Search

Objective The primary objectives of this study were to analyze data on time to diagnosis and correlate this with overall survival. We secondarily analyzed the effects of emergency room visits, symptoms, incidental findings, residence, socioeconomic status, and residual disease on overall survival. Methods This retrospective population-based descriptive cohort study examined all invasive ovarian cancer cases in Manitoba, Canada, between 2004 and 2010. Clinicopathologic, socioeconomic, and outcome data were collected. Analysis was performed with Cox and logistic regression stratified by early and late stage. Results Six hundred eighty-seven ovarian cancer patients were identified, with a final cohort of 601 patients: 210 with early-stage (1/2) and 391 with late-stage (3/4) disease. No presenting symptoms were associated with survival outcome. Poorer survival was associated with increasing age (P = 0.0016) and neoadjuvant chemotherapy (P = 0.0037). Higher income within the urban setting was also associated with a survival advantage (P = 0.0037), whereas initial presentation to the emergency room (P = 0.0399) was associated with decreased survival. Finally, for advanced-stage disease, incidental diagnosis had a significantly improved overall survival (hazard ratio, 0.424; 95% confidence interval, 0.27–0.67; P = 0.0003), even when accounting for confounding factors. Time from first presentation to diagnosis was associated with survival (P = 0.0309). Conclusions This study found that time to diagnosis did not negatively impact overall survival, although there was an association. Age, morphology, treatment type, residual disease, medical comorbidities, and income were significant prognostic factors. This is the first study to show a survival advantage to incidentally finding an ovarian cancer. Further research is needed on the outcomes of pelvic examination.

BACKGROUND Epithelial ovarian cancer has the highest mortality of all gynecologic cancers. The poor survival rates are often attributed to the advanced stage at which most of these cancers are detected. We sought to examine the effects of patient demographics, comorbidities and presenting symptoms on diagnostic and referral intervals by location of first presentation (emergency department v. elsewhere) and to identify factors that affect these intervals. METHODS We performed a retrospective analysis of chart and medical record data for ovarian cancers, with the exceptions of sex cord and germ cell tumours, diagnosed between 2004 and 2010 in Manitoba, Canada. Data were collected on baseline characteristics, time to diagnosis and referral, number and type of physician visits and emergency department visits. RESULTS The final cohort consisted of 601 patients. Sixty-three percent of patients received their diagnosis within 60 days of initial presentation, and 75.2% had their cancer diagnosed within 2 physician encounters. The median diagnostic interval for all stages of patients presenting to the emergency department was 7 days, compared with 55 days for patients presenting elsewhere. Early stage patients not presenting to the emergency department had their diagnosis a median of 34.0 days later than patients with advanced disease (95% confidence interval [CI] 22.22 to 45.69, p < 0.0001). The presence of some symptoms was associated with shortened diagnostic intervals. Patients with serous, clear-cell or endometrioid histotypes were less likely to have first presentation beginning in the emergency department (odds ratio [OR] 0.40, 95% CI 0.24 to 0.64, p = 0.0001; OR 0.28, 95% CI 0.14 to 0.59, p = 0.007) than those with unclassified epithelial histotype. INTERPRETATION For this group of patients, the main factor associated with diagnostic and referral intervals is presentation to the emergency department. These patients likely required more urgent attention for their more symptomatic disease, leading to quicker diagnosis and referral patterns, despite poorer prognosis.

Inherent or acquired drug resistance is a major contributor to epithelial ovarian cancer (EOC) mortality. Novel drugs or drug combinations that produce EOC cell death or resensitize drug resistant cells to standard chemotherapy may improve patient treatment. After conducting drug tolerability studies for the multikinase inhibitors dorsomorphin (DM) and it is structural analogue LDN-193189 (LDN), these drugs were tested in a mouse intraperitoneal xenograft model of EOC. DM significantly increased survival, whereas LDN showed a trend toward increased survival. In vitro experiments using cisplatin (CP)-resistant EOC cell lines, A2780-cp or SKOV3, we determined that pretreatment or cotreatment with DM or LDN resensitized cells to the killing effect of CP or carboplatin (CB). DM was capable of blocking EOC cell cycle and migration, whereas LDN produced a less pronounced effect on cell cycle and no effect on migration. Subsequent analyses using primary human EOC cell samples or additional established EOC cells lines showed that DM or LDN induced a dose-dependent autophagic or cell death response, respectively. DM induced a characteristic morphological change with the appearance of numerous LC3B-containing acidic vacuoles and an increase in LC3BII levels. This was coincident with a decrease in cell growth and the altered cell cycle consistent with DM-induced cytostasis. By contrast, LDN produced a caspase 3-independent, reactive oxygen species-dependent cell death. Overall, DM and LDN possess drug characteristics suitable for adjuvant agents used to treat chemotherapy-sensitive and -resistant EOC.

Inherent or acquired drug resistance is a major contributor to epithelial ovarian cancer (EOC) mortality. Novel drugs or drug combinations that produce EOC cell death or resensitize drug resistant cells to standard chemotherapy may improve patient treatment. After conducting drug tolerability studies for the multikinase inhibitors dorsomorphin (DM) and it is structural analogue LDN-193189 (LDN), these drugs were tested in a mouse intraperitoneal xenograft model of EOC. DM significantly increased survival, whereas LDN showed a trend toward increased survival. In vitro experiments using cisplatin (CP)-resistant EOC cell lines, A2780-cp or SKOV3, we determined that pretreatment or cotreatment with DM or LDN resensitized cells to the killing effect of CP or carboplatin (CB). DM was capable of blocking EOC cell cycle and migration, whereas LDN produced a less pronounced effect on cell cycle and no effect on migration. Subsequent analyses using primary human EOC cell samples or additional established EOC cells lines showed that DM or LDN induced a dose-dependent autophagic or cell death response, respectively. DM induced a characteristic morphological change with the appearance of numerous LC3B-containing acidic vacuoles and an increase in LC3BII levels. This was coincident with a decrease in cell growth and the altered cell cycle consistent with DM-induced cytostasis. By contrast, LDN produced a caspase 3-independent, reactive oxygen species-dependent cell death. Overall, DM and LDN possess drug characteristics suitable for adjuvant agents used to treat chemotherapy-sensitive and -resistant EOC.