Kirsten Marie Jochumsen

MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancer - a multicenter prospective comparative study.

OBJECTIVES The aim of this prospective multicenter study was to evaluate and compare the diagnostic performance of PET/CT, MRI and transvaginal two-dimensional ultrasound (2DUS) in the preoperative assessment of endometrial cancer (EC). METHODS 318 consecutive women with EC were included when referred to three Danish tertiary gynecological centers for surgical treatment. Preoperatively they were PET/CT-, MRI-, and 2DUS scanned. The imaging results were compared to the final pathological findings. This study was approved by the National Committee on Health Research Ethics. RESULTS For predicting myometrial invasion, we found sensitivity, specificity, PPV, NPV, and accuracy for PET/CT to be 93%, 49%, 41%, 95% and 61%, for MRI to be 87%, 57%, 44%, 92%, and 66% and for 2DUS to be 71%, 72%, 51%, 86% and 72%. For predicting cervical invasion, the values were 43%, 94%, 69%, 85% and 83%, respectively, for PET/CT, 33%, 95%, 60%, 85%, and 82%, respectively, for MRI, and 29%, 92%, 48%, 82% and 78% for 2DUS. Finally, for lymph node metastases, the values were 74%, 93%, 59%, 96%, and 91% for PET/CT and 59%, 93%, 40%, 97% and 90% for MRI. When comparing the diagnostic performance we found PET/CT, MRI and 2DUS to be comparable in predicting myometrial invasion. For cervical invasion and lymph node metastases, however, PET/CT was the best. CONCLUSIONS None of the modalities can yet replace surgical staging. However, they all contributed to important knowledge and were, furthermore, able to upstage low-risk patients who would not have been recommended lymph node resection based on histology and grade alone.

The relation between endometriosis and ovarian cancer - a review

Endometriosis is known to harbor characteristics substantiating its possible role as a precursor of ovarian cancer.

HE4 and CA125 levels in the preoperative assessment of endometrial cancer patients: a prospective multicenter study (ENDOMET)

To evaluate whether human epididymis protein 4 (HE4) and CA125 correlate with known high‐risk prognostic factors for endometrial cancer.

SUVmax of 18FDG PET/CT as a predictor of high-risk endometrial cancer patients

OBJECTIVE To evaluate SUVmax in the assessment of endometrial cancer preoperatively with particular focus on myometrial invasion (MI), cervical invasion (CI), FIGO stage, risk-stratification and lymph node metastases (LNM). METHODS A total of 268 women with endometrial cancer or atypical endometrial hyperplasia underwent FDG PET/CT imaging before surgical treatment. SUVmax of the primary tumour was compared with histological prognostic factors. RESULTS SUVmax was significantly higher in patients with high FIGO stages (p<0.0001), deep MI (p=0.002), CI (p=0.04), LNM (p=0.04) and high risk tumours (p=0.003). Linear regression found that SUVmax was dependent of MI (p=0.001, 95% CI 2.863-11.098), CI (p=0.001, 95% CI 2.896-11.499), risk (p=0.004, 95% CI 0.077-0.397), LNM (p=0.04, 95% CI 0.011-0.482) and FIGO stage (p<0.0001, 95% CI 0.158-0.473). CONCLUSIONS Preoperative PET/CT scanning and SUVmax measurements of the primary tumour may provide additional clinical and prognostic information about MI, CI, LNM and high risk disease in patients with endometrial cancer and allow for individualization of patient care. However, the sensitivity and specificity of the SUVmax in staging endometrial cancer is not high enough to reliably replace surgical staging.

Gene expression in epithelial ovarian cancer: a study of intratumor heterogeneity

The aim of this study was to investigate the intratumor heterogeneity of gene expression profiles in epithelial ovarian cancer (EOC). This was done to evaluate whether sampling of a single macrodissected tissue sample from each EOC case would bias the data and result in, eg, prognostic studies based on gene expression microarray experiments. From nine EOCs removed at Odense University Hospital, Denmark, three tumor samples of 200–300 mg each were taken with greatest possible mutual distance. The samples were immediately flash frozen. A parallel section was taken for histopathologic comparison. RNA was extracted from the tissue samples. Five micrograms of each RNA sample was used for labeling. The fragmented biotin-labeled complementary RNA was hybridized to Affymetrix GeneChip Human Genome U133 plus 2.0 arrays, and scanning was performed on the GeneArray scanner 3000 (Affymetrix, Santa Clara, CA). Data were evaluated using hierarchical clustering and intraclass correlation coefficient (ICC) from reliability analysis. All evaluation methods revealed low intratumor heterogeneity. Intratumor ICCs ranged from 0.888 to 0.978. In contrast, “between-tumor” ICC was 0.549 indicating much lower intra- than intertumor heterogeneity. Due to a low degree of intratumor variation, we conclude that it is sufficiently accurate in a clinical setup to use single, macrodissected tumor samples in the evaluation of gene expression in EOCs.

The value of random biopsies, omentectomy, and hysterectomy in operations for borderline ovarian tumors.

Objective Borderline ovarian tumors (BOTs) are treated surgically like malignant ovarian tumors with hysterectomy, salpingectomy, omentectomy, and multiple random peritoneal biopsies in addition to removal of the ovaries. It is, however, unknown how often removal of macroscopically normal-appearing tissues leads to the finding of microscopic disease. To evaluate the value of random biopsies, omentectomy, and hysterectomy in operations for BOT, the macroscopic and microscopic findings in a cohort of these patients were reviewed retrospectively. Materials Women treated for BOT at Odense University Hospital from 2007 to 2011 were eligible for this study. Data were extracted from electronic records. Intraoperative assessment of tumor spread (macroscopic disease) and the microscopic evaluation of removed tissues were the main outcome measures. Results The study included 75 patients, 59 (78.7%) in International Federation of Gynecology and Obstetrics stage I, 9 (12%) in stage II, and 7 (9.3%) in stage III. The histologic subtypes were serous (68%), mucinous (30.7%), and Brenner type (1.3%). Macroscopically radical surgery was performed in 62 patients (82.7%), and 46 (61.3%) received complete staging. The surgeon’s identification of macroscopic tumor spread to the contralateral ovary and the peritoneum had a sensitivity of 88% and 69.2% and a specificity of 90.2% and 92.5%, respectively. The macroscopic assessment of the uterine surface, the omentum, and the pelvic and para-aortal lymph nodes was not a good predictor of microscopic disease. During follow-up, 4 patients (5.3%) relapsed with no relation to surgical radicality or the extent of staging procedures. Conclusions Ovaries and peritoneal surfaces with a macroscopically normal appearance rarely contain a microscopic focus of BOT.

Gene expression meta-analysis identifies chromosomal regions involved in ovarian cancer survival

Ovarian cancer cells exhibit complex karyotypic alterations causing deregulation of numerous genes. Some of these genes are probably causal for cancer formation and local growth, whereas others are causal for metastasis and recurrence. By using publicly available data sets, we have investigated the relation of gene expression and chromosomal position to identify chromosomal regions of importance for early recurrence of ovarian cancer. By use of “Gene Set Enrichment Analysis,” we have ranked chromosomal regions according to their association to survival. Over‐representation analysis including 1–4 consecutive cytogenetic bands identified regions with increased expression for chromosome 5q12‐14, and a very large region of chromosome 7 with the strongest signal at 7p15‐13 among tumors from short‐living patients. Reduced gene expression was identified at 4q26‐32, 6p12‐q15, 9p21‐q32, and 11p14‐11. We summarized mutation load in these regions by a combined mutation score that is statistical significantly associated to survival by analysis in the data sets used for identification of the regions. Furthermore, the prognostic value of the combined mutation score was validated in an independent large data set using death (P = 0.015) and recurrence (P = 0.002) as outcome. The combined mutation score is strongly associated to upregulation of several growth factor pathways.

Gene expression profiles as prognostic markers in women with ovarian cancer.

The purpose was to find a gene expression profile that could distinguish short-term from long-term survivors in our collection of serous epithelial ovarian carcinomas. Furthermore, it should be able to stratify in an external validation set. Such a classifier profile will take us a step forward toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III/IV) was analyzed using Affymetrix U133 plus 2.0 microarrays. A multistep statistical procedure was applied to the data to find the gene set that optimally split the patients into short-term and long-term survivors in a Kaplan-Meier plot. A 14-gene prognostic profile with the ability to distinguish short-term survivors (median overall survival of 32 months) from long-term survivors (median overall survival not yet reached after a median follow-up of 76 months) with a P value of 3.4 × 10−9 was found. The prognostic gene set was also able to distinguish short-term from long-term survival in patients with advanced disease. Furthermore, its ability to classify in an external validation set was demonstrated. The identified 14-gene prognostic profile was able to predict survival (short- vs long-term survival) with a strength that is better than any other prognostic factor in epithelial ovarian cancer including FIGO stage. This stratification method may form the basis of determinations for new therapeutic approaches, as patients with poor prognosis could obtain the biggest advantage from new treatment modalities.

Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers

Endometrial and ovarian cancers can be detected through the analysis of DNA from Pap test fluids, intrauterine samples, and plasma. Brushing up on early cancer detection Despite the many recent advances in cancer diagnosis and treatment, ovarian cancer remains one of the most lethal malignancies, in part because there are no accurate screening methods for this disease and it is often diagnosed at a late stage. To develop a screening tool for ovarian and endometrial cancers, Wang et al. combined genetic analysis of fluids obtained through routine Papanicolau testing, normally done for cervical cancer, with analysis of tumor DNA circulating in the blood. The authors also used intrauterine sampling with Tao brushes to further increase the sensitivity of detection for the less accessible tumors. We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.

Gene Selection for Predicting Survival Outcomes of Cancer Patients in Microarray Studies

In this paper, we introduce a multivariate approach for selecting genes for predicting survival outcomes of cancer patients in gene expression microarray studies. Combined with survival analysis for gene filtering, the method makes full use of individual’s survival information (both censored and uncensored) in selecting informative genes for survival outcome prediction. Application of our method to published data on epithelial ovarian cancer has identified genes that discriminate unfavorable and favorable outcomes with high significance ( χ2 = 21.933, p = 3e - 06 ). The method can also be generalized to categorical variables for selecting gene expression signatures for predicting tumor metastasis or tumor subtypes.