Correlation between Surgeon's assessment and radiographic evaluation of residual disease in women with advanced stage ovarian cancer reported to have undergone optimal surgical cytoreduction: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: We sought to determine the level of concordance among surgeons' assessment of residual disease (RD) and pre-treatment computed tomography (CT) findings among women who underwent optimal surgical cytoreduction for advanced stage ovarian cancer. METHODS: This is a post-trial ad hoc analysis of a phase 3 randomized clinical trial evaluating the impact of bevacizumab in primary and maintenance therapy for patients with advanced stage ovarian cancer following surgical cytoreduction. All subjects underwent imaging of the chest/abdomen/pelvis to establish a post-surgical baseline prior to the initiation of chemotherapy. Information collected on trial was utilized to compare surgeon's operative assessment of RD, to pre-treatment imaging. RESULTS: Of 1873 enrolled patients, surgical outcome was described as optimal (RD≤1cm) in 639 subjects. Twelve patients were excluded as they did not have a baseline, pretreatment imaging, leaving 627 participants for analysis. The average interval from surgery to baseline scan was 26days (range: 1-109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD>1cm in size. RD>1cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD>1.5cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD>1cm on pre-treatment CT (discordant) exhibited a significantly greater risk of disease progression (HR 1.30; 95% CI 1.08-1.56; p=0.0059). CONCLUSIONS: Among patients reported to have undergone optimal cytoreduction, 40% were found to have lesions >1cm on postoperative, pretreatment imaging. Although inflammatory changes and/or rapid tumor regrowth could account for the discordance, the impact on PFS and distribution of RD may suggest underestimation by the operating surgeon.

Outcomes and Cost Analysis of Surveillance Strategies After Initial Treatment for Women With Recurrent Ovarian Cancer.

OBJECTIVE: The aim of this study was to determine whether there is a survival or cost benefit dependent on detection strategy of recurrent ovarian cancer (ie, imaging, physical examination findings, report of symptoms, or rising cancer antigen 125 [CA-125] levels). METHODS/MATERIALS: A retrospective chart review of 112 ovarian cancer patients was conducted, and method of detection of recurrent disease was determined from medical records. The following primary outcomes were determined using Cox proportional hazards regression model: progression-free survival (PFS) after diagnosis of recurrence and time to death after diagnosis of recurrence (overall survival [OS]). Several approaches to disease surveillance were proposed, and a cost model was applied. RESULTS: Median time to recurrence was 13.5 months. Overall, 6.3% presented with only physical examination findings; 24.1%, with elevating CA-125 levels; 34.8%, with imaging; and 32.1%, with symptoms. Most patients presenting with recurrent disease diagnosed by rising CA-125 were white (62.9%); those with imaging and symptomatic recurrences were blacks (56.4% and 57.1%, respectively). There was a small but not statistically significant OS benefit for recurrence detected via CA-125 (P = 0.85; OS per detection method: PE, 20.7 months; CA-125, 26.8 months; imaging, 17.8 months; and symptoms, 6.6 months). We modeled costs of surveillance in our patient cohort; up to 40.8% of cases of ovarian cancer recurrences would have been missed if no imaging were obtained during surveillance. CONCLUSIONS: Results indicate minimal differences in PFS and statistically insignificant differences in OS, depending on detection method. Notably, black patients with Medicaid presented most often with symptomatic recurrences, which surprisingly did not affect patient OS and PFS; and interestingly, pr\ivate or self-pay insurance was associated with decreased OS among black patients. From our cost analysis, we estimate that the most cost-effective surveillance strategy for the first year costs $9.2 million annually and includes office visit biannually, biannual CA-125 levels, and annual asymptomatic imaging.

Examining the Effects of Time to Diagnosis, Income, Symptoms, and Incidental Detection on Overall Survival in Epithelial Ovarian Cancer: Manitoba Ovarian Cancer Outcomes (MOCO) Study Group.

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.

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer.

OBJECTIVES: To evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed "BRCA") testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first- and second-degree relatives of BRCA mutation-positive individuals, compared with no testing. Female BRCA mutation-positive relatives of patients with ovarian cancer could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy. METHODS: A cost-effectiveness model was developed that included the risks of breast and ovarian cancer; the costs, utilities, and effects of risk-reducing surgery on cancer rates; and the costs, utilities, and mortality rates associated with cancer. RESULTS: BRCA testing of all women with epithelial ovarian cancer each year is cost-effective at a UK willingness-to-pay threshold of £20,000/quality-adjusted life-year (QALY) compared with no testing, with an incremental cost-effectiveness ratio of £4,339/QALY. The result was primarily driven by fewer cases of breast cancer (142) and ovarian cancer (141) and associated reductions in mortality (77 fewer deaths) in relatives over the subsequent 50 years. Sensitivity analyses showed that the results were robust to variations in the input parameters. Probabilistic sensitivity analysis showed that the probability of germline BRCA mutation testing being cost-effective at a threshold of £20,000/QALY was 99.9%. CONCLUSIONS: Implementing germline BRCA testing in all patients with ovarian cancer would be cost-effective in the United Kingdom. The consequent reduction in future cases of breast and ovarian cancer in relatives of mutation-positive individuals would ease the burden of cancer treatments in subsequent years and result in significantly better outcomes and reduced mortality rates for these individuals.

Assessment of objective responses in thymic epithelial tumors using ITMIG modified criteria.

OBJECTIVES: Pleural metastases of thymic epithelial tumors (TETs) are relatively common, and this unique growth pattern makes the use of RECIST (response evaluation criteria in solid tumors) response criteria difficult. To standardize tumor measurement in TETs, the International Thymic Malignancy Interest Group (ITMIG) has proposed newly developed criteria. We compared evaluation of objective response between ITMIG modified criteria and RECIST 1.1 in patients with TET treated with systemic chemotherapy. PATIENTS AND METHODS: We retrospectively evaluated the tumor response of 40 patients with unresectable TET who were enrolled in a phase II clinical trial using ITMIG modified criteria, and compared the findings with prospectively evaluated tumor response assessed by RECIST 1.1. Agreement analyses for the response at each time point, including overall response and declaring progression, were performed and the time to progression (TTP) was also assessed using the two different measurements. RESULTS: The overall response rate assessed by the two methods did not differ significantly, with kappa value of 0.897. Agreement analysis for declaring progression of disease (PD) at the date of RECIST 1.1-designated PD showed 95% concordance rate with ITMIG modified criteria (p=1.000, kappa index=0.875). The median TTP according to RECIST 1.1 and ITMIG modified criteria was 8.4 and 7.9 months (p=0.983), respectively. Validation with another cohort of 27 TET patients treated with neoadjuvant chemotherapy also showed a 96% concordance rate in overall response between the two different criteria. CONCLUSIONS: ITMIG modified criteria showed a high concordance rate with RECIST 1.1 criteria in response assessment of TETs. Given the rarity of TETs, further evaluation of ITMIG modified criteria in a larger number of patients will be required before their implementation in clinical trials.

Cost-effectiveness analysis of a multivariate index assay compared to modified American College of Obstetricians and Gynecologists criteria and CA-125 in the triage of women with adnexal masses.

OBJECTIVE: To evaluate the cost-effectiveness of the multivariate index assay (MIA) for use in triaging women with an adnexal mass relative to modified American College of Obstetricians and Gynecologists (mACOG) referral guidelines and CA-125 testing alone. METHODS: The MIA triage algorithm was based on qualitative serum testing of five biomarkers: transthyretin, apolipoprotein, A-1, 2-microglobulin, transferrin, and CA-125. An economic analysis was developed to evaluate the clinical and cost implications of adopting MIA in clinical practice versus the mACOG referral guidelines and CA-125 alone, over a lifetime horizon, from the perspective of the public payer. Clinical parameters used to characterize patients' disease status, quality of life, and treatment decisions were estimated using the results of published studies; costs were approximated using reimbursement rates from CMS fee schedules. Model endpoints included overall survival (OS), costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The cost-effectiveness threshold was set to $50,000 per QALY. One-way sensitivity analysis was performed to assess uncertainty of individual parameters included in the analysis. All costs were reported in 2014 US dollars. RESULTS: Use of MIA was cost-effective, resulting in fewer re-operations and pre-treatment CT scans. Overall MIA resulted in an ICER of $35,094/QALY gained. MIA was also cost-saving and QALY-increasing compared to use of CA-125 alone with an ICER of $12,189/QALY gained. One-way sensitivity analysis showed the ICER was most affected by the following parameters: (1) sensitivity of MIA; (2) sensitivity of mACOG; and (3) percentage of patients, not referred to a gynecologic oncologist, who were correctly diagnosed with advanced epithelial ovarian cancer (EOC). CONCLUSION: Use of MIA is a more cost-effective triage strategy than mACOG or CA-125. It is expected to increase the percentage of women with ovarian cancer that are referred to gynecologic oncologists, which is shown to improve clinical outcomes. Limitations include the use of assumptions when published data was unavailable, and the use of multiple sources for survival data.

Value of 18F-FDG PET/CT for Predicting the World Health Organization Malignant Grade of Thymic Epithelial Tumors: Focused in Volume-Dependent Parameters.

PURPOSE: We investigated whether preoperative parameters of 18F-FDG PET/CT were correlated with the World Health Organization (WHO) classification and/or Masaoka staging of thymic epithelial tumors. PATIENTS AND METHODS: We reviewed 61 patients retrospectively who were diagnosed with thymic epithelial tumors after surgical resection and PET/CT. A volume of interest was drawn on the primary lesion, using an SUV cutoff of 2.5, and metabolic indices such as SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. RESULTS: There were 24 male patients (38.7%), and the mean (SD) age was 50.23 (12.54) years. The mean (SD) tumor size was 6.11 (3.41) cm. There were 22 low-risk thymomas (36.9%) (A, AB, B1), 32 high-risk thymomas (51.6%), and 7 thymic carcinomas (11.5%). The Masaoka stage was I in 15 (24.6%), II in 30 (49.2%), III in 11 (18.0%), and IV in 5 patients (8.2%). Mean (SD) SUVmax was 3.43 (1.01) in low-risk thymomas, 4.42 (1.70) in high-risk thymomas, and 8.23 (2.61) in thymic carcinoma; the differences were significant (P < 0.001). Mean (SD) MTV and TLG were 90.74 (114.56) and 229.36 (300.56) in low-risk thymomas, 80.82 (112.49) and 233.93 (340.91) in high-risk thymomas, and 90.63 (90.74) and 390.94 (437.62), respectively, in thymic carcinomas. MTV and TLG showed no correlation with the WHO classification. On receiver operating characteristic curve analysis, the cutoff value for discriminating thymomas and thymic carcinomas was 5.05. SUVmax and TLG were correlated with Masaoka stage. CONCLUSIONS: Although volume-dependent parameters were not correlated with the WHO classification, a significant relationship was observed between SUVmax and WHO classification and Masaoka stage.

The influence of neighborhood socioeconomic status and race on survival from ovarian cancer: a population-based analysis of Cook County, Illinois.

PURPOSE: Despite significant improvements in treatment for ovarian cancer, survival is poorer for non-Hispanic black (NHB) women compared to non-Hispanic white (NHW) women. Neighborhood socioeconomic status (SES) has been implicated in racial disparities across a variety of health outcomes and may similarly contribute to racial disparities in ovarian cancer survival. The purpose of this analysis is to assess the influence of neighborhood SES on NHB-NHW survival differences after accounting for differences in tumor characteristics and in treatment. METHODS: Data were obtained from 2432 women (443 NHB and 1989 NHW) diagnosed with epithelial ovarian cancer in Cook County, Illinois between 1998 and 2007. Neighborhood (i.e., census tract) SES at the time of diagnosis was calculated for each woman using two well-established composite measures of affluence and disadvantage. Cox proportional hazard models measured the association between NHB race and survival after adjusting for age, tumor characteristics, treatment, year of diagnosis, and neighborhood SES. RESULTS: There was a strong association between ovarian cancer survival and both measures of neighborhood SES (P < .0001 for both affluence and disadvantage). After adjusting for age, tumor characteristics, treatment, and year of diagnosis, NHB were more likely than NHW to die of ovarian cancer (hazard ratio [HR] = 1.47, 95% confidence interval [CI]: 1.28-1.68). The inclusion of neighborhood affluence and disadvantage into models separately and together attenuated this risk (HRaffluence = 1.37, 95% CI: 1.18-1.58; HRdisadvantage = 1.28, 95% CI: 1.08-1.52; and HRaffluence + disadvantage = 1.28, 95% CI: 1.08-1.52. CONCLUSIONS: Neighborhood SES, as measured by composite measures of affluence and disadvantage, is a predictor of survival in women diagnosed with ovarian cancer in Cook County, Illinois and may contribute to the racial disparity in survival.

Assessment of estrogen receptor expression in epithelial ovarian cancer patients using 16α-18F-fluoro-17ß-estradiol PET/CT.

UNLABELLED: The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-(18)F-fluoro-17ß-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. METHODS: (18)F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. (18)F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERß, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. RESULTS: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERß expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. (18)F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that (18)F-FES PET could provide reliable information about current tumor ERα status. CONCLUSION: (18)F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of (18)F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

Risk assessment for epithelial ovarian cancer: proposing a new approach to a deadly problem.

Presently the majority of women diagnosed with epithelial ovarian cancer (EOC) have advanced stage disease (III-IV) with a poor 5-year survival rate (12-30 %). This significantly contrasts when early stage disease is detected, which has a 5-year survival rate approximating 90 %. Therefore, detection of early stage disease is critical to making an impact on outcome. By using genetic algorithms, modifications of transvaginal ultrasonography and use of novel biomarkers, we propose a risk assessment profile to identify at-risk women and enable ovarian cancer screening to become a reality. Such a novel algorithm starts by applying classic genetic pedigree assessment and uses a panel of multiple biomarkers that identify both phenotypic and genotypic expression of high-risk markers followed with conventional ultrasound and advanced ultrasound techniques such as microvascular contrast-enhancement as a secondary test. We presently employ a multidisciplinary program incorporating genetics, molecular biology, tumor immunology, gynecologic oncology and diagnostic imaging to identify asymptomatic high risk women.

A repertoire of biomarkers helps in detection and assessment of therapeutic response in epithelial ovarian cancer.

In epithelial ovarian cancer (EOC), the cancer antigen 125 (CA-125) has been conventionally used to help in diagnosis and assessment of response to treatment. Currently, YKL-40 (Tyrosine-Lysine-Leucine-40) and circulating cell-free DNA are being evaluated for possession of similar ability. In this study, we aimed to assess the ability of a repertoire of potential biomarkers in detecting and assessing therapeutic response, in advanced EOC. Blood levels of CA-125, YKL-40, total cell-free DNA (CFDNA), cell-free nuclear DNA (CFnDNA), and cell-free mitochondrial DNA (CFmDNA) levels were measured in 100 untreated patients of advanced EOC from November 2009 to June 2011, and again on treatment completion from the 20 patients who appeared for follow-up analysis. Significantly, higher proportion of untreated patients had serum CA-125 >3 times upper limit of normal (ULN) (90.0%; P < 0.0001) and plasma YKL-40 >ULN (77.0%; P < 0.0001), both of which significantly decreased, Posttherapy. posttherapy, CFDNA (P < 0.0001), and CFnDNA (P < 0.0001) levels significantly decreased as compared to pretreatment levels. Positive and significant correlations existed between pretherapy CFDNA and CFnDNA [Spearman rho (ρ) = 1.000; P < 0.0001], and also with CFmDNA (ρ = 0.301; P = 0.002), separately between CFnDNA and CFmDNA (ρ = 0.303; P = 0.002), as well as between plasma YKL-40 and patient age (ρ = 0.353; (P < 0.0001). On treatment completion, CFDNA and CFnDNA levels showed positive and significant correlation (ρ = 1.000; P < 0.0001). Therefore serum CA-125 and plasma YKL-40 aid detection and assessment of therapeutic response, in advanced EOC. CFDNA and CFnDNA help in estimating extent of therapeutic response in advanced EOC.

Multicentre external validation of IOTA prediction models and RMI by operators with varied training.

BACKGROUND: Correct characterisation of ovarian tumours is critical to optimise patient care. The purpose of this study is to evaluate the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) logistic regression model (LR2), ultrasound Simple Rules (SR), the Risk of Malignancy Index (RMI) and subjective assessment (SA) for preoperative characterisation of adnexal masses, when ultrasonography is performed by examiners with different background training and experience. METHODS: A 2-year prospective multicentre cross-sectional study. Thirty-five level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardised approach. The final outcome was the surgical findings and histological diagnosis. To characterise the adnexal masses, the six-variable prediction model (LR2) with a cutoff of 0.1, the RMI with cutoff of 200, ten SR (five rules for malignancy and five rules for benignity) and SA were applied. The area under the curves (AUCs) for performance of LR2 and RMI were calculated. Diagnostic performance measures for all models assessed were sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and the diagnostic odds ratio (DOR). RESULTS: Nine-hundred and sixty-two women with adnexal masses underwent transvaginal ultrasonography, whereas 255 had surgery. Prevalence of malignancy was 29% (49 primary invasive epithelial ovarian cancers, 18 borderline ovarian tumours, and 7 metastatic tumours). The AUCs for LR2 and RMI for all masses were 0.94 (95% confidence interval (CI): 0.89-0.97) and 0.90 (95% CI: 0.83-0.94), respectively. In premenopausal women, LR2-RMI difference was 0.09 (95% CI: 0.03-0.15) compared with -0.02 (95% CI: -0.08 to 0.04) in postmenopausal women. For all masses, the DORs for LR2, RMI, SR+SA (using SA when SR inapplicable), SR+MA (assuming malignancy when SR inapplicable), and SA were 62 (95% CI: 27-142), 43 (95% CI: 19-97), 109 (95% CI: 44-274), 66 (95% CI: 27-158), and 70 (95% CI: 30-163), respectively. CONCLUSION: Overall, the test performance of IOTA prediction models and rules as well as the RMI was maintained in examiners with varying levels of training and experience.

FDG PET-CT aids in the preoperative assessment of patients with newly diagnosed thymic epithelial malignancies.

INTRODUCTION: Advanced thymoma (stage III and IV) is difficult to detect by computed tomography (CT), yet it is important to distinguish between early (stage I and II) and advanced disease before surgery, as patients with locally advanced tumors require neoadjuvant chemotherapy to enable effective resection. This study assessed whether the amount of fluorodeoxyglucose (FDG) uptake can predict advanced thymoma and whether it can separate thymoma from thymic cancer. METHODS: We retrospectively reviewed FDG positron emission tomography (PET)-CT scans of 51 consecutive newly diagnosed patients with thymic epithelial malignancy. PET-CT findings documented focal FDG activity: SUVmax, SUVmean, SUVpeak, and total body volumetric standardized uptake value (SUV) measurements. These were correlated with Masaoka-Koga staging and World Health Organization classification. Wilcoxon ranked sum tests were used to assess association between SUV and pathological stage, cancer type, and classification. RESULTS: Among the study patients, 37 had thymoma, 12 thymic carcinoma, and 2 thymic carcinoid. Higher focal FDG uptake was seen in patients with type B3 thymoma than in those with type A, AB, B1, or B2 thymoma (p < 0.006). FDG uptake was higher in patients with thymic carcinoma or carcinoid than in patients with thymoma (p < 0.0003), with more variable associations with volumetric SUV measurements. There was no significant association observed between higher focal FDG uptake and advanced-stage disease in thymoma patients (p > 0.09), although greater FDG-avid tumor volume was significantly associated with advanced disease (p < 0.03). CONCLUSIONS: Focal FDG uptake cannot predict advanced thymoma but is helpful in distinguishing thymoma from thymic carcinoma, or the more aggressive thymoma, type B3.

Safety assessment of ovarian cryopreservation and transplantation in nude mice bearing human epithelial ovarian cancer.

OBJECTIVE: Nude mice with orthotopic transplantation of human ovarian epithelial cancer were used to investigate screening criteria for paraneoplastic normal ovarian tissue and the security of the freezing and thawing for ovarian tissue transplantation. METHODS: Expression of CK-7, CA125, P53, survivin, MMP-2/TIMP- 2 in paraneoplastic normal ovarian tissues were detected by RT-PCR as well as immunohistochemistry. The tissues of the groups with all negative indicators of RT-PCR, all negative indicators of immunohistochemistry, negative expression of CK-7, CA125 and survivin, positive expression of CK-7, CA125 and survivin, cancer tissues and normal ovarian tissues of nude mice were used for freezing and thawing transplantation, to analyze overt and occult carcinogenesis rates after transplantation. RESULTS: When all indicators or the main indicators, CK-7, CA125 and survivin, were negative, tumorigenesis did not occur after transplantation. In addition the occult carcinogenesis rate was lower than in the group with positive expression of CK-7, CA125 and survivin (P<0.01). After subcutaneous and orthotopic transplantation of ovarian tissues, rates did not change (P>0.05). There was no statistical significance among rates after transplantation of ovarian tissues which were obtained under different severity conditions (P>0.05). CONCLUSION: Negative expression of CK-7, CA125 and survivin can be treated as screening criteria for security of ovarian tissues for transplantation. Immunohistochemical methods can be used as the primary detection approach. Both subcutaneous and orthotopic transplantation are safe. The initial severity does not affect the carcinogenesis rate after tissue transplantation. Freezing and thawing ovarian tissue transplantation in nude mice with human epithelial ovarian carcinoma is feasible and safe.

Impact of screening test performance and cost on mortality reduction and cost-effectiveness of multimodal ovarian cancer screening.

Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests [CA125 and transvaginal sonography (TVS)]. Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current limits. This study estimates the mortality reduction, years of life saved, and cost-effectiveness achievable by annual multimodal screening using increasing CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counterparts with better performance characteristics. An existing stochastic microsimulation model is refined and used to screen a virtual cohort of 1 million women from ages 45 to 85 years. Each woman is assigned a detailed disease course and screening results timeline. The preclinical behavior of CA125 and TVS is simulated using empirical data derived from clinical trials. Simulations in which the disease incidence and performance characteristics of the screening tests are independently varied are conducted to evaluate the impact of these factors on overall screening performance and costs. Our results show that when applied to women at average risk, annual screening using increasing CA125 to select women for TVS achieves modest mortality reduction (~13%) and meets currently accepted cost-effectiveness guidelines. Screening outcomes are relatively insensitive to second-line test performance and costs. Identification of a first-line test that does substantially better than CA125 and has similar costs is required for screening to reduce ovarian mortality by at least 25% and be reasonably cost-effective.

Validity of the semi-infinite tumor model in diffuse reflectance spectroscopy for epithelial cancer diagnosis: a Monte Carlo study.

The accurate understanding of optical properties of human tissues plays an important role in the optical diagnosis of early epithelial cancer. Many inverse models used to determine the optical properties of a tumor have assumed that the tumor was semi-infinite, which infers infinite width and length but finite thickness. However, this simplified assumption could lead to large errors for small tumor, especially at the early stages. We used a modified Monte Carlo code, which is able to simulate light transport in a layered tissue model with buried tumor-like targets, to investigate the validity of the semi-infinite tumor assumption in two common epithelial tissue models: a squamous cell carcinoma (SCC) tissue model and a basal cell carcinoma (BCC) tissue model. The SCC tissue model consisted of three layers, i.e. the top epithelium, the middle tumor and the bottom stroma. The BCC tissue model also consisted of three layers, i.e. the top epidermis, the middle tumor and the bottom dermis. Diffuse reflectance was simulated for two common fiber-optic probes. In one probe, both source and detector fibers were perpendicular to the tissue surface; while in the other, both fibers were tilted at 45 degrees relative to the normal axis of the tissue surface. It was demonstrated that the validity of the semi-infinite tumor model depends on both the fiber-optic probe configuration and the tumor dimensions. Two look-up tables, which relate the validity of the semi-infinite tumor model to the tumor width in terms of the source-detector separation, were derived to guide the selection of appropriate tumor models and fiber optic probe configuration for the optical diagnosis of early epithelial cancers.

Atypical glandular cells in cervical smears: histological correlation and a suggested plan of management based on age of the patient in a low-resource setting.

OBJECTIVES: To perform an audit of all smears reported as atypical glandular cells (AGC) using the Bethesda system (TBS) 2001. METHODS: A total of 18 376 cervical smears were screened from January 2005 to June 2007, of which 65 cases were reported as AGC. Follow-up histology was available in 31 cases (47.7%), in whom a detailed cytological/histological correlation was carried out. RESULTS: AGC constituted 0.35% of all Pap smears. Follow-up histology was normal or benign in 20 cases, whereas a squamous or glandular abnormality was seen in 11 cases. Squamous abnormalities included one case each of cervical intraepithelial neoplasia (CIN)1, CIN2 and CIN3 and five cases of squamous cell carcinoma. All glandular epithelial abnormalities were endometrial in origin and included two endometrial adenocarcinomas and one uterine serous carcinoma. Neither in situ nor invasive adenocarcinoma of the endocervix was observed. Review of smears and reclassification as AGC, not otherwise specified and favour neoplasia revealed a higher proportion of abnormality in the latter group, reaffirming the utility of subtyping. The median age of women with AGC was 41 years. The outcome was analysed with respect to the median age. In women aged equal or more than 40 years, AGC reflected a high-grade squamous or glandular epithelial abnormality in 50% of cases compared with none in those less than 40 years old (P = 0.010). CONCLUSION: The age of the woman as well as the subtype of atypical glandular cells influences outcome and hence must be taken into consideration while formulating an acceptable management strategy in these women in a low-resource setting.

A computational approach to resolve cell level contributions to early glandular epithelial cancer progression.

BACKGROUND: Three-dimensional (3D) embedded cell cultures provide an appropriate physiological environment to reconstruct features of early glandular epithelial cancer. Although these are orders of magnitude simpler than tissues, they too are complex systems that have proven challenging to understand. We used agent-based, discrete event simulation modeling methods to build working hypotheses of mechanisms of epithelial 3D culture phenotype and early cancer progression. Starting with an earlier software analogue, we validated an improved in silico epithelial analogue (ISEA) for cardinal features of a normally developed MDCK cyst. A set of axiomatic operating principles defined simulated cell actions. We explored selective disruption of individual simulated cell actions. New framework features enabled recording detailed measures of ISEA cell activities and morphology. RESULTS: Enabled by a small set of cell operating principles, ISEA cells multiplied and self-organized into cyst-like structures that mimicked those of MDCK cells in a 3D embedded cell culture. Selective disruption of "anoikis" or directional cell division caused the ISEA to develop phenotypic features resembling those of in vitro tumor reconstruction models and cancerous tissues in vivo. Disrupting either process, or both, altered cell activity patterns that resulted in morphologically similar outcomes. Increased disruption led to a prolonged presence of intraluminal cells. CONCLUSIONS: ISEA mechanisms, behaviors, and morphological properties may have biological counterparts. To the extent that in silico-to-in vitro mappings are valid, the results suggest plausible, additional mechanisms of in vitro cancer reconstruction or reversion, and raise potentially significant implications for early cancer diagnosis based on histology. Further ISEA development and use are expected to provide a viable platform to complement in vitro methods for unraveling the mechanistic basis of epithelial morphogenesis and cancer progression.

Intraoperative assessment of epithelial and non-epithelial ovarian tumors: a 7-year review.

OBJECTIVE: To determine the accuracy of frozen section diagnosis of ovarian tumors and to discuss discrepant diagnostic cases. METHODS: 932 ovarian tumors were submitted for frozen section examination. Cases with a significant diagnostic discrepancy between the intraoperative and the final histological diagnosis were reviewed. RESULTS: The sensitivity of frozen section diagnosis for benign, borderline and malignant epithelial tumors was 98.82%, 98.97% and 87.66% and the specificity 98.01%, 97.06% and 100%, respectively. There were 27 cases with diagnostic discrepancy. All non teratomatous sex cord/stromal and germ cell tumors were correctly diagnosed while a diagnostic discrepancy was observed in teratomatous tumors. CONCLUSION: Frozen section diagnosis is a reliable method for the surgical management of an ovarian mass. Nevertheless, care should be taken for large tumors measuring > 20 cm in diameter, particularly when the intraoperative diagnosis reveals an epithelial borderline tumor or a teratomatous tumor with an extensive neural component.

Combined Monte Carlo and finite-difference time-domain modeling for biophotonic analysis: implications on reflectance-based diagnosis of epithelial precancer.

Monte Carlo (MC) modeling of photon transport in tissues is generally performed using simplified functions that only approximate the angular scattering properties of tissue constituents. However, such approximations may not be sufficient for fully characterizing tissue scatterers such as cells. Finite-difference time-domain (FDTD) modeling provides a flexible approach to compute realistic tissue phase functions that describe probability of scattering at different angles. We describe a computational framework that combines MC and FDTD modeling, and allows random sampling of scattering directions from FDTD phase functions. We carry out simulations to assess the influence of incorporating realistic FDTD phase functions on modeling spectroscopic reflectance signals obtained from normal and precancerous epithelial tissues. Simulations employ various fiber optic probe designs to analyze the sensitivity of different probe geometries to FDTD-generated phase functions. Combined MC/FDTD modeling results indicate that the form of the phase function used is an important factor in determining the reflectance profile of tissues, and detected reflectance intensity can change up to approximately 30% when a realistic FDTD phase function is used instead of an approximating function. The results presented need to be taken into account when developing photon propagation models or implementing inverse algorithms to extract optical properties from measurements.