Understanding the role of oncogenic human papillomavirus (HPV) status on adherence behaviors among women with abnormal cervical cytology.

BACKGROUND: With the introduction of oncogenic Human Papillomavirus (HPV) testing into cervical screening there is a renewed focus on primary prevention among high-risk groups. To date, little is known about the effectiveness of this program, and the extent to which individual-level factors, such as psychosocial health and agency, may play a role. In particular, it is unclear if knowledge of one's oncogenic HPV status impacts on adherence behaviors amongst women with screening abnormalities. The purpose of this study was to identify if clinical, demographic or psychosocial factors predict non-adherence with recommended colposcopy follow-up. METHODS: This prospective pilot study included 145 women referred to a large Toronto colposcopy clinic between December, 2013 and September, 2014. Demographic, clinical and psychosocial characteristics were collected at three points in time: (1) at initial colposcopy consultation; (2) 4-6 weeks following initial consultation, and; (3) at time of follow-up appointment (within 12 months of initial consultation). RESULTS: Overall, 13% (n = 145) of the women were classified as non-adherent. Older women (OR = 0.73, p < 0.01) and those with higher-grade lesions (OR = 0.10, p < 0.01) were less likely to be non-adherent, whereas current smokers (OR = 22.46, p < 0.01) were more likely to be non-adherent. While not statistically significant, variation in rates of non-adherence amongst the various HPV status groups (untested; 15.3%, HPV positive; 5.3%, HPV negative; 6.7%) warrants further study. CONCLUSION: Findings of this study indicate that younger women, those with higher-grade lesions and current smokers were more likely to be non-adherent to recommended colposcopy follow-up. While HPV status did not reach statistical significance, the direction of this finding suggests that testing for HPV may have a positive reinforcing role on adherence to follow-up. The direction of this finding warrants further study, and potentially a practical clinical goal as HPV testing for women becomes standard of care.

Same-Day Discharge Among Patients With Obesity Undergoing Laparoscopic Gynaecologic Oncology Surgery.

OBJECTIVES: To determine the likelihood of same-day discharge (SDD) among patients with obesity undergoing laparoscopic gynaecologic oncology surgery and identify predictors of SDD. METHODS: We conducted a retrospective cohort study of gynaecologic oncology patients who underwent laparoscopic procedures between January 2012 and June 2016. Patients were categorized as non-obese, obese class I/II and obese class III (BMI <30, 30-39.9, and ≥40 kg/m2, respectively). We used univariate and multivariable logistic regression to identify variables associated with SDD. RESULTS: Of 496 patients, 288 were non-obese, 161 were obese class I/II, and 47 were obese class III. Overall, 182 patients (36.7%) were discharged same day; 44% of these were non-obese, 30% class I/II and 15% class III. On multivariable analysis, we found negative predictors for SDD to be obesity (OR 0.54; P = 0.03), procedure length (OR 0.51; P < 0.01), and higher American Society of Anesthesiologists (ASA) score (OR 0.63; P < 0.01), while we found being pre-booked for SDD (OR 9.16; P <0.01) was a positive predictor of SDD. Among all patients with obesity, only procedure length (OR 0.47; P < 0.01) and being pre-booked for SDD (OR 9.67; P < 0.01) were associated with SDD when we controlled for BMI, ASA score, intraoperative complications, type of surgery, and surgical start time. Patients discharged same day were less likely to present to the emergency department within 30 days of surgery (OR 0.48; P = 0.01). CONCLUSION: Among the study cohort and after controlling for potential confounders, women with class I, II, and III obesity had a much lower likelihood of SDD than non-obese women. The only significant predictors of SDD among patients with obesity were duration of procedure and pre-booking for SDD. Further study is needed to identify strategies to improve SDD rates among patients with obesity.

Risk of Cervical Dysplasia After Colposcopy Care and Risk-Informed Return to Population-Based Screening: A Systematic Review.

This systematic review examined the risk of cervical dysplasia among women who have undergone a colposcopy episode of care to inform their return to population-based cervical screening. PubMed, Embase, and grey literature were searched between January 2000 and 2018. One reviewer screened citations against pre-defined eligibility criteria. A second reviewer verified 10% and 100% of exclusions at title and abstract and at full-text screening, respectively. One reviewer extracted data and assessed methodological quality of included articles; a second reviewer verified these in full. The primary outcome was incidence of cervical intraepithelial neoplasia grade 2 or greater (CIN2+) subsequent to initial colposcopy evaluation. Secondary outcomes included incidence of CIN2+ after negative follow-up test results and performance of follow-up strategies. Results were synthesized narratively. A total of 48 studies were included. The 1- to 5-year CIN2+ risks after colposcopy evaluation ranged from 2.4% to 16.5% among women treated for CIN2+ and from 0.7% to 16.8% among women untreated for CIN grade 1 or less (≤CIN1). Follow-up strategies included single or repeat cytology, human papillomavirus (HPV) testing, or combined HPV/cytology co-testing at various intervals. After negative follow-up test results, risk varied by follow-up strategy for both groups and by referral cytology severity for untreated women. Performance of follow-up strategies varied among treated women. Among untreated women, co-testing demonstrated greater sensitivity than cytology alone. In conclusion, women treated during colposcopy for CIN2+ and women with ≤CIN1 who were referred to colposcopy for low-grade cytology and who did not receive treatment may be able to return to population-based screening after negative co-testing results. Current evidence does not suggest that women untreated for ≤CIN1 who are referred for high-grade cytology be returned to screening at an average risk interval. The optimal strategy for colposcopy discharge needs ongoing evaluation as implementation of HPV testing evolves.

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells.

Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC.

The optimal time for surgery in women with serous ovarian cancer.

BACKGROUND: Advanced high-grade serous ovarian carcinoma (HGSC) is commonly treated with surgery and chemotherapy. We investigated the survival of patients treated with primary or interval surgery at different times following neoadjuvant chemotherapy. Their survival was compared with that of patients treated with primary cytoreductive surgery and adjuvant chemotherapy. METHODS: Patients with stage III or IV HGSC were included in this retrospective cohort study. Clinical data were obtained from patient records. Patients were divided into 2 groups based on treatment with neoadjuvant chemotherapy and interval cytoreductive surgery (NAC) or with primary cytoreductive surgery and adjuvant chemotherapy (PCS). Study groups were stratified by several clinical variables. RESULTS: We included 334 patients in our study: 156 in the NAC and 178 in the PCS groups. Survival of patients in the NAC group was independent of when they underwent interval cytoreductive surgery following initiation of neoadjuvant chemotherapy (p < 0.001). Optimal surgical cytoreduction had no impact on overall survival in the NAC group (p < 0.001). Optimal cytoreduction (p < 0.001) and platinum sensitivity (p < 0.001) were independent predictors of improved survival in the PCS but not in the NAC group. Patients in the NAC group had significantly worse overall survival than those in the PCS group (31.6 v. 61.3 mo, p < 0.001). CONCLUSION: Women with advanced HGSC who underwent PCS had better survival than those who underwent interval NAC, regardless of the number of cycles of neoadjuvant therapy. Optimal cytoreduction did not provide a survival advantage in the NAC group.

BACKGROUND: La chirurgie et la chimiothérapie sont habituellement le traitement recommandé pour les carcinomes ovariens séreux bien différenciés de haut grade. Nous avons étudié le taux de survie de patientes ayant subi une chirurgie initiale ou d'intervalle à divers moments après une chimiothérapie néoadjuvante et l'avons comparé avec celui de patientes ayant subi une chirurgie de réduction tumorale initiale et une chimiothérapie adjuvante. METHODS: Cette étude de cohorte rétrospective a été menée auprès de patientes présentant un carcinome de stade III ou IV. Les données cliniques ont été tirées de leur dossier médical. Les patientes ont été séparées en 2 groupes : le premier était formé des patientes ayant subi une chimiothérapie néoadjuvante et une chirurgie de réduction tumorale d'intervalle (groupe NAC), et le deuxième de celles ayant subi une chirurgie de réduction tumorale initiale et une chimiothérapie adjuvante (groupe PCS). On a stratifié les 2 groupes à l'aide de plusieurs variables cliniques. RESULTS: L'étude portait sur 334 patientes, soit 156 dans le groupe NAC et 178 dans le groupe PCS. Dans le groupe NAC, aucune corrélation n'a été observée entre le taux de survie des patientes et le temps écoulé entre la chimiothérapie néoadjuvante et la chirurgie de réduction tumorale d'intervalle (p < 0,001). La réduction tumorale optimale n'a eu aucune incidence sur le taux de survie global des patientes du groupe NAC (p < 0,001). La réduction tumorale optimale (p < 0,001) et la sensibilité au platine (p < 0,001) ont été ciblés comme étant 2 prédicateurs indépendants d'un taux de survie accru chez les patientes du groupe PCS, mais pas chez celles du groupe NAC. Le taux de survie des patientes du groupe NAC était beaucoup plus faible que celui des patientes du groupe PCS (31,6 mo contre 61,3 mo, p < 0,001). CONCLUSION: Les femmes atteintes d'un carcinome ovarien séreux bien différencié de haut grade ayant subi une chirurgie de réduction tumorale initiale et une chimiothérapie adjuvante (PCS) ont affiché un taux de survie plus élevé que les patientes ayant subi une chimiothérapie néoadjuvante et une chirurgie de réduction tumorale d'intervalle (NAC), peu importe le nombre de cycles de chimiothérapie néoadjuvante. La réduction tumorale optimale n'a pas été associée à un taux de survie plus élevé chez ces dernières.

Molecular profiling and clinical outcome of high-grade serous ovarian cancer presenting with low- versus high-volume ascites.

Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes.

Management of abnormal cervical cytology screening in adolescent and young women in a canadian colposcopy centre: a descriptive analysis.

OBJECTIVE: To describe and analyze the management of young women referred for colposcopy at a Canadian comprehensive cancer centre for evaluation of atypical squamous intraepithelial lesion of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). METHODS: We conducted a retrospective descriptive study by searching the eCancerCare Colposcopy Database at our centre for 15- to 29-year-old females with referral cytology of ASC-US and LSIL who were seen between January 2000 and January 2009. Women in three age cohorts (15 to 19 years, 20 to 24 years, and 25 to 29 years) were reviewed for risk factors and relevant medical history, cytology and histology results, treatment, and follow-up visits. RESULTS: A total of 407 women met the entry criteria, with 36 women in the group aged 15 to 19, 173 in the group aged 20 to 24, and 198 in the group aged 25 to 29. Ten excisional procedures were performed among the 36 participants in the group aged 15 to 19, with normal histology found in two (20%), low-grade cervical intraepithelial neoplasia (CIN) in four (40%), and high-grade CIN in four (40%). An excisional procedure was performed in 52 of 173 participants in the group aged 20 to 24, with normal histology in 15%, low-grade CIN in 37%, and high-grade CIN in 48%. Among the group aged 25 to 29, 74 of 198 participants had an excisional procedure, with normal histology in 12%, low-grade CIN in 27%, high-grade CIN in 59%, and microinvasive squamous cell carcinoma in one woman (1%). CONCLUSION: Many women under the age of 25 who were referred with low-grade abnormal cervical cytology underwent treatment(s) and many did not have significant pathology. One case of microinvasive cervical cancer was identified in a patient in the group aged 25 to 29 over the nine years of our study. Our results support the safety of developing a more conservative and coordinated approach to cervical cancer screening in adolescent and young women in Canada.

Low-grade and high-grade serous Mullerian carcinoma: review and analysis of publicly available gene expression profiles.

OBJECTIVE: Mullerian low grade serous carcinoma (LGSC) and high grade serous carcinoma (HGSC) have distinct molecular profiles, clinical behavior and treatment response. Our objective was to study the biological profiles of these carcinomas. METHODS: This study examines publicly available gene expression profiles of LGSC and HGSC to identify differentially expressed genes and key pathways involved in carcinogenesis and chemotherapy response. RESULTS: Our analysis supports the hypothesis that serous mullerian carcinoma develop through two different pathways yielding two distinct malignancies, namely LGSC and HGSC. Furthermore, genes potentially involved in chemotherapeutic resistance of LGSC were identified. Suppressing the levels of these genes/proteins may increase clinical response to standard chemotherapy in patients with LGSC. CONCLUSION: In summary, this review shows the molecular profile of LGSC and HGSC through multi-center analysis of gene expression profiles of these tumors. The gene signatures of these neoplasms may potentially be used to develop disease-specific, targeted therapy for LGSC and HGSC.

Cell-cell and cell-matrix dynamics in intraperitoneal cancer metastasis.

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis.

The development and implementation of an electronic departmental note in a colposcopy clinic.

Hospital-wide electronic medical records can be limited in addressing clinical department needs. A study was undertaken to examine the development and implementation of an electronic informaton system in a colposcopy unit in a large teaching hospital in Canada. A case study design was used, and 24 semistructured interviews were conducted with nurses and physicians working in the colposcopy clinic and individuals from the information technology team. Interviews occurred in two phases-directly after implementation and again 9 months later. Computerized audit data were gathered to examine usage patterns. The results provide insight into the processes and challenges of defining and capturing information for both clinical and research purposes and creating a standardized referral note. The findings demonstrated some initial uncertainty around roles and responsibilities concerning the electronic system and its integration into clinical routines. After a period of 12 months, and further refinement, it was found that the system was accessible and user-friendly, although some concerns raised during the developmental stage persisted. Audit data revealed that 9 months after its introduction, nurses' adoption of the system rate reached 89%, and physicians, 96%. This study has demonstrated that practitioners in a colposcopy clinic successfully collaborated with information technology specialists and each other to develop and implement a clinical departmental information system. While certain challenges were encountered, nurses and physicians have bought into the system, recognize its potential for research and patient care, and are therefore committed to figuring out how to adapt to the changes in communication both within the clinic and with referring physicians.

Breast and ovarian cancer: the forgotten paternal contribution.

Five to 10% of all cases of breast and ovarian cancer are attributed to a heritable genetic predisposition. Transmission of BRCA1 and BRCA2 mutations is equally likely through maternal or paternal lineage; however, fewer referrals to cancer genetics clinics appear to be made for a paternal, than maternal, family history of breast and/or ovarian cancer. To examine this potential bias, a retrospective review of 315 patient and family charts was conducted by one familial cancer clinic in Toronto, Canada. Referral letters, risk estimates, and family histories were analyzed to identify significant differences between patients referred with maternal and paternal family histories. It was determined that patients are approximately five times more likely to be referred with a maternal family history of breast and/or ovarian cancer as compared to those with a paternal family history (p = <.0001). Individuals with a paternal family history were found to have a different, and higher, pattern of risk estimates (p = .00064). No significant difference was seen between the type of referrals sent by general practitioners, oncologists, and gynecologists. Recommendations to increase the awareness of paternal family history in assessing cancer risk are provided.

Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary.

OBJECTIVE: Low-grade serous carcinoma (LGSC) is a chemoresistant ovarian neoplasm thought to potentially arise in a background of low malignant potential tumors (LMP), which are typically non-aggressive. However, LMP with micropapillary features (LMP-MP) have more aggressive clinical behavior and may represent an intermediate in progression to LGSC. The objective of this study was to obtain and compare gene expression profiles of LMP, LMP-MP and LGSC to determine if LMP-MP more closely resembles LGSC, and to identify genes involved in LGSC carcinogenesis. METHODS: Epithelial cells from LMP (n=17), LMP-MP (n=9) and LGSC (n=11) were isolated by laser capture microdissection. RNA was extracted, reverse transcribed to cDNA, amplified and hybridized to Affymetrix U133 Plus2 genechip arrays. Gene expression data were checked for quality, filtered and significantly altered genes between subgroups were identified. Differential expression of selected genes was verified by RT-qPCR and immunohistochemistry. RESULTS: Gene expression analysis identified differential expression between LMP and LMP-MP, LMP and LGSC but not LMP-MP and LGSC. Integration of differentially expressed genes into the protein interaction database CytoScape highlighted gene products in the MAPK pathway as differentially regulated between LMP and LGSC. Four genes were selected and validated by RT-qPCR performed on microarray samples (n=15) and immunohistochemistry on a representative microarray (n=57). CONCLUSION: The gene expression profile of LMP-MP is similar to LGSC and distinct from LMP, reflecting their more aggressive clinical behavior. Candidate genes in the MAPK pathway were highlighted which may play a role in LGSC carcinogenesis and indicate potential therapeutic targets.

Microarray expression identification of differentially expressed genes in serous epithelial ovarian cancer compared with bulk normal ovarian tissue and ovarian surface scrapings.

The lack of reliable early detection of ovarian cancer and the absence of specific symptoms result in diagnosis of ovarian cancer at advanced stage in the majority of the patients. Through gene expression profiling we can identify important genes that may help understand the evolution from normal ovarian tissue to ovarian cancer. The gene expression profiles of 7 normal ovaries and 26 ovaries with serous epithelial ovarian cancer (SEOC) were examined by cDNA microarrays using supervised and unsupervised analysis, with sequential significance filtering. Real-time RT-PCR was used to measure and compare the expression levels of 5 selected genes: WAP four-disulfide core domain protein HE4 (WAP, up-regulated), secreted phosphoprotein 1 (SPP1, osteopontin; up-regulated), activin A receptor, type I (ACVR1, up-regulated), tumor necrosis factor (TNF superfamily, member 2; TNF, up-regulated) and decorin (DCN, down-regulated) in 4 epithelial scrapings and in 6 bulk-extracted normal ovaries. The gene expression profile of SEOC was not dependent on the stage of the disease at diagnosis. A supervised microarray data analysis identified a subset of 329 genes showing significant differential expression between SEOC samples and bulk normal ovarian tissue and ovarian surface scrapings, including several new genes such as TNFalpha and activin A receptor type I. The real-time RT-PCR for the up-regulated genes did not differ significantly between normal ovarian epithelial scrapings and bulk-extracted ovaries. However, decorin showed a statistically significant difference (P=0.0073) in expression between epithelial scrapings and bulk-extracted ovaries. Previously uncharacterized genes are associated with the malignant phenotype of SEOC. Bulk normal ovarian tissue may serve as control for SEOC tissue in gene expression profiling. Gene expression profiling and sequential statistical analyses of gene subsets can identify new genes and molecular pathways affecting development of SEOC. The genes of interest can be potential targets for future research of SEOC.