Jesus Gonzalez Bosquet

The impact of multi-modal therapy on survival for uterine carcinosarcomas

OBJECTIVES To investigate treatment outcomes of patients with carcinosarcoma of the uterus and to identify parameters predictive of survival. Secondary objectives included (a) the assessment of treatment failures as a function of histologic subtypes and (b) the impact of the new FIGO staging classification system. METHODS This is a retrospective outcomes analysis of 121 patients diagnosed with primary carcinosarcoma of the uterus. Clinical, surgical and pathological data were reviewed and patients were classified according to the new 2009 FIGO staging system for endometrial carcinoma. Survivorship curves were evaluated with the log-rank test and associations between events and variables with Cox proportional hazards model. RESULTS In the multivariate analyses for disease-specific survival (DSS) and disease-free survival (DFS), the only independent factors were FIGO stage, adjuvant chemotherapy after surgery and the presence of clear cell histology in the tumor. The 5-year DSS for stages I-II, III and IV was 59%, 22% and 9%, respectively. The administration of platin-based chemotherapy provided a significant benefit with regard to both DFS (OR=0.28; p=0.001) and DSS (OR=0.35; p=0.01). While radiotherapy (RT) appeared to control vaginal failures in all stages, pelvic RT did not impact DSS. Of importance, the epithelial component was the predominant histology in both the primary extrauterine metastases (94%) and the distant failure sites (82%). CONCLUSIONS This highly aggressive uterine malignancy warrants comprehensive surgical staging to assess tumor dissemination followed by systemic therapy in patients with both early and advanced stage disease.

Analysis of gene expression in stage I serous tumors identifies critical pathways altered in ovarian cancer

OBJECTIVE Despite recent advances in the conceptual understanding of the pathogenesis of ovarian cancer, it remains the foremost cause of death from gynecologic malignancies in developed countries. The main reason for such a high rate of mortality is the lack of sensitive and specific biomarkers and imaging techniques for early detection of ovarian cancer. Additional biological insights into early-stage ovarian carcinogenesis are needed to help speed the development of markers for early detection of ovarian cancer. The objective of this study was to characterize differentially expressed genes in high-grade stage I serous carcinoma of the ovary. METHODS We analyzed gene expression in macrodissected formalin-fixed, paraffin-embedded samples from 5 high-grade stage I serous carcinomas and 5 stage I borderline tumors of the ovary using the Illumina Whole Genome DASL assay (cDNA-mediated annealing, selection, extension, and ligation) corresponding to 24,000 genes. Significance Analysis of Microarrays was performed to determine differentially expressed genes in stage I serous carcinoma, and class prediction analysis was performed to determine the predictive value of differentially expressed gene sets to correctly classify serous carcinoma from borderline tumors in 3 independent data sets. Altered transcription factor pathways and biological pathways unique to stage I serous carcinoma were identified through class comparison of differentially expressed genes. RESULTS Unsupervised cluster analysis of gene expression correctly classified stage I serous carcinomas from serous borderline tumors. Supervised analysis identified several known, as well as novel, genes differentially expressed in stage I ovarian cancer. Using a differentially expressed gene set, class comparison prediction analysis correctly identified serous carcinomas from serous borderline tumors in 3 independent data sets at over 80% accuracy, sensitivity, and specificity. Pathway analysis demonstrated the significance of p53 and E2F pathways in serous carcinogenesis and significant involvements of cell cycle and immune response pathways in stage I serous epithelial ovarian cancer. CONCLUSION We have identified differentially expressed genes associated with the carcinogenesis of high-grade stage I serous EOC. Furthermore, integrative analysis of biological and transcription pathway data contributed to the confirmation of important biological pathways and discovery of additional unique genes and pathways that may have potential importance in ovarian pathogenesis and biomarker development.

Risk of occult inguinofemoral lymph node metastasis from squamous carcinoma of the vulva.

PURPOSE This study was undertaken to correlate preoperative primary tumor size and American Joint Committee on Cancer and International Federation of Gynecology and Obstetrics categories with the risk of subclinical metastases from squamous carcinoma of the vulva to inguinofemoral nodes in patients with a palpably negative groin preoperatively. METHODS AND MATERIALS Clinical notes, operative reports, and pathology reports from 1955 to 1990 were reviewed to assign retrospectively 1969 American Joint Committee on Cancer N(0) and N(1) and 1988 International Federation of Gynecology and Obstetrics T categories. RESULTS Of 446 patients with primary carcinoma of the vulva, 226 had a groin without features indicative of lymph node metastasis. Occult groin node metastases were detected in 15.2%, 30.0%, 24.5%, and 0% of patients with T(1), T(2), T(3), and T(4) cancers, respectively. Subclinical node metastases were found in 7.0%, 22.2%, 26.9%, 34.1%, and 20.0% of patients with primary cancers measuring 1.0 cm or less, 1.1 to 2.0 cm, 2.1 to 3.0 cm, 3.1 to 5.0 cm, and larger than 5 cm, respectively. CONCLUSIONS Efficacy assessment for elective groin node irradiation and quantitative description of the radiation dose-control relationship for subclinical disease should be based on estimates of the risk of subclinical disease within the target volume. This study may help to assess the effectiveness of current therapies.

Comparison of gene expression patterns between avian and human ovarian cancers

OBJECTIVES A putative model of spontaneous cancer has been described in the laying hen that bears significant similarities to human ovarian cancer. Our objective was to characterize and compare the patterns of gene expression in chicken and human forms of this disease. METHODS RNA from 20 localized and metastatic ovarian and oviductal chicken tumor samples was isolated, amplified using in vitro transcription, and hybridized against normal ovarian epithelium to a customized cDNA microarray constructed for these studies. Differentially expressed genes were identified for localized ovarian, metastatic ovarian, and oviductal (or tubal) cancer by class comparison using BRB-ArrayTools. Results were validated with semi-quantitative PCR. A gene list (prediction model) constructed with the class prediction tool was used in a human ovarian cancer microarray obtained from the GEO datasets (GSE6008) in order to compare these results across species. RESULTS Class comparison analysis between localized ovarian, metastatic ovarian and oviductal cancer yielded 41 different informative probes that coded for 27 unique genes. Localized ovarian samples clustered between metastatic ovarian and oviductal cancer samples. Using our chicken data as a training set and leaving oviductal samples out of the analysis, we created a prediction model that classified early stage and advanced stage human ovarian cancer gene expression arrays with 78% overall accuracy. CONCLUSIONS Gene expression of spontaneous ovarian cancer in the chicken is comparable to gene expression patterns of human ovarian cancer.

Hepatic resection for metachronous metastases from ovarian carcinoma

Recently, several authors have reported that optimal primary cytoreduction of both hepatic and extrahepatic disease is not only feasible but improves survival. However, the role of hepatic resection in combination with secondary cytoreduction for epithelial ovarian cancer is unclear. Patients with recurrent ovarian cancer and metachronous intrahepatic metastases are often evaluated by a multidisciplinary team at the Mayo Clinic comprising pelvic and hepatobiliary surgeons for consideration of cytoreductive surgery. The purpose of this report is to update the outcome of cytoreductive surgery including hepatic resection for patients with metastatic ovarian carcinoma.

Small bowel obstruction associated with post-hysterectomy vaginal vault prolapse

BACKGROUND Patients may present with post-hysterectomy vaginal vault prolapse in conjunction with small bowel obstruction. Prior pelvic surgery, malignancy, and radiation therapy may be associated with this presentation. CASE An 83-year-old multiparous woman with a history of poorly differentiated endometrial adenocarcinoma was treated with radiation therapy, total abdominal hysterectomy, and salpingo-oophorectomy. Anterior exenteration was performed for a recurrence. Seventeen years after her last pelvic operation, she had small bowel obstruction that coincided with a worsening post-hysterectomy vaginal vault prolapse. Surgical management included a side-to-side ileoileostomy and excision with closure of the vaginal apex. CONCLUSION Although pelvic organ prolapse primarily affects quality of life, clinicians should be alert for bowel obstruction occurring with post-hysterectomy vaginal vault prolapse.

Association between endometrial cancer risk classification and gene expression in the cancer genome atlas database.

INTRODUCTION: To investigate if gene expression can differentiate endometrial cancer risk classification based on GOG 99 study in The Cancer Genome Atlas patients. METHODS: Gene expression was extracted from 271 endometrioid endometrial cancer samples in the TCGA database. Patients were stratified to high risk, high intermediate risk, and low or low intermediate risk based on clinicopathologic parameters from GOG 99. Genes differentially expressed between the classes at univariate significance level of less than .001 were included in the gene signature. RESULTS: There were 167 patients in the low-risk group, 81 patients in the high intermediate-risk group, and 23 patients in the high-risk group in The Cancer Genome Atlas database. GOG 99 risk classification and FIGO (International Federation of Gynecology and Obstetrics) stage were independently significant for survival in the multivariate analysis (P<.001). A total of 18,048 genes were included in the initial analysis. Four hundred forty-six genes classified high risk, high intermediate risk, and low or low intermediate risk subgroup individually (P=.01) with an accuracy of 58% and a &kgr; coefficient of 0.32. When combining high-risk and high intermediate-risk groups, the gene signature compared with low-risk patients included 608 genes (P=.01) with an accuracy of 69% and a &kgr; coefficient of 0.36 (area under the curve 0.69), closer to the values of the gene signature including only low-risk compared with high-risk patients (accuracy 81%, &kgr; 0.33, area under the curve 0.74). CONCLUSIONS: Gene expression analysis could differentiate risk groups in endometrioid endometrial cancer. The gene signature grouping high intermediate risk and high risk compared with low risk seems to be more accurate than using all three risk groups. This gene signature may help to identify higher risk patients with endometrial cancer before surgery.

Gene Expression and Prediction of Complete Cytoreduction in Ovarian Cancer

INTRODUCTION: The objective of this study was to investigate the role of microarray gene expression analysis in predicting the feasibility of complete cytoreduction in ovarian cancer. METHODS: Microarray expression of 507 women with ovarian cancer from The Cancer Genome Atlas was initially analyzed and a gene expression signature created. Complete cytoreduction was defined as removal of all tumors with no macroscopic residual disease. The model was applied to the Australian Ovarian Cancer Study data set with 216 ovarian cancer samples. RESULTS: One hundred fifteen women had complete cytoreduction in The Cancer Genome Atlas data set with significantly higher 5-year overall survival as compared with the 392 women with macroscopic residual disease (P<.001). A total of 12,718 genes were analyzed; 142 predicted accuracy of complete cytoreduction 69% of the time (P=.02). The model was more precise in predicting incomplete cytoreduction with macroscopic residual tumor with a sensitivity of 82% and a positive predictive value of 78%. The performance, measured by the area under the receiver operating characteristic curve was 63%. When applied to the Australian Ovarian Cancer Study set, with 58 women with complete cytoreduction and 158 with macroscopic residual, the accuracy was 72% (P<.019) and it was still more sensitive predicting incomplete cytoreduction with a sensitivity of 83% and a positive predictive value of 79%, and the area under the receiver operating characteristic curve was 68%. CONCLUSIONS: This analysis stresses again on the importance of complete cytoreductive surgery in ovarian cancer to microscopic disease and shows that gene expression analysis might have a role in predicting patients who are not amenable to complete cytoreduction and thus would have shorter survival.