Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic ...antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.
Abstract Background Ovarian cancer (OC) requires complex multidisciplinary care with wide variations in outcome. We sought to determine the impact of institutional and process of care factors on ...overall survival (OS) and delivery of guideline care nationally. Methods This was a retrospective cohort study of primary OC diagnosed from 1998 to 2007 using the National Cancer Data Base (NCDB) capturing 80% of all U.S. cases. Patient- (demographics, comorbidities, stage/grade), process of care (adherence to guidelines) and institutional- (facility type, case volume) factors were evaluated. Primary outcomes were OS and delivery of guideline therapy. Multivariable logistic regression and Cox proportional hazards models were used for analysis. Results We analyzed 96,802 consecutive cases. Five-year OS was 84%, 66.3%, 32% and 15.7% for stages I, II, III and IV, respectively. The annual mean facility case volumes varied by cancer center type (range: 5.7 to 26.7), with 25% of cases spread over 65% of centers — all treating fewer than 8 cases. Overall, 56% of cases received non-guideline care. Low facility case volume and higher comorbidity index independently predicted non-guideline care; high volume centers were less likely to deliver non-guideline care (OR: 0.44, 95% CI: 0.41–0.47). Delivery of non-guideline care (OR: 1.4, 95% CI: 1.36–1.44), and higher facility case volume (OR: 0.91, 95% CI: 0.86–0.96) were both independent predictors of OS. Conclusions Delivery of guideline care and facility case volume are important drivers of overall survival. Most cancer centers treat very few women with OC. National efforts should focus on improved access to centers with expertise in OC and ensuring delivery of guideline care.
Abstract Objective To prospectively define the prevalence of lymph node metastasis (LNM) in at risk endometrial cancer (EC). Methods From 2004 to 2008, frozen section based Mayo Criteria ...prospectively identified patients “not at-risk” of LNM (30% EC population; grade I/II, < 50% myometrial invasion and tumor diameter ≤ 2 cm) where lymphadenectomy was not recommended. The remaining 70% EC cohort was considered “at-risk” of LNM; where a systematic pelvic and infrarenal paraaortic lymphadenectomy was recommended. Patients were prospectively followed. The area between renal vein and inferior mesenteric artery (IMA) was labeled as high paraaortic area. For calculating the prevalence of LNM in high paraaortic area, the denominator was the population with known anatomic location of nodal tissue in relation to the IMA. Results Of the 742 patients, 514 were at risk; of which 89% underwent recommended lymphadenectomy. A mean (± standard deviation) of 36 (± 14) pelvic and 18 (± 9) paraaortic nodes were harvested. The prevalence of pelvic and paraaortic LNM was 17% and 12%, respectively. In presence of pelvic LNM, 51% had paraaortic LNM. In absence of pelvic LNM, 3% had paraaortic LNM; of which 67% was located exclusively in high paraaortic area. Among patients with paraaortic LNM, 88% had high paraaortic LNM; and 35% had only high paraaortic LNM. The cases of paraaortic LNM with negative pelvic nodes seemed to cluster in moderate to high grade endometrioid EC with ≥ 50% myometrial invasion. Conclusion We present reference data for the prevalence of LNM in at-risk EC patients to guide lymphadenectomy decisions for clinical and research purposes.
To compare survival after nodal assessment using a sentinel lymph node (SLN) algorithm versus comprehensive pelvic and paraaortic lymphadenectomy (LND) in serous or clear cell endometrial carcinoma, ...and to compare survival in node-negative cases.
Three-year recurrence-free survival (RFS) and overall survival were compared between one institution that used comprehensive LND to the renal veins and a second institution that used an SLN algorithm with ultra-staging with inverse-probability of treatment weighting (IPTW) derived from propensity scores to adjust for covariate imbalance between cohorts.
214 patients were identified (118 SLN cohort, 96 LND cohort). Adjuvant therapy differed between the cohorts; 84% and 40% in the SLN and LND cohorts, respectively, received chemotherapy ± radiation therapy. The IPTW-adjusted 3-year RFS rates were 69% and 80%, respectively. The IPTW-adjusted 3-year OS rates were 88% and 77%, respectively. The IPTW-adjusted hazard ratio (HR) for the association of surgical approach (SLN vs LND) with progression and death was 1.46 (95% CI: 0.70–3.04) and 0.44 (95% CI: 0.19–1.02), respectively. In the 168 node-negative cases, the IPTW-adjusted 3-year RFS rates were 73% and 91%, respectively. The IPTW-adjusted 3-year OS rates were 88% and 86%, respectively. In this subgroup, IPTW-adjusted HR for the association of surgical approach (SLN vs LND) with progression and death was 3.12 (95% CI: 1.02–9.57) and 0.69 (95% CI: 0.24–1.95), respectively.
OS was not compromised with the SLN algorithm. SLN may be associated with a decreased RFS but similar OS in node-negative cases despite the majority receiving chemotherapy. This may be due to differences in surveillance.
•Overall survival in non-endometrioid endometrial carcinoma appears uncompromised using a sentinel lymph node algorithm.•With negative nodes, recurrence-free survival is shorter with a sentinel node algorithm, but overall survival is similar.•Lymphatic recurrences do not appear increased with sentinel lymph node assessment in non-endometrioid endometrial carcinoma.
Abstract Background It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer ...(HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs. Methods We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF). Results We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p < 0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype. Conclusions Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.
Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between ...stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.
•The SLN algorithm does not compromise overall detection of higher-risk Stage IIIC EC•Stage IIIC2 is detected more frequently by LND than by SLN in deeply invasive EC•Use of an SLN algorithm may be ...considered in the detection of nodal metastasis
To determine if a sentinel lymph node (SLN) mapping algorithm will detect metastatic nodal disease in patients with intermediate−/high-risk endometrial carcinoma.
Patients were identified and surgically staged at two collaborating institutions. The historical cohort (2004–2008) at one institution included patients undergoing complete pelvic and paraaortic lymphadenectomy to the renal veins (LND cohort). At the second institution an SLN mapping algorithm, including pathologic ultra-staging, was performed (2006–2013) (SLN cohort). Intermediate-risk was defined as endometrioid histology (any grade), ≥50% myometrial invasion; high-risk as serous or clear cell histology (any myometrial invasion). Patients with gross peritoneal disease were excluded. Isolated tumor cells, micro-metastases, and macro-metastases were considered node-positive.
We identified 210 patients in the LND cohort, 202 in the SLN cohort. Nodal assessment was performed for most patients. In the intermediate-risk group, stage IIIC disease was diagnosed in 30/107 (28.0%) (LND), 29/82 (35.4%) (SLN) (P=0.28). In the high-risk group, stage IIIC disease was diagnosed in 20/103 (19.4%) (LND), 26 (21.7%) (SLN) (P=0.68). Paraaortic lymph node (LN) assessment was performed significantly more often in intermediate−/high-risk groups in the LND cohort (P<0.001). In the intermediate-risk group, paraaortic LN metastases were detected in 20/96 (20.8%) (LND) vs. 3/28 (10.7%) (SLN) (P=0.23). In the high-risk group, paraaortic LN metastases were detected in 13/82 (15.9%) (LND) and 10/56 (17.9%) (SLN) (%, P=0.76).
SLN mapping algorithm provides similar detection rates of stage IIIC endometrial cancer. The SLN algorithm does not compromise overall detection compared to standard LND.
Abstract Objective To examine the influence of diabetes and metformin therapy on overall survival (OS) and progression-free survival (PFS) in patients with endometrial cancer (EC) by using propensity ...score (PS) matching to account for confounding factors. Methods We retrospectively identified consecutive patients with stage I–IV EC managed surgically from 1999 through 2008 and stratified patients by diabetes status. PS matching was used to adjust for confounding covariates. OS and PFS were compared between diabetic and nondiabetic matched pairs and between matched pairs of diabetic patients with or without metformin therapy. Cox proportional hazards models were fit to estimate the effects on outcomes. Results Among 1303 eligible patients (79% stage I, 28% grade 3), 277 (21.3%) had a history of diabetes. Among diabetic patients, treatment consisted of metformin in 116 (41.9%); 57 (20.6%) had other oral agents, 51 (18.4%) insulin with or without other oral agents, and 53 (19.1%) diet modification only. For PS-matched diabetic and nondiabetic patients with EC, OS (hazard ratio HR, 1.01; 95% CI, 0.72–1.42) and PFS (HR, 1.01; 95% CI, 0.60–1.69) were similar between matched subsets. No differences in OS and PFS were observed when comparing PS-matched metformin users with nondiabetic patients (OS HR, 1.03; 95% CI, 0.57–1.85; PFS HR, 1.14; 95% CI, 0.49–2.62) or with other diabetic patients (OS HR, 0.61; 95% CI, 0.30–1.23; PFS HR, 1.06; 95% CI, 0.34–3.30). Conclusions When adjusted for confounding covariates, OS and PFS are similar between diabetic and nondiabetic patients with EC and between metformin users and nonusers or nondiabetic patients.
To compare oncologic outcomes in the staging of deeply invasive endometrioid endometrial carcinoma (EEC) using a sentinel lymph node algorithm (SLN) versus pelvic and paraaortic lymphadenectomy to ...the renal veins (LND); to compare outcomes in node-negative cases.
At two institutions, patients with deeply invasive (≥50% myometrial invasion) EEC were identified. One institution used LND (2004–2008), the other SLN (2005–2013). FIGO stage IV cases were excluded. Clinical characteristics and follow-up data were recorded.
176 patients were identified (LND, 94; SLN, 82). SLN patients were younger (p = 0.003) and had more LVSI (p < 0.001). 9.8% in the SLN and 29.8% in the LND cohorts, respectively, received no adjuvant therapy (p < 0.001). There was no association between type of assessment and recurrence; adjusted hazard ratio (aHR; LND vs. SLN) 0.87 (95%CI 0.40, 1.89) PFS. After controlling for age and adjuvant therapy, there was no association between assessment method and OS (aHR 2.54; 95%CI 0.81, 7.91). The node-negative cohort demonstrated no association between survival and assessment method: aHR 0.69 (95%CI 0.23, 2.03) PFS, 0.81 (95%CI 0.16, 4.22) OS. In the node-negative cohort, neither adjuvant EBRT+/-IVRT (HR 1.63; 95%CI 0.18, 14.97) nor adjuvant chemotherapy+/-EBRT+/-IVRT (HR 0.49; 95%CI 0.11, 2.22) were associated with OS, compared to no adjuvant therapy or IVRT-only.
Use of an SLN algorithm in deeply invasive EEC does not impair oncologic outcomes. Survival is excellent in node-negative cases, irrespective of assessment method. Adjuvant chemotherapy in node-negative patients does not appear to impact outcome.
•SLN assessment does not adversely affect outcomes in deeply invasive endometrioid endometrial cancer.•Survival is excellent in node-negative cases regardless of nodal assessment method.•Nodal recurrence rates are similar between SLN and full LND.
PDF
