OLT1177, a ß-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.

Activation of the NLRP3 inflammasome induces maturation of IL-1ß and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active ß-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1ß and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1ß levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1ß release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1ß release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1ß precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1ß content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

Endometrial adenocarcinoma following supracervical hysterectomy managed with radiation due to dabigatran etexilate.

BACKGROUND: Dabigatran etexilate, a new oral anticoagulant, has been developed for use in atrial fibrillation. This medication does not require therapeutic monitoring and there is no reversal agent in the event of life-threatening bleeding. We present a case of vaginal hemorrhage because of endometrial adenocarcinoma after a supracervical hysterectomy in a patient using dabigatran. CASE: 74-year-old woman status after supracervical hysterectomy presented with profuse vaginal bleeding. Biopsy confirmed high-grade adenocarcinoma, suggesting endometrial origin. Because of recent use of dabigatran and vaginal bleeding she underwent treatment with full-dose radiation and brachytherapy. CONCLUSION: Adenocarcinoma following supracervical hysterectomy is a rare occurrence. In the presence of profuse bleeding because of an anticoagulant with no reversal agents and extended activity, alternate modalities may be used.

The effect of ovarian imaging on the clinical interpretation of a multivariate index assay.

OBJECTIVE: The purpose of this study was to investigate the relationship between imaging and the multivariate index assay (MIA) in the prediction of the likelihood of ovarian malignancy before surgery. STUDY DESIGN: Subjects were recruited in 2 related prospective, multiinstitutional trials that involved 44 sites across the United States. Women had ovarian imaging, biomarker analysis, and surgery for an adnexal mass. Ovarian tumors were classified as high risk for solid or papillary morphologic condition on imaging study. Biomarker and imaging results were correlated with surgical findings. RESULTS: Of the 1110 women who were enrolled with an adnexal mass on imaging, 1024 cases were evaluable. There were 255 malignant and 769 benign tumors. High-risk findings were present in 46% of 1232 imaging tests and 61% of 1024 MIA tests. The risk of malignancy increased with rising MIA scores; similarly, the likelihood of malignancy was higher for high-risk, compared with low-risk, imaging. Sensitivity and specificity for the prediction of malignancy were 98% (95% CI, 92-99) and 31% (95% CI, 27-34) for ultrasound or MIA; 68% (95% CI, 58-77) and 75% (95% CI, 72-78) for ultrasound and MIA, respectively. For computed tomography scan or MIA, sensitivity was 97% (95% CI, 92-99) and specificity was 22% (95% CI, 16-28); the sensitivity and specificity for computed tomography scan and MIA were 71% (95% CI, 62-79) and 70% (95% CI, 63-76). Only 1.6% of ovarian tumors were malignant when both tests indicated low risk. A logistic regression model to predict risk of malignancy is presented. CONCLUSION: An understanding of how pelvic imaging influences the MIA score can help clinicians better interpret the malignant risk of an ovarian tumor.

Ovarian cyst fluids are a cache of tumor biomarkers that include calgranulin A and calgranulin B isoforms.

SELDI-TOF MS analysis of cyst fluids identified 95 peaks that discriminate malignant, borderline, and benign ovarian tumors. Three prominent peaks, which correspond to calgranulin A (m/z 10847) and two isoforms of calgranulin B (m/z 12717 and 13294), have higher concentrations in borderline and malignant cyst fluids. Together, calgranulin A and B distinguish borderline and malignant tumors from benign tumors with 28.6% and 63.6% sensitivity for early stage disease, respectively, at 95% specificity and with 74.8% accuracy. Ovarian cyst fluids are useful for discovering discriminatory biomarkers, such as calgranulin, which may have utility for detecting, diagnosing, and biochemically classifying ovarian tumors.

Ten-year relative survival for epithelial ovarian cancer.

OBJECTIVE: Most patients with epithelial ovarian cancer who are alive at 5 years have active disease. Thus, 10-year survival rather than 5-year survival may be a more appropriate endpoint. Relative survival adjusts for the general survival of the United States population for that race, sex, age, and date at which the diagnosis was coded. Our objective was to estimate relative survival in epithelial ovarian cancer over the course of 10 years. METHODS: Using the Surveillance, Epidemiology and End Results 1995-2007 database, epithelial ovarian cancer cases were identified. Using the actuarial life table method, relative survival over the course of 10 years was calculated, stratified by stage, classification of residence, surgery as the first course of treatment, race, and age. RESULTS: There were 40,692 patients who met inclusion criteria. The overall relative survival was 65%, 44%, and 36% at 2, 5, and 10 years, respectively. The slope of decline in relative survival was reduced for years 5-10 as compared with years 1-5 after diagnosis. Relative survival at 5 years was 89%, 70%, 36%, and 17%, and at 10 years relative survival was 84%, 59%, 23%, and 8% for stages I, II III, and IV, respectively. At all stages, patients with nonsurgical primary treatment and those with advanced age had reduced relative survival. CONCLUSIONS: The 10-year relative survival for stage III is higher than expected. This information provides the physician and the patient with more accurate prognostic information.

Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening.

OBJECTIVE: To estimate the effect of ultrasonographic screening on stage at detection and long-term disease-specific survival of women with epithelial ovarian cancer. METHODS: Eligibility included all asymptomatic women aged 50 years and older and women aged 25 years and older with a documented family history of ovarian cancer. From 1987 to 2011, 37,293 women received annual ultrasonographic screening. Women with abnormal screens underwent tumor morphology indexing, serum biomarker analysis, and surgery. RESULTS: Forty-seven invasive epithelial ovarian cancers and 15 epithelial ovarian tumors of low malignant potential were detected. No women with low malignant potential tumors experienced recurrent disease. Stage distribution for invasive epithelial cancers was: stage I, 22 (47%); stage II, 11 (23%); stage III, 14 (30%), and stage IV, 0 (0%). Follow-up varied from 2 months to 20.1 years (mean, 5.8 years). The 5-year survival rate for invasive epithelial ovarian cancers detected by screening was: stage I, 95%±4.8%; stage II, 77.1%±14.5%; and stage III, 76.2%±12.1%. The 5-year survival rate for all women with invasive epithelial ovarian cancer detected by screening as well as interval cancers was 74.8%±6.6% compared with 53.7%±2.3% for unscreened women with ovarian cancer from the same institution treated by the same surgical and chemotherapeutic protocols (P<.001). CONCLUSION: Annual ultrasonographic screening of asymptomatic women achieved increased detection of early-stage ovarian cancer cases and an increase in 5-year disease-specific survival rate for women with ovarian cancer. LEVEL OF EVIDENCE: II.

Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors.

OBJECTIVE: To compare the effectiveness of physician assessment with a new multivariate index assay in identifying high-risk ovarian tumors. METHODS: The multivariate index assay was evaluated in women scheduled for surgery for an ovarian tumor in a prospective, multi-institutional trial involving 27 primary- care and specialty sites throughout the United States. Preoperative serum was collected, and results for the multivariate index assay, physician assessment, and CA 125 were correlated with surgical pathology. Physician assessment was documented by each physician before surgery. CA 125 cutoffs were chosen in accordance with the referral guidelines of the American College of Obstetricians and Gynecologists. RESULTS: The study enrolled 590 women, with 524 evaluable for the multivariate index assay and CA 125, and 516 for physician assessment. Fifty-three percent were enrolled by nongynecologic oncologists. There were 161 malignancies and 363 benign ovarian tumors. Physician assessment plus the multivariate index assay correctly identified malignancies missed by physician assessment in 70% of nongynecologic oncologists, and 95% of gynecologic oncologists. The multivariate index assay also detected 76% of malignancies missed by CA 125. Physician assessment plus the multivariate index assay identified 86% of malignancies missed by CA 125, including all advanced cancers. The performance of the multivariate index assay was consistent in early- and late-stage cancers. CONCLUSION: The multivariate index assay demonstrated higher sensitivity and lower specificity compared with physician assessment and CA 125 in detecting ovarian malignancies.

Performance of the American College of Obstetricians and Gynecologists' ovarian tumor referral guidelines with a multivariate index assay.

OBJECTIVE: The American College of Obstetricians and Gynecologists (the College) published referral guidelines for women with a pelvic mass that incorporate CA 125. A new multivariate index assay assesses the malignant risk of ovarian tumors before surgery. Our objective was to estimate the performance of the College guidelines with this new multivariate index assay. METHODS: This prospective, multi-institutional trial included 27 primary care and specialty sites throughout the United States. The College guidelines were evaluated in women scheduled for surgery for an ovarian mass. Clinical criteria and blood for biomarkers were collected before surgery. A standard CA 125-II assay was used and the value applied to the multivariate index assay algorithm and the CA 125 analysis. Study results were correlated with surgical pathology. RESULTS: Of the 590 women enrolled with ovarian mass on pelvic imaging, 516 were evaluable. There were 161 malignancies (45 premenopausal and 116 postmenopausal). The College referral criteria had a modest sensitivity in detecting malignancy. Replacing CA 125 with the multivariate index assay increased the sensitivity (77-94%) and negative predictive value (87-93%) while decreasing specificity (68-35%) and positive predictive value (52-40%). Similar trends were noted for premenopausal women and early-stage disease. CONCLUSION: Replacing CA 125 with the multivariate index assay improves the sensitivity and negative predictive value of the College referral guidelines while decreasing specificity and positive predictive value. The high sensitivity is maintained in premenopausal women and early-stage disease.

Risk of malignancy in sonographically confirmed septated cystic ovarian tumors.

OBJECTIVE: To determine the risk of malignancy in septated cystic ovarian tumors. MATERIALS: 1319 (4.4%) of 29,829 women were identified by transvaginal sonography (TVS) as having a complex cystic ovarian tumor with septations without solid areas or papillary projections and were placed on long-term ultrasound surveillance for ovarian malignancy. RESULTS: These 1319 patients had a total of 2870 septated cystic ovarian tumors. 2288 tumors (79.7%) had a septal width <2 mm and 582 (20.3%) had a septal width >or=2 mm. 2286 tumors (79.6%) were <5 cm in diameter and 584 (20.4%) were>or=5 cm in diameter. 1114 septated cystic tumors (38.8%) resolved spontaneously (mean duration to resolution-12 months) and 1756 (61.2%) tumors persisted. 128 patients underwent surgical tumor removal within 3 months of ultrasound. Most common histopathology was: serous cystadenoma (75), mucinous cystadenoma (13), and endometrioma (10). One patient had an ovarian tumor of borderline malignancy (Stage IB). There were no cases of ovarian cancer. Patients were followed from 4 to 252 months (mean-77 months). One patient developed papillary morphology in the contralateral ovary 3.2 years after detection of a septated ovarian cyst and had epithelial ovarian cancer in that ovary and in the omentum (Stage IIIC disease). The remaining patients are all free of ovarian neoplasia after a total of 7642 follow-up years. CONCLUSIONS: Septated cystic ovarian tumors without solid areas or papillary projections have a low risk of malignancy and can be followed sonographically without surgery.

Predicting risk of malignancy in adnexal masses.

OBJECTIVE: To estimate the accuracy of preoperative ultrasonography, serum CA 125, and patient demographics as a means of predicting risk of malignancy in women with a ultrasonographically confirmed adnexal mass. METHODS: Tumor morphology derived from ultrasonographic images, tumor size, tumor bilaterality, serum CA 125, and patient demographics were evaluated preoperatively in 395 patients undergoing surgery from 2001 to 2008. Tumor morphology was classified as complex, solid, or cystic. Preoperative findings were compared with tumor histologic findings at the time of surgery. Multivariable classification and regression tree analysis were used to identify a group of patients at high risk of ovarian malignancy. RESULTS: One hundred eighteen patients had ovarian cancer, 13 patients had ovarian tumors of borderline malignancy, and 264 had benign ovarian tumors. Multivariable classification and regression tree analysis defined women at high risk of ovarian malignancy as those with an adnexal mass having complex or solid morphology and a serum CA 125 value greater than 35 units/mL. This definition had a positive predictive value of 84.7% and a negative predictive value of 92.4% and correctly identified 77.3% of patients with stage I and stage II ovarian cancer and 98.6% of patients with stage III and stage IV ovarian cancer. CONCLUSION: Patients with solid or complex ovarian tumors and an elevated serum CA 125 level (greater than 35 units/mL) are at high risk of ovarian malignancy. LEVEL OF EVIDENCE: II.

Clinical implementation of soluble EGFR (sEGFR) as a theragnostic serum biomarker of breast, lung and ovarian cancer.

Signal transduction pathways regulated by the EGFR/ERBB/HER proto-oncogene family and receptor tyrosine kinases encoded by these genes are known to become dysregulated during cellular transformation and carcinogenesis. Consequently, biologically targeted antibodies and tyrosine kinase inhibitors directed toward EGFR/ErbB1/HER1 (eg, cetuximab, erlotinib and gefitinib) and ErbB2/HER2 (eg, trastuzumab), and more recently toward ErbB3/HER3 and ErbB4/HER4, are being investigated as therapeutic agents for treating patients with EGFR/ERBB/HER proto-oncogene-driven malignancies. The accurate selection of patients who will respond efficaciously to these agents a priori is a medical challenge. Understanding the clinical utility of soluble EGFR/ErbB/HER (ie, sEGFR/sErbB/sHER) isoforms, which are present in circulatory fluids, as theragnostic cancer biomarkers is an emerging area of contemporary biomedical investigation. This feature article reviews the literature regarding the clinical utility of serum sEGFR/sErbB1/sHER1 in breast, lung and ovarian cancer, and discusses the potential role of sEGFR in predicting and monitoring therapeutic responsiveness, as well as disease recurrence, and/or predicting disease outcome in patients treated with specific small-molecule, hormonal or biotherapeutic drug regimens. Well-designed translational research studies are needed to validate sEGFR as a theragnostic biomarker further and to achieve routine clinical implementation.

Modeling an integrative physical examination program for the Departments of Defense and Veterans Affairs.

Current policies governing the Departments of Defense and Veterans Affairs physical examination programs are out of step with current evidence-based medical practice. Replacing periodic and other routine physical examination types with annual preventive health assessments would afford our service members additional health benefit at reduced cost. Additionally, the Departments of Defense and Veterans Affairs repeat the physical examination process at separation and have been unable to reconcile their respective disability evaluation systems to reduce duplication and waste. A clear, coherent, and coordinated strategy to improve the relevance and utility of our physical examination programs is long overdue. This article discusses existing physical examination programs and proposes a model for a new integrative physical examination program based on need, science, and common sense.

Update on the treatment of recurrent ovarian cancer.

Ovarian cancer is the leading cause of death for all gynecologic malignancies in developed countries, largely owing to the late stage of diagnosis. Despite response to initial surgery and chemotherapy, more than 65% of patients will have recurrent or persistent diseases. Approximately 50% of patients with recurrent ovarian cancer are asymptomatic. Recurrences are often diagnosed using a combination of tests, including cancer antigen 125, computed tomography, magnetic resonance imaging and positron emission tomography scan. The most significant prognostic factor among women with recurrent ovarian cancer is the length of time from initial diagnosis to recurrence. Treatment of recurrent ovarian cancer involves chemotherapy, with or without surgery. In selected patients, secondary cytoreductive surgery might significantly improve survival. Radiotherapy may have a role in the treatment of a small group of patients with localized symptomatic masses. New treatment modalities for women with recurrent ovarian cancer are needed, as none of the available treatments are curative.