Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Objective

In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics.

Methods

The PLCO ovarian cancer screening arm included 39,105 women aged 55-74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ (n = 121); all CA125+/TVU+ (n = 46); and a random sample of TVU+ (n = 373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ², Fisher's exact, or Wilcoxon-Mann-Whitney tests.

Results

Women with a false-positive TVU were younger (P < 0.001), heavier (P < 0.001), and reported a higher frequency of prior hysterectomy (P < 0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ (P < 0.001). Benign non-ovarian findings were commonly associated with all false-positives, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups (P = 0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ (P < 0.001).

Conclusions

False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.     

Predictive value of circulating tumor cells (CTCs) in newly-diagnosed and recurrent ovarian cancer patients

Objective

To determine whether circulating tumor cells (CTCs), as detected and enumerated by the Veridex CellSearch^TM system, could predict for clinical outcomes in women with newly diagnosed or recurrent epithelial ovarian cancer.

Methods

Serial measurements of CTC s and paired serum CA125 were collected in a series of 78 women with newly diagnosed or recurrent ovarian cancer seen at our institution over a period of 15 months. Clinical data were abstracted from patient medical records. CTCs were detected and enumerated by the CellSearch^TM protocol, and patients were divided into CTC negative (< 2 CTCs) or positive (≥ 2 CTCs) groups. CTC groups were correlated with clinical characteristics and outcomes. A longitudinal analysis of CTC change and CA125 trends was also performed.

Results

At least one CTC was isolated from the peripheral blood of over 80% of the women participating in this study, with a range from 0 to 8. No correlations were observed between CTC numbers and clinical characteristics or outcomes. Although both serum CA125 and CTC number exhibited an overall significant decreasing trend over time, there was no correlation observed between change in CTCs and CA125.

Conclusion

Using the FDA-approved CellSearch^TM system, CTCs can be isolated from women with newly diagnosed or recurrent ovarian cancer. However, CTC numbers do not significantly correlate with clinical characteristics or patient outcomes. Future studies should focus on phenotypic characterization of CTCs and whether different isolation protocols yield a higher number of CTCs or add prognostic value.     

Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass

Objective

Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes.

Methods

Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI.

Results

809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI = 200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI).

Conclusion

HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.     

卵巢癌患者术后NDV-ATV-ASI与化疗对免疫功能的影响

目的 :评价新城鸡瘟病毒修饰的自体肿瘤细胞疫苗特异性主动免疫治疗(NDV ATV ASI)及化疗后患者免疫功能的变化 ,为实施肿瘤生物治疗 +化疗联合方案提供依据。方法 :卵巢癌患者术后 3 4例给予NDV ATV ASI及化疗 ,采用流式细胞术免疫荧光双标记法检测患者治疗后外周血单个核细胞 (PBMC)中CD4+ 、CD8+ 细胞内IFN γ和IL 4的表达 ;体外实验以NDV修饰的自体肿瘤细胞与PBMC共培养 (MLTC) ,观察其早期活化分子CD2 5、CD69的表达。结果 :治疗后CD4+ 、CD8+ T淋巴细胞内IFN γ的表达明显增高 ,IL 4表达轻度增高 ,且增高的时间较晚。外周血CD4+ 、CD8+ T淋巴细胞CD2 5、CD69的表达增加。单纯化疗组CD4+ 、CD8+ 细胞内IFN γ表达降低。结论 :NDV ATV ASI可诱导机体产生抗肿瘤免疫应答 ,检测单个T细胞水平的细胞因子可作为一种简单且可靠的免疫治疗效果评价参数 ;而化疗对机体的免疫功能有抑制作用 ,二者联合应用应选择适当的时间。     

Impact of obesity on chemotherapy dosing for women with advanced stage serous ovarian cancer in the Australian Ovarian Cancer Study (AOCS)

Objectives

Obesity is an increasing health problem that is reported to influence chemotherapy dosing. The extent to which this occurs and whether this affects outcomes in ovarian cancer was unclear.To describe chemotherapy dosing practices in normal, overweight and obese patients treated for FIGO Stage III/IV serous ovarian cancer in the Australian Ovarian Cancer Study (AOCS).To evaluate the relationship between body mass index (BMI), dose intensity of chemotherapy received, overall survival (OS) and progression free survival (PFS).

Methods

Patient characteristics including age, height, weight, FIGO stage, serum creatinine, primary chemotherapy received and outcome data were extracted from medical records and entered into the AOCS database. Outcomes were analysed against BMI and relative dose intensity (RDI) received, based on calculations derived from a standard regimen (carboplatin AUC 5 and paclitaxel 175 mg/m²).

Results

333 women were included in the analysis. 27% were overweight and 21% were obese. In cycle 1 66% of obese patients received carboplatin doses more than 5% below their optimal calculated dose, and 32% received sub-optimal paclitaxel doses, compared to 25% and 13% of normal weight patients respectively. Obese women were more likely to have received < 85% RDI for carboplatin compared to normal weight women (p < 0.001). BMI group and RDI of carboplatin and paclitaxel were not predictors of OS. Women who received less than 85% RDI for carboplatin had a worse PFS (univariate analysis, median PFS 11 versus 15 months; p = 0.04). There was no significant association between RDI and OS or PFS in multivariate analysis.

Conclusions

Obesity is common in ovarian cancer patients, and commonly results in lower chemotherapy dosing than recommended. Analysis of chemotherapy dosing from this study suggests that reduced dose intensity of carboplatin, which was more common in obese women, may impact on PFS in patients with advanced serous ovarian cancer.     

Brush Cytology of the Fallopian Tube and Implications in Ovarian Cancer Screening

Study ObjectiveTo determine whether fallopian tube epithelial cells adequate for cytopathology can be obtained via a minimally invasive approach using brush cytology.DesignProspective feasibility study (Canadian Task Force classification II-1).SettingTertiary-care university-based teaching hospital.PatientsTen patients who underwent laparoscopic hysterectomy, with or without adnexal surgery, because of benign indications.InterventionsAttempted hysteroscopic and laparoscopic brush cytologic sampling of the fallopian tubes.Measurements and Main ResultsThinPrep slides and cell blocks were prepared and analyzed. P53 and KI-67 immunostaining was performed on cell block specimens if adequate cellularity was present. The first 5 patients underwent attempted hysteroscopic sampling of the fallopian tube, with successful collection only in 1 patient. The protocol was then modified to enable sampling of the fallopian tube laparoscopically as well as hysteroscopically. In the other 5 patients sampling of the fallopian tubes was successful laparoscopically, including successful sampling hysteroscopically in 1 patient. The brush biopsy catheter could not be passed through the entire length of the fallopian tube in either the hysteroscopic or laparoscopic approach. All cytologic findings were interpreted as benign, although findings of nuclear overlapping, crowding, and small nucleoli were initially considered benign atypia. Immunohistochemistry for P53 and KI-67 yielded uniformly negative findings.ConclusionTo our knowledge, this is the first study to describe endoscopic brush cytology of the fallopian tubes with correlated cytologic narrative. In the future, cytologic sampling of the fallopian tube may have implications for an ovarian cancer screening test.     

Low serum T3 levels are associated with false-positive results when using the risk of ovarian malignancy algorithm (ROMA) in women with benign ovarian disease

ObjectiveWe investigated factors that could cause false-positive results when using the risk of ovarian malignancy algorithm (ROMA) for assessing ovarian cancer risk.Materials and methodsROMA scores were calculated from patients followed surgery to remove a pelvic mass. We compared a false-positive group with a true-negative group of ROMA scores.ResultsWe analyzed 324 patients using medical records. There were 22 with an epithelial ovarian cancer (EOC), 15 with a borderline ovarian tumor, and 287 with benign disease. Twenty-nine (10.1%) of the patients with benign disease showed high-risk ROMA score (false positive) and 13/37 (35%) patients with EOC, or borderline ovarian tumor showed low ROMA scores (false negatives). The median serum triiodothyronine (T3) level of the false-positive ROMA group in patients with benign disease was lower than in the true-negative ROMA group (p < 0.001) and the estimated glomerular filtration rate (eGFR) was also lower (p = 0.001) in the false-positive ROMA group. Median serum T3 levels in the true-positive ROMA group among patients with EOC, or borderline ovarian tumor were lower than in the false-negative ROMA group (p = 0.043).ConclusionMedian serum T3 level and eGFR in the false-positive ROMA group in patients with benign ovarian disease were lower than in the true-negative group.     

Gonadotropin (LH,FSH) levels in serum and cyst fluid in epithelial tumors of the ovary

Objectives The aim of this work was to determine gonadotropin (LH, FSH) levels in serum and cyst fluid in various type of ovarian epithelial neoplasms (benign, borderline, malignant) and to compare them with levels in benign cysts. Additionally we decided to estimate if there were some significant correlations between serum and ovarian cyst fluid in gonadotropin levels in all investigated groups.Materials and methods The study group included 74 patients before (n=36) and after (n=38) menopause, divided into four groups depending on the histopathologic diagnosis. Serum and cyst fluid levels of LH and FSH were determined in all patients.Results We found statistically significant differences concerning LH and FSH levels in serum and cyst fluid between malignant and borderline tumors, between malignant tumors and benign cystadenomas and between malignant tumors and non-neoplastic cysts. We also found statistically significant correlations between serum and cyst fluid as to FSH and LH levels in patients with borderline tumors. There were no statistically significant correlations between serum and cyst fluid as to FSH and LH levels in patients with malignant epithelial tumors (group 1) and in patients with benign cystadenomas (group 3).Conclusions High FSH and LH levels in cyst fluid of malignant epithelial tumors of the ovary are in line with the gonadotropin theory of tumor growth. Simultaneous determination of various types inhibin levels appears to be an interesting topic for our future research.     

Clinical significance of c-Met and phospho-c-Met (Tyr1234/1235) in ovarian cancer

Objective

c-Met is expressed in human ovarian cancer tissues, and its phosphorylation activates signaling cascades that might affect the behavior of cancer cells. In this study, we evaluated the association of c-Met and phosphorylated c-Met (phospho-c-Met) expressions with the clinical outcomes of ovarian cancer patients.

Opportunities and challenges in ovarian cancer research, a perspective from the 11th Ovarian cancer action/HHMT Forum, Lake Como, March 2007

Advances in surgery and chemotherapy have improved the 5-year survival for patients with epithelial ovarian cancer, but have not impacted on the ultimate rate of cure in a disease that is diagnosed in late stage and that recurs in the majority of patients. “Omic” technologies promise to define genetically driven aberrant signaling pathways in malignant cells, provided that bioinformatic expertise can be focused on a cancer that is neither common nor rare. Molecular therapeutics must be linked to molecular diagnostics to permit individualized therapy. Not only epithelial cancer cells but also stroma, vasculature and the immune response must be targeted. Closer collaboration between academic institutions, biotech and pharma will be required to facilitate this process and to interest the private sector in an orphan disease. New preclinical models may permit more efficient development of drugs and siRNA that can target dormant drug resistant stem cells. Strategies must be developed to deal with the heterogeneity of different grades and histotypes. Identification of women at increased risk will facilitate prevention and early detection in subsets of patients. BRCA1/2 might be sequenced in all ovarian cancer patients to identify new kindreds. Epidemiologic algorithms are being developed and validated. Awareness must be raised that oral contraceptives can reduce risk of developing ovarian cancer by 50%. Early detection is likely to require panels of complementary biomarkers, analyzed by sophisticated statistical techniques, to improve sensitivity while maintaining extremely high specificity. As ovarian cancer becomes a chronic disease, greater emphasis will be placed on the challenges facing survivors.     

Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis

OBJECTIVE: Women with endometriosis may be at an increased risk of ovarian cancer. It is not known whether reproductive factors that reduce the risk of ovarian cancer in general also reduce risk in women with endometriosis. We investigated whether the odds ratios for ovarian cancer that were associated with oral contraceptive use, childbearing, hysterectomy, and tubal ligation differ among women with and without endometriosis. STUDY DESIGN: We pooled information on the self-reported history of endometriosis from 4 population-based case-controlled studies of incident epithelial ovarian cancer, comprising 2098 cases and 2953 control subjects. We obtained data on oral contraceptive use, childbearing, breastfeeding, gynecologic surgical procedures, and other reproductive factors on each woman. Multivariable unconditional logistic regression was used to calculate odds ratios and 95% CI for ovarian cancer among women with endometriosis compared with women without endometriosis. Similar methods were used to assess the frequencies of risk factors among women with and without endometriosis. Adjustments were made for age, parity, oral contraceptive use, tubal ligation, family history of ovarian cancer, and study site. RESULTS: Women with endometriosis were at an increased risk of ovarian cancer (odds ratio, 1.32; 95% CI, 1.06-1.65). Using oral contraceptives, bearing children, and having a tubal ligation or hysterectomy were associated with a similar reduction in the odds ratios for ovarian cancer among women with and without endometriosis. In particular, the use of oral contraceptives for >10 years was associated with a substantial reduction in risk among women with endometriosis (odds ratio, 0.21; 95% CI, 0.08-0.58). CONCLUSION: Women with endometriosis are at an increased risk of epithelial ovarian cancer. Long-term oral contraceptive use may provide substantial protection against the disease in this high-risk population.     

Statins,aspirin and risk of thromboembolic events in ovarian cancer patients

Objectives

Studies suggest that statins and low dose aspirin reduce risk of VTEs in the general population. We aimed to study the effect of these drugs on the incidence of VTEs in patients with ovarian cancer.

Methods

Patients diagnosed with ovarian cancer between 2000 and 2011 were identified through the Clalit Health Services (CHS) chronic disease registry. Data were extracted from CHS database and from computerized pharmacy records. Use of medications was analyzed as a time dependent covariate in a Cox regression model.

Results

Of 1746 patients 175 (10%) had a VTE during a median follow up of 3.13 years. 83 patients (5.6%) had a VTE within 2 years of diagnosis of ovarian cancer. Use of chemotherapy and stage 3 and 4 at presentation were associated with an increased risk for VTEs.Statins were used by 43.5% of the patients, and 32.3% used aspirin. Aspirin use was associated with a marginally significant reduction in incidence of VTEs within 2 years of diagnosis, HR 0.423 (95% CI 0.182–1.012, p-value 0.053). Statin use was not associated with risk of VTEs.

Conclusion

This is the first study looking at the effect of statins and aspirin on the incidence of VTEs in ovarian cancer patients. In our cohort, statins did not decrease the risk for a VTE and aspirin use was associated with a reduced risk which was marginally significant. Our results might be explained by use of low potency statins and by alternate mechanisms for VTE formation in cancer patients.     

Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum

OBJECTIVE: Previously reported data have suggested the lack of complete cross-resistance between docetaxel and paclitaxel in ovarian cancer. We wished to evaluate the biological and clinical activity of docetaxel in a patient population with well-characterized platinum and paclitaxel-refractory ovarian cancer. METHODS: In this single-institution phase 2 trial, 30 women with advanced ovarian cancer whose disease had either failed to respond to primary platinum-paclitaxel chemotherapy or where the cancer had progressed within 3 months of their last treatment with both a platinum agent and paclitaxel were treated with single agent docetaxel (75 mg/m(2) q 3 weeks). Due to a prior history of excessive chemotherapy-induced neutropenia, 3 patients initiated treatment at a dose of 60 mg/m(2). RESULTS: The median number of courses of docetaxel delivered on this protocol was 3 (range 1-7), with 7 patients requiring dose reductions due to treatment-related side effects. The most common toxicities included grade 4 neutropenia, neutropenic fever, and grade >/=2 fatigue experienced by 9 (30%), 2 (7%), 5 (17%) patients, respectively. Three patients (10%) achieved both an objective response (by CA-125 criteria) and symptomatic improvement (e.g., decrease in pain and ascites). The durations of responses were 3, 4, and 6 months. CONCLUSION: Single-agent docetaxel has modest, but definite activity in patients with well-characterized platinum and paclitaxel-resistant ovarian cancer. Use of this drug should be considered a rational management approach in appropriately selected patients in this clinical setting.