety and efficacy is lacking. AIMS: We aim to investigate the current practice regarding VTE prophylaxis among gynaecological oncologists in Australia and New Zealand following laparotomy for gynaecological malignancy, in particular the use of DOACs for VTE prophylaxis. MATERIALS AND METHODS: Sixty-seven practising gynaecologic oncologists (GO) were identified through Royal Australia and New Zealand College of Obstetricians and Gynaecologists database and emailed online surveys that asked about VTE prophylaxis practice and views of DOACs in this setting. Data were then collected through Survey Monkey and evaluated. RESULTS: The majority (77.1%) routinely prescribed 28 days of enoxaparin following laparotomy for gynaecological malignancies. In clinical circumstance such as laparoscopy for gynaecological malignancies and surgery for vulva malignancies, there was variation in thromboprophylaxis practices. No GO reported routine use of DOACs in any clinical circumstance. There were 56% of GOs who used a DOAC in their practice at some point. Barriers to routine use of DOACs in current practice included insufficient evidence (68%), issue with cost (40.4%) and concerns about safety (29.7%). CONCLUSIONS: Enoxaparin prescribed for 28 days remains the current clinical practice in preventing VTE following laparotomy for gynaecological malignancy. The main barrier to routine DOAC use as post-operative thromboprophylaxis is a lack of evidence which reflects the need for a larger prospective study.

A Model for Empowering Rural Solutions for Cervical Cancer Prevention (He Tapu Te Whare Tangata): Protocol for a Cluster Randomized Crossover Trial.

BACKGROUND: Maori are the Indigenous people of Aotearoa (New Zealand). Despite global acceptance that cervical cancer is almost entirely preventable through vaccination and screening, wahine Maori (Maori women) are more likely to have cervical cancer and 2.5 times more likely to die from it than non-Maori women. Rural Maori residents diagnosed with cervical cancer have worse outcomes than urban residents. Living in rural Aotearoa means experiencing barriers to appropriate and timely health care, resulting from distance, the lack of community resourcing, and low prioritization of rural needs by the health system and government. These barriers are compounded by the current screening processes and referral pathways that create delays at each step. Screening for high-risk human papillomavirus (hrHPV) and point-of-care (POC) testing are scientific advances used globally to prevent cervical cancer. OBJECTIVE: This study aims to compare acceptability, feasibility, timeliness, referral to, and attendance for colposcopy following hrHPV detection between a community-controlled pathway and standard care. METHODS: This is a cluster randomized crossover trial, with 2 primary care practices (study sites) as clusters. Each site was randomized to implement either pathway 1 or 2, with crossover occurring at 15 months. Pathway 1 (community-controlled pathway) comprises HPV self-testing, 1-hour POC results, face-to-face information, support, and immediate referral to colposcopy for women with a positive test result. Pathway 2 (standard care) comprises HPV self-testing, laboratory analysis, usual results giving, information, support, and standard referral pathways for women with a positive test result. The primary outcome is the proportion of women with hrHPV-positive results having a colposcopy within 20 working days of the HPV test (national performance indicator). Qualitative research will analyze successes and challenges of both pathways from the perspectives of governance groups, clinical staff, women, and their family. This information will directly inform the new National Cervical Screening Program. RESULTS: In the first 15-month period, 743 eligible HPV self-tests were performed: 370 in pathway 1 with POC testing and 373 in pathway 2 with laboratory testing. The positivity rate for hrHPV was 7.3% (54/743). Data collection for the second period, qualitative interviews, and analyses are ongoing. CONCLUSIONS: This Maori-centered study combines quantitative and qualitative research to compare 2 clinical pathways from detection of hrHPV to colposcopy. This protocol draws on rural community practices strengths, successfully engaging Maori from a whanau ora (family wellness) approach including kanohi ki te kanohi (face-to-face), kaiawhina (nonclinical community health workers), and multiple venues for interventions. It will inform the theory and practice of rural models of the use of innovative technology, addressing Maori cervical cancer inequities and facilitating Maori wellness. The findings are anticipated to be applicable to other Indigenous and rural people in high-income countries. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000553875; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621000553875. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51643.

The High-Risk Human Papillomavirus Type Influences the Tissue Microenvironment in Cervical Intraepithelial Neoplasia Grade 2.

High-risk, cancer-causing human papillomavirus (HPV) types are associated with cervical precancer and cancer. A high proportion of high-risk HPV precancer lesions undergo immune-mediated regression. The purpose of this study was to determine if the tissue microenvironment of HPV16 and 18 (HPV16/18) cervical intraepithelial neoplasia grade 2 lesions differed from other high-risk types (HPV 'other'). Consistent with other studies, we found that progression to higher-grade disease was more frequent in HPV16/18 lesions when compared with HPV 'other' lesions. HPV16/18 lesions were significantly more likely to be indoleamine 2,3,-dioxygenase 1 (IDO1)-positive and were associated with reduced CD8 and FoxP3 T cells in the lesion. In the stroma, reduced Tbet- and CD32-positive cells and increased Blimp1-positive cells were significantly associated with HPV16/18 lesions when compared with HPV 'other' types. On analysis of the IDO1-positive tissues, lesional IDO1 was associated with significantly decreased numbers of CD4-, CD8-, and FoxP3-positive cells in the stroma compared with IDO1-negative tissues. These data suggest that IDO1 expression may impair infiltration of CD4, CD8, and FoxP3 cells into the stroma beneath the precancer lesion. Increased expression of IDO1 may contribute to immune avoidance and an increased frequency of disease progression in HPV16- and 18-positive lesions.

Endometrial cancer diagnoses prompted by routine cervical cytology: a retrospective case study.

AIMS: Endometrial cancer is the commonest gynaecological cancer in New Zealand. Some women have their diagnosis of endometrial cancer prompted by an abnormal cervical cytology screening test. When high-risk human papillomavirus (hr-HPV) testing becomes the primary test for cervical screening, this avenue of incidental diagnosis will be reduced. Therefore, our aims were to estimate the proportion of women whose diagnosis of endometrial cancer follows incidental detection on routine cervical cytology, and to understand the clinicopathologic characteristics of these cases. METHODS: Retrospective analysis of patient medical records from women of cervical screening age diagnosed with endometrial cancer between 2015-2019 in the South Island of New Zealand. RESULTS: Of 334 women, 26 (7.8%) had endometrial cancer diagnosis prompted by abnormal cervical cytology. Most women had low-grade (17/26, 65.4%), low-stage (18/26, 69.2%) disease of endometrioid histologic subtype (21/26, 80.8%). The small cohort prevented significant correlations with clinicopathologic characteristics and outcomes. Overall, cervical cytology had low sensitivity (32.3%) for the detection of endometrial cancer in the 6 months before diagnosis. CONCLUSIONS: A small number of women currently have diagnoses of endometrial cancer prompted by routine cervical screening with cytology. However, the undefined clinical benefit from and poor sensitivity of cervical cytology for detecting endometrial cancer does not justify its use in screening, or opposition to hr-HPV cervical screening.

Potential drug repurposing of ruxolitinib to inhibit the JAK/STAT pathway for the treatment of patients with epithelial ovarian cancer.

AIM: This review aimed to describe the potential for therapeutic targeting of the JAK/STAT signaling pathway by repurposing the clinically-approved JAK inhibitor ruxolitinib in the patients with epithelial ovarian cancer (OC) setting. METHODS: We reviewed publications that focus on the inhibition of the JAK/STAT pathway in hematological and solid malignancies including OC. RESULTS: Preclinical studies showed that ruxolitinib effectively reduces OC cell viability and metastasis and enhances the anti-tumor activity of chemotherapy drugs. There are a number of recent clinical trials exploring the role of JAK/STAT inhibition in solid cancers including OC. Early results have not adequately supported efficacy in solid tumors. However, there are preclinical data and clinical studies supporting the use of ruxolitinib in combination with both chemotherapy and other targeted drugs in OC setting. CONCLUSION: Inflammatory conditions and persistent activation of the JAK/STAT pathway are associated with tumourigenesis and chemoresistance, and therapeutic blockade of this pathway shows promising results. For women with OC, clinical investigation exploring the role of ruxolitinib in combination with chemotherapy agents or other targeted therapeutics is warranted.

Primary care experiences in the 'Let's test for HPV' study: a qualitative analysis.

Introduction The National Cervical Screening Programme (NCSP) will switch from cervical cytology to Human Papillomavirus (HPV) testing as the primary cervical screening modality in 2023. To prepare for rollout an implementation study of HPV testing in primary care commenced in August 2022 in three different geographic regions in NZ. Aims This study explores Primary Care Staff's experience of using the HPV testing pathway in the 'Let's test for HPV' study so that recommendations can be made to improve the testing process before nationwide roll-out. Method Thirty-nine primary care staff were interviewed across all 17 practices in the Capital and Coast, Canterbury and Whanganui region participating in the 'Let's Test For HPV' study. In total 19 interviews took place which followed a semi-structured approach. These interviews were recorded and transcribed. Template analysis was carried out on transcripts to aid in identifying themes. Results Three key themes, with additional subthemes, were identified. Staff were strongly supportive of the new testing regime. Interviewees identified some issues with the new pathway. Educational needs for both patients and clinicians were identified. Conclusion Primary care staff described the experience of using the HPV testing pathway positively; however, there were requests for ongoing additional support and nationwide rollout to be supported by practitioner and patient education programmes. With the right support this new pathway for cervical cancer screening has the potential to improve access for previously underserved and unserved groups.

Correction: LHRH conjugated gold nanoparticles assisted efficient ovarian cancer targeting evaluated via spectral photon-counting CT imaging: a proof-of-concept research.

Correction for 'LHRH conjugated gold nanoparticles assisted efficient ovarian cancer targeting evaluated via spectral photon-counting CT imaging: a proof-of-concept research' by Dhiraj Kumar et al., J. Mater. Chem. B, 2023, 11, 1916-1928, https://doi.org/10.1039/D2TB02416K.

Te Ara Waiora-Implementing human papillomavirus (HPV) primary testing to prevent cervical cancer in Aotearoa New Zealand: A protocol for a non-inferiority trial.

BACKGROUND: Cervical cancer is caused by high-risk types of human papillomavirus (HPV). Testing for high-risk HPV is a more sensitive screening method than cervical cytology for detecting cervical changes that may lead to cancer. Consistent with recent evidence of efficacy and acceptability, Aotearoa New Zealand plans to introduce HPV testing as the primary approach to screening, replacing cervical cytology, from mid-2023. Any equitable cervical screening programme must be effective across a diverse population, including women that the current programme fails to reach, particularly Maori and those in rural areas. Currently, we do not know the best model for implementing an equitable HPV self-testing screening programme. METHODS: This implementation trial aims to assess whether a universal offer of HPV self-testing (offered to all people eligible for cervical screening) achieves non-inferior screening coverage (equal) to a universal offer of cervical cytology alone (the present programme). The study population is all people aged from 24.5 to 70 years due for cervical screening in a 12-month period (including those whose screening is overdue or who have never had screening). A range of quantitative and qualitative secondary outcomes will be explored, including barriers and facilitators across screening and diagnostic pathways. This study takes place in Te Tai Tokerau/Northland which covers a diverse range of urban and rural areas and has a large Indigenous Maori population. A total of fourteen practices will be involved. Seven practices will offer HPV self-testing universally to approximately 2800 women and will be compared to seven practices providing routine clinical care (offer of cervical cytology) to an approximately equal number of women. DISCUSSION: This trial will answer important questions about how to implement an equitable, high-quality, effective national programme offering HPV self-testing as the primary screening method for cervical cancer prevention. TRIAL REGISTRATION: Prospectively registered with the Australian New Zealand Clinical Trials Registry 07/12/2021: ACTRN12621001675819.

LHRH conjugated gold nanoparticles assisted efficient ovarian cancer targeting evaluated via spectral photon-counting CT imaging: a proof-of-concept research.

Emerging multifunctional nanoparticulate formulations take advantage of nano-meter scale size and surface chemistry to work as a therapeutic delivery agent and a diagnostic tool for non-invasive real-time monitoring using imaging technologies. Here, we evaluate the selective uptake of 18 nm and 80 nm sized gold nanoparticles (AuNPs) by SKOV3 (4 times higher) ovarian cancer (OC) cells (compared to OVCAR5) in vitro, quantified by inductively coupled plasma (ICP) and MARS spectral photon-counting CT imaging (MARS SPCCT). Based on in vitro analysis, pristine AuNPs (18 nm) and surface modified AuNPs (18 nm) were chosen as a contrast agent for MARS SPCCT. The chemical analysis by FTIR spectroscopy confirmed the luteinizing hormone-releasing hormone (LHRH) conjugation to the AuNPs surface. For the first time, LHRH conjugated AuNPs were used for in vitro and selective in vivo OC targeting. The ICP-MS analysis confirmed preferential uptake of LHRH modified AuNPs by organs residing in the abdominal cavity with OC nodules (pancreas: 0.46 ng mg-1, mesentery: 0.89 ng mg-1, ovary: 1.43 ng mg-1, and abdominal wall: 2.12 ng mg-1) whereas the MARS SPCCT analysis suggested scattered accumulation of metal around the abdominal cavity. Therefore, the study showed the exciting potential of LHRH conjugated AuNPs to target ovarian cancer and also as a potential contrast agent for novel SPCCT imaging technology.

Shifting incidence and survival of epithelial ovarian cancer (1995-2014): A SurvMark-2 study.

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom). Data on invasive EOC diagnosed in women aged 15 to 99 years during 1995 to 2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995 and 2014 among women aged 65 to 99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma "not otherwise specified" with estimates ranging between 4.4% and 7.4% in women aged 15 to 64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival.

Patient choice may improve adherence to follow-up in cervical screening: a randomised-control trial.

AIMS: We investigated whether patient choice of follow-up type improves health-related quality of life (HrQOL) and follow-up attendance in women who have undergone large loop excision of the transformation zone (LLETZ) for cervical intraepithelial neoplasia grade 2 to 3 (CIN 2-3). METHODS: A three-armed randomised controlled trial including women with newly diagnosed CIN 2-3 post-LLETZ treatment was performed. Consenting women were randomised (1:1:1) to either: (a) colposcopy review at the hospital, (b) follow-up with high-risk human papilloma virus (HrHPV) and smear test in the community or (c) a choice of the aforementioned follow-up options, six months post-treatment. HrQOL was measured and participants were surveyed at baseline and six months regarding preferences for follow-up. RESULTS: Sixty-eight participants were randomised to follow-up (a), 67 to follow-up (b) and 65 to follow-up (c) (n=200). At six months post-treatment, 47% of patients indicated a preference for (a), 24% for (b) and 26% for (c). We found no significant difference in HrQOL between the study arms. Attendance was greater among patients who chose their follow-up (95.5% vs 91.1%, p=0.06). CONCLUSION: Choice of follow-up was associated with greater attendance. However, larger studies examining the effects of HrQOL and attendance to different follow-ups are warranted.

Blimp-1 is a prognostic indicator for progression of cervical intraepithelial neoplasia grade 2.

BACKGROUND: Progression of cervical intraepithelial neoplasia (CIN) to higher grade disease is associated with persistent human papillomavirus (HPV) infection and an absence of immune-mediated regression. However, the immune microenvironment that distinguishes progression from persistent or regressing lesions has not been well defined. METHODS: A total of 69 patients under the age of 25 with high-risk HPV-positive cytology and biopsy-confirmed p16-positive CIN2 were included in the study. Biopsies were stained using 20 antibodies to a range of immune markers. Based on a 2-year follow-up, samples were analysed in "progressor" (CIN3 +) or "persister/regressor" (CIN1, 2 or normal) groups. RESULTS: Progression was most strongly associated with Blimp-1 positive cell staining in the lesion (P = 0.0019) and with low numbers of infiltrating CD4 cells in the dermal region beneath the lesion (P = 0.0022). The presence of CD4, CD8 and T bet-positive cells in the dermal region most strongly correlated with CD11c cells in the persister/regressor but not the progressor group. CONCLUSION: High numbers of Blimp-1 + cells in CIN2 lesions may predict progression to more severe disease. Measurement of Blimp-1 may have diagnostic utility for the determination of the need to treat women with cervical pre-cancer. HIGHLIGHTS: CIN2 progression is associated with high numbers of Blimp-1 positive cells in the lesion. Detection of Blimp-1 in the lesion may have utility as a prognostic test to inform the need to treat CIN2.

Use of direct oral anticoagulants for postoperative venous thromboembolism prophylaxis after surgery for gynecologic malignancies.

Venous thromboembolism is a preventable cause of postoperative mortality in patients undergoing surgery for malignancy. Current standard of care based on international guideline recommends 28 days of extended thromboprophylaxis after major abdominal and pelvic surgery for malignancies with unfractionated heparin or low molecular weight heparin. Direct oral anticoagulants have been approved for the treatment of venous thromboembolism in the general population. This regimen has a significant advantage over other types of anticoagulation regimens, particularly being administered by non-parenteral routes and without the need for laboratory monitoring. In this review, we evaluate the role of direct anticoagulation and provide an update on completed and ongoing clinical trials.

The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models.

Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and BRAF in several ovarian cancer subtypes. However, monotherapies targeting one of these pathways have shown modest effects in clinical trials. This limited efficacy of the agents could be due to upregulation and increased signaling via the adjacent alternative pathway. In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. The inhibitor combination reduced cellular proliferation in a synergistic manner in OV-90 and OVCAR8 monolayers and in OV-90, OVCAR5 and SKOV3 aggregates. Sensitivity to the inhibitors was reduced in three-dimensional cell aggregates in comparison to monolayers. OV-90 cells cultured in large spheroids were sensitive to the inhibitors and displayed a robust synergistic antiproliferative response to the inhibitor combination. In contrast, OVCAR8 spheroids were resistant to the inhibitors. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors.

Collagen I dysregulation is pivotal for ovarian cancer progression.

As a principal matrisomal protein, collagen is involved in the regulation of the structural framework of extracellular matrix (ECM) and therefore is potentially crucial in determining the biophysical character of the ECM. It has been suggested that collagen architecture plays a role in ovarian cancer development, progression and therapeutic responses which led us to examine the collagen morphology in normal and cancerous ovarian tissue. Also, the behaviour of ovarian cancer cells cultured in four qualitatively different collagen gels was investigated. The results here provide evidence that collagen I morphology in the cancerous ovary is distinct from that in the normal ovary. Tumour-associated collagen I showed streams or channels of thick elongated collagen I fibrils. Moreover, fibril alignment was significantly more prevalent in endometrioid and clear cell cancers than other ovarian cancer subtypes. In this work, for the first-time collagen I architecture profiling (CAP) was introduced using histochemical staining, which distinguished between the collagen I morphologies of ovarian cancer subtypes. Immunohistochemical examination of ovarian normal and cancerous tissues also supported the notion that focal adhesion and Rho signalling are upregulated in ovarian cancers, especially in the high-grade serous tumours, as indicated by higher expression of p-FAK and p190RhoGEF. The results also support the concept that collagen I architecture, which might be collagen I concentration-dependent, influences proliferation in ovarian cancer cells. The study provides evidence that modification of collagen I architecture integrity is associated with ovarian cancer development and therapeutic responses.

Predicting regression of cervical intraepithelial neoplasia grade 2 in women under 25 years.

BACKGROUND: A number of retrospective and prospective studies have documented substantial rates of regression in cervical intraepithelial neoplasia grade 2 lesions in young women. Initial observational management of cervical intraepithelial neoplasia grade 2 is increasingly accepted as appropriate for women under 25 years of age with screen-detected abnormalities and is included in a number of clinical guidelines. However, there has been a paucity of large prospective studies on observational management with strict inclusion criteria. A number of important questions remain, specifically regarding the clinical variables that are associated with the risk of progression or persistence of disease. To investigate these factors and to ensure that young women with cervical intraepithelial neoplasia grade 2 undergoing observational management were being managed in a well-monitored and an appropriately informed fashion, we conducted a large, multicenter prospective study on observational management of cervical intraepithelial neoplasia grade 2 in women under 25 years. OBJECTIVE: This study aimed to determine the regression rates and clinical, cytologic, and pathologic predictors of regression of cervical intraepithelial neoplasia grade 2 in women under 25 years undergoing observational management over 24 months. STUDY DESIGN: This study was a multicenter prospective study on observational management of cervical intraepithelial neoplasia grade 2 (ie, repeat colposcopy, cytology, and cervical biopsy every 6 months) for up to 24 months. A total of 615 consenting women under 25 years with newly-diagnosed, biopsy-proven cervical intraepithelial neoplasia grade 2 were recruited (from 2010 to 2016) through 16 hospital-based colposcopy units in New Zealand and Australia. RESULTS: At completion, 326 women had confirmed regression, 156 had persistent high-grade cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ, and 24 had unconfirmed regression (ie, first regression at the 24-month follow-up). A total of 109 women did not complete the protocol (41 because of delayed follow-up, 41 lost to follow-up, 22 elected treatment, 4 refused a biopsy, and 1 died of an unrelated cause). Confirmed regression was observed in 53% (326 of 615) of all women enrolled in the study and, when missing data were imputed, it was estimated that 64% of women (95% confidence interval, 60%-68%) would have experienced regression. Similarly, lesions regressed in 64% (326 of 506) of women who completed the observational protocol. Based on a multivariable analysis, detection of human papillomavirus 16 in a liquid-based cytology sample at the time of initial colposcopy decreased the chance of regression by 31% (risk ratio, 0.69; 95% confidence interval, 0.56-0.86; P<.001). In addition, at initial colposcopy, low-grade or normal colposcopic impression, later year of diagnosis, low-grade or normal cytology, and being a nonsmoker were all independently associated with an increased chance of regression. CONCLUSION: More than half of women under 25 years with cervical intraepithelial neoplasia grade 2 will regress to cervical intraepithelial neoplasia grade 1 or normal within 24 months without destructive treatment. The absence of human papillomavirus 16 is the most important predictor of regression.

A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial.

BACKGROUND: Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs. METHODS: 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity. RESULTS: The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5-13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5-13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%-24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade. CONCLUSIONS: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.

Identifying management practices that drive production-line workers' engagement through qualitative analysis.

INTRODUCTION: Engagement research - most often defined by a worker's psychological state of vigor, dedication, and absorption - pays little attention to production-line workers. This study therefore explores factors that drive workers' engagement with health and safety (H&S) in a production-line context as well as their perception of managerial influence Furthermore, the study adds to the body of research by exploring H&S engagement concepts through the use of qualitative research methods. METHOD: 38 semi-structured interviews were conducted and analyzed through template analysis to identify themes that promote and hinder engagement. RESULTS: The main engagement drivers were found to be: (a) the displayed safety focus of the company in organizational and social aspects; (b) the quality of the communication approach with respect to quality, consistency and direction; and (c) the environment encompassing the relationship between workers and supervisors and peers as well as the psychological environment. Notably, a trusting relationship between supervisors and workers appeared to be the most influential driver in determining engaged H&S behavior. Discussion and impact in industry: The study highlights factors that could be adapted to improve engagement and consequently enhance H&S approaches. Originality: The study reported in this paper offers a unique insight into individual production workers' perceived drivers of H&S engagement using Qualitative Analysis. Practical applications: The study identified the important role that supervisors play in workers' H&S engagement levels and what skills they need to employ to enhance workers' engagement in general and in the context of H&S behavior and performance. Furthermore, the importance of psychological and sociological factors in safety approaches are highlighted and were found to be key for creating safer workplaces.