Neural network-derived multivariate index assay demonstrates effective clinical performance in longitudinal monitoring of ovarian cancer risk.

OBJECTIVE: We recently characterized the clinical performance of a multivariate index assay (MIA3G) to assess ovarian cancer risk for adnexal masses at initial presentation. This study evaluated how MIA3G varies when applied longitudinally to monitor risk during clinical follow-up. METHOD: The study evaluated women presenting with adnexal masses from eleven centers across the US. Patients received an initial blood draw at enrollment and at the standard-of-care follow-up visits. MIA3G was determined for all visits but physicians did not have access to MIA3G scores to determine clinical management. The primary outcome was the relative change value (RCV) of MIA3G over the period of clinical observation. RESULTS: A total of 510 patients of 785 enrolled met study criteria. Of these, 30.8% had a second, 25.4% a third and 22.2% a fourth blood draw following initial collection. The median duration from initial draw was 131 d to second draw, 301.5 d to the third draw and 365.5 d to the fourth draw. MIA3G RCV of >50% was observed in 22-26% patients, whereas 70-75% patients had MIA3G RCV >5%. An empirical baseline RCV of 56% - transformed to 1 in logarithmic scale - was calculated from averaging RCVs of all patients who had no malignancy risk after 210 days. RCV > 1 log was associated with higher incidence of surgical intervention (29.6%) compared to RCV < 1 log (16.9%). CONCLUSIONS: Variation in MI3AG does not change the accuracy of the test for excluding malignancy, while marked changes may be associated with a slightly higher likelihood of surgical intervention. In addition to MIA3G score itself, the MIA3G RCV may be important for clinical management.

Ovarian Cancer surgical consideration is markedly improved by the neural network powered-MIA3G multivariate index assay.

Background: Surgery remains the main treatment option for an adnexal mass suspicious of ovarian cancer. The malignancy rate is, however, only 10-15% in women undergoing surgery. This results in a high number of unnecessary surgeries. A surveillance-based approach is recommended to form the basis for surgical referrals. We have previously reported the clinical performance of MIA3G, a deep neural network-based algorithm, for assessing ovarian cancer risk. In this study, we show that MIA3G markedly improves the surgical selection for women presenting with adnexal masses. Methods: MIA3G employs seven serum biomarkers, patient age, and menopausal status. Serum samples were collected from 785 women (IQR: 39-55 years) across 12 centers that presented with adnexal masses. MIA3G risk scores were calculated for all subjects in this cohort. Physicians had no access to the MIA3G risk score when deciding upon a surgical referral. The performance of MIA3G for surgery referral was compared to clinical and surgical outcomes. MIA3G was also tested in an independent cohort comprising 29 women across 14 study sites, in which the physicians had access to and utilized MIA3G prior to surgical consideration. Results: When compared to the actual number of surgeries (n = 207), referrals based on the MIA3G score would have reduced surgeries by 62% (n = 79). The reduction was higher in premenopausal patients (77%) and in patients ≤55 years old (70%). In addition, a 431% improvement in malignancy prediction would have been observed if physicians had utilized MIA3G scores for surgery selection. The accuracy of MIA3G referral was 90.00% (CI 87.89-92.11), while only 9.18% accuracy was observed when the MIA3G score was not used. These results were corroborated in an independent multi-site study of 29 patients in which the physicians utilized MIA3G in surgical consideration. The surgery reduction was 87% in this cohort. Moreover, the accuracy and concordance of MIA3G in this independent cohort were each 96.55%. Conclusion: These findings demonstrate that MIA3G markedly augments the physician's decisions for surgical intervention and improves malignancy prediction in women presenting with adnexal masses. MIA3G utilization as a clinical diagnostic tool might help reduce unnecessary surgeries.

Multimodal hyperspectroscopy as a triage test for cervical neoplasia: pivotal clinical trial results.

OBJECTIVE: To prospectively evaluate a new non invasive device that combines fluorescence and reflectance spectroscopy in a population in women at risk for cervical dysplasia. METHODS: A total of 1607 women were evaluated with multimodal hyperspectroscopy (MHS), a painless test with extremely high spectral resolution. Subjects who were referred to colposcopy based on abnormal screening tests or other referral criteria underwent the MHS test and also had a sample taken for additional cytology and presence of high risk human papilloma virus (HPV) prior to undergoing biopsy. RESULTS: Sensitivity of MHS for cervical intraepithelial neoplasia (CIN) 2+ was 91.3% (252/276). Specificity, or the potential reduction in referrals to colposcopy and biopsy, was 38.9% (222/570) for women with normal or benign histology and 30.3% (182/601) for women with CIN1 histology. Two year follow-up data, collected for a subgroup of 804 women, revealed 67 interval CIN2+ that originally were diagnosed at enrollment as normal or CIN1. MHS identified 60 of these (89.6%) as positive for CIN2+ prior to their discovery during the two year follow-up period. CONCLUSIONS: MHS provides an immediate result at the point of care. Recently, the limitations of cytology have become more obvious and as a consequence greater emphasis is being placed on HPV testing for cervical cancer screening, creating a need for an inexpensive, convenient and accurate test to reduce false positive referrals to colposcopy and increase the yield of CIN2+ at biopsy. MHS appears to have many of the attributes necessary for such an application.

High-risk HPV DNA testing and HPV-16/18 genotyping: what is the clinical application?

OBJECTIVE: There are currently 2 tests approved for clinical use that nonspecifically detect the presence of multiple oncogenic or high-risk human papillomavirus (HPV) types. One HPV genotyping test is also available for use that specifically detects the presence of high-risk HPV types 16 and 18. The purpose of this review was to evaluate the clinical performance of these HPV DNA tests and the utility of the tests within current screening recommendations. MATERIALS AND METHODS: The sensitivity and specificity of currently available HPV DNA tests to detect the presence of precancerous high-grade cervical lesions are reviewed. Appropriate test usage is discussed in the context of the natural history of HPV infection. RESULTS: Molecular testing for the presence of high-risk HPV is more sensitive but less specific than cytologic testing for the detection of high-grade cervical lesions. Current patient management guidelines recommend the use of high-risk HPV DNA testing to triage women 21 years or older with equivocal cytology results and in conjunction with cytology for cervical screening in women 30 years or older. The HPV-16/18 genotyping test may be used in women 30 years or older with negative cytology and positive high-risk HPV DNA test results to determine the need for colposcopy. CONCLUSIONS: Although infection with high-risk HPV is highly prevalent in adult females, most infections are transient and do not require intervention. Clinical application of appropriate age-adjusted use of HPV DNA testing and its use in conjunction with atypical squamous cells of undetermined significance cytology will avoid unnecessary follow-up procedures.

Laparoendoscopic single-site extraperitoneal aortic lymphadenectomy: first experience.

OBJECTIVES: To report the first clinical experience with laparoendoscopic single-site (LESS) extraperitoneal aortic lymphadenectomy. MATERIALS AND METHODS: A 33-year-old woman with biopsy proven locally advanced squamous cell carcinoma of the cervix was taken to the operating room for surgical staging. Preoperative imaging did not detect any aortic lymph node metastases. Informed consent for LESS extraperitoneal aortic lymphadenectomy was obtained. A 2 cm transverse incision was made on the left side midway between the iliac crest and inferior costal margin along the middle axillary line. The preperitoneal space was created and the Triport(TM) inserted. Using the Deflectable-Tip EndoEye(TM) laparoscope and two straight instruments, the aortic lymphadenectomy was performed as defined by the disease-specific oncologic principles. RESULTS: The procedure was completed in 125 minutes. There were no intraoperative or postoperative complications, and the blood loss was minimal (10 mL). The patient was discharged home on postoperative day number 1. LESS extraperitoneal aortic lymphadenectomy yielded 10 lymph nodes. Microscopic metastatic squamous cell carcinoma was detected in 1 out of the 10 lymph nodes. Her treatment plan was modified to extend the field of radiation to include the paraaortic lymphatic basins. CONCLUSIONS: LESS extraperitoneal aortic lymphadenectomy is feasible and safe, and provides a comprehensive assessment of aortic lymph nodes as defined by the disease-specific oncologic principles.

A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium.

OBJECTIVE: To evaluate the feasibility of combining low-dose fractionated whole abdominal radiation (LDF-WAR) with weekly full-dose cisplatin (FD-CDDP) for patients with stage III/IV endometrial carcinoma. METHODS: Patients with optimally debulked stage III/IV carcinoma of the endometrium (without extra-abdominal disease) were eligible for the study. Postoperatively, patients received the institutional standard systemic chemotherapy and vaginal brachytherapy. Patients then underwent experimental six weekly cycles of FD-CDDP (40 mg/m², maximum 70 mg IV) followed by LDF-WAR 6-8 hours after initiation of chemotherapy. In a conservative design, 6 patients were accrued to two sequential cohorts of LDF-WAR, at 0.5 Gy/fraction [Fx] (total 3 Gy) and 0.75 Gy/Fx (total 4.5 Gy). Toxicities and laboratory studies were evaluated at each visit. RESULTS: Twelve patients were enrolled from January 2005 to June 2009 with median follow-up of 13.5 months (range: 5-27 months). Seventy-five percent of enrolled patients had uterine papillary serous histology. Eleven patients at least partially completed therapy (range: 2-6 cycles of FD-CDDP/LDF-WAR) with one additional patient opting out at the higher dose level. Combination therapy overall was well tolerated. Three patients in each cohort experienced grade 3 acute hematologic events with one recorded grade 4 toxicity in the second cohort. Of patients receiving any of the experimental treatment, five have experienced recurrences. Three of these patients were in cohort one and received 0.5 Gy/Fx LDF-WAR. CONCLUSION: Combination therapy with LDF-WAR as a novel chemopotentiator to FD-CDDP is a feasible adjuvant regimen in optimally debulked patients with stage III/IV endometrial carcinoma. Further investigation is warranted to determine treatment efficacy.

Metastatic gestational trophoblastic neoplasia complicated by tumor lysis syndrome, heart failure, and thyrotoxicosis: a case report.

BACKGROUND: Tumor lysis syndrome (TLS) is an extremely rare complication of solid tumors and is more frequently observed in patients with hematologic malignancies. This report describes a novel approach to the management of a rare case of TLS in metastatic gestational trophoblastic neoplasia (GTN). CASE: A 17-year-old female presented 8 weeks postpartum with severe anemia, thyrotoxicosis, and elevated serum beta-human chorionic gonadotropin (beta-hCG). Imaging studies confirmed metastatic GTN to the lungs. The patient developed grade 4 TLS after the first cycle of etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA-CO). She did not respond to standard treatment of aggressive hydration and allupurinol and continued to be in renal failure with elevated uric acid. A single dose of recombinant urate oxidase, rasburicase, rendered the uric acid level undetectable in 3 days and completely reversed the renal failure, avoiding hemodialysis. Three more cycles of EMA-CO were then administered. Subsequently, the patient developed congestive heart failure and was switched to single-agent actinomycin-D. Beta-hCG became negative after 5 cycles, and her ejection fraction returned to baseline. CONCLUSION: This is a rare case of TLS in the setting of metastatic GTN. To our knowledge this is the first reported case of utilizing rasburicase for the management of TLS in GTN.

Women with HIV are more commonly infected with non-16 and -18 high-risk HPV types.

OBJECTIVE: To review and summarize evidence from clinical, translational and epidemiologic studies which have examined the clinically relevant aspects of HPV type prevalence and cervical dysplasia in HIV-infected women. METHODS: Relevant studies were identified through a MEDLINE search. References of identified reports were also used to identify additional published articles for review. RESULTS: HIV-infected women in different geographic regions (such as Zambia, Brazil, Rochester NY) appear to be infected with less prevalent types of HR-HPV as compared to the general population who, across all continents, are more commonly infected with types 16 and 18. Secondly, integration of HPV DNA into the host genome is no longer thought to be a necessary cause of malignant transformation of cervical cells. However, rate of integration appears to differ by the type of HPV. In fact, the types of HPV which appear to be more common in cervical dysplasia of HIV-infected women are the same types which are more likely to require integration for malignant transformation. Finally, HPV types found in HIV-infected women are relatively common and likely to persist. The most common among these types belong to the alpha-9 and -7 species which are the most carcinogenic species. CONCLUSION: Given that current vaccines target HR-HPV-16/18, the findings from the above mentioned studies may have important implications for the design of HPV vaccines that target the types of HPV associated with disease risk in HIV-infected women. HPV typing and assessment of the physical state (whether it is integrated or episomal) appear to be two valuable parameters for the prognostic evaluation of dysplastic lesions of the uterine cervix. This, however, has not yet been assessed in HIV-infected women. Recent data about the immune response in HPV/HIV co-infection may lead to understanding potential mechanisms for less virulent HPV causing malignant transformation in HIV-infected women.

Association of human papillomavirus with vulvar and vaginal intraepithelial disease: opportunities for prevention.

While the majority of studies regarding the health benefits from human papillomavirus (HPV) vaccination have focused on cervical neoplasia and cancer, few have investigated how the epidemiology of vaginal and vulvar disease may be affected. To better understand how occurrence rates for vaginal and vulvar neoplasias and carcinomas may change in the future, we must have an understanding of the overall disease prevalence within a given population, the efficacy of vaccination and the proportion of cases attributable to HPV types administered in the vaccine. In this review, we will examine basic HPV epidemiology and prevalence, the molecular transformation events carried out by HPV oncoproteins, and clinical trials monitoring HPV-induced disease of the female genital tract. While precise projections of exactly how vaginal and vulvar disease prevalence will change with vaccination will require more studies, the preliminary data are promising.

Human papillomavirus vaccination: the policy debate over the prevention of cervical cancer--a commentary.

The human papillomavirus (HPV) family causes a variety of benign, premalignant, and malignant lesions in men and women. HPV types 16 and 18 are responsible for causing 70% of all cases of cervical cancer each year. Recently, a vaccine that can prevent cervical cancer by protecting women from infection with the most common types of HPV has been made available. Following Food and Drug Administration approval and endorsement by the Centers for Disease Control and Prevention, it is the right and the duty of the state legislatures to implement vaccination programs. This vaccine, a vaccine for a sexually transmitted disease, has stirred a fierce debate. Religion and sexuality have dominated the discussion, and political calculations are inherent to the process; nonetheless, epidemiological analyses are also essential to the decision to mandate the HPV vaccine. HPV vaccine program implementation processes are at many stages in many states, and programs vary widely. Some provide information to families, whereas others allot a range of funding for voluntary vaccination. Virginia is, thus far, the only state to have enacted a mandate. This article discusses the various programs in place, the proposed legislation, and the debate surrounding the political process.

Hormone replacement therapy in endometrial cancer survivors: new perspectives after the heart and estrogen progestin replacement study and the women's health initiative.

OBJECTIVE: Dramatic shifts in prescription practices during the last 30 years have left physicians confused and uncertain about the use of hormone replacement therapy (HRT) in endometrial cancer survivors. MATERIALS AND METHODS: This article reviews the published literature concerning both the safety of prescribing HRT to endometrial cancer survivors and the therapy s potential risks and benefits. RESULTS: Prescribing HRT to endometrial cancer survivors does not seem to be contraindicated and may even confer modest protection, depending on the doses and the specific drugs used. The potential benefits of HRT are more conflicting. Although the medical community agrees on the positive effects for bone density and relief of vasomotor symptoms, the results of our review offer no clear consensus in regard to HRT's effects on coronary heart disease, health-related quality of life, cognitive functioning, and cancer incidence. CONCLUSIONS: Until the medical community can concur on the proper prescription practices in endometrial cancer survivors, an individualized patient-based approach must be taken.

Searching for an efficient institutional review board review model: Interrelationship of trainee-investigators, funding, and initial approval.

In this study we sought to identify variables associated with institutional review board (IRB) decisions to develop an efficient "pre-IRB" review model. We explored several variables, including relationships among the identification of trainees as investigators, external sources of funding, and initial approval. The sample consisted of all new submissions reviewed by the 2 medical IRBs at the University of Miami (UM) during a 1-year period. Trainees included students, residents, and fellows. At least 1 trainee had to be identified for a proposal to be considered a trainee submission. The medical-science committees (MSCs) were similar with regard to the numbers of new submissions they reviewed during convened meetings (MSC-A 242, MSC-B 241) and the percentages of proposals that were initially approved (MSC-A 52.9%, MSC-B 53.1%). Approved submissions were defined as those initially approved or conditionally approved pending minor modifications. We noted a robust statistical difference between the percentages of trainee submissions initially approved (39.9%) and submissions that did not identify a trainee (59.4%) ( P <.0001). Of the proposals that were initially not approved (tabled [deferred] or rejected [not approved]), 28.9% of those including a trainee were rejected, compared with 11.0% without a trainee ( P <.001). Proposals in which the source of funding was identified were more likely to be approved (64.2%) than were those in which it was not (30.8%) ( P <.0001). Funding also seemed to influence the trainee and initial-approval interaction. Our results show that new submissions that identified trainee investigators were more likely to be deferred or not approved than those that did not. Nonapproved proposals that identified a trainee were 3.8 times more likely to be initially rejected than those that did not. A prereview model could target those submissions that list a trainee, lack funding, or both.

Twenty-five year outcome of sequential abdominal radiotherapy and melphalan:implications for future management of epithelial carcinoma of the ovary.

OBJECTIVE: The purpose of the present study is evaluation of the long-term efficacy of sequential abdominopelvic radiotherapy and melphalan in the management of ovarian carcinoma. METHODS: From 1970 to 1976, 94 women with stages I-III epithelial ovarian carcinoma enrolled in a prospective nonrandomized clinical trial were prescribed 20 Gy to the upper abdomen and 50 Gy to the pelvis followed by courses of melphalan (1 mg/kg/course). Primary endpoints were survival, recurrence, and toxicity. RESULTS: There were 19 stage I, 25 stage II, and 50 stage III patients. For all stages, overall survival was 42% at 5 years, 30% at 10 years, and 17% at 25 years. Median follow-up of the survivors was 24 years. Disease-free survival was 48% at 5 years and remained at 45% from 10 to 25 years. All but two recurrences occurred within the first 27 months. No recurrence or treatment-related death occurred after 8 years. No recurrence was salvaged. All but one initial recurrence was within the peritoneal cavity. Of the 31 patients undergoing a second-look surgical procedure, 84% were free of tumor. Only 8% of patients recurred after a negative second look. Stage and the presence of palpable postoperative disease were significant prognostic factors. Disease-free survivals were 95% from 5 to 25 years for stage I, 70% at 5 years and 60% at 25 years for stage II, and 20% from 5 to 25 years for stage III (P < 0.0001). Although no patient with postoperative palpable tumor was cured, 25% lived beyond 2 years. Stage III patients without postoperative palpable tumor achieved a 47% 25-year disease-free survival. Acute toxicity was acceptable, and 98% of patients completed radiation therapy. Chronic toxicity included a 12% small bowel obstruction rate and a 3% fatal second malignancy/hematological toxicity rate (two cases of acute myelocytic leukemia, one case of thrombocytopenia). CONCLUSIONS: The long-term disease-free survival obtained with abdominopelvic radiotherapy followed by single alkylating agent chemotherapy has not been exceeded by three subsequent decades of multiagent chemotherapy trials. Abdominal radiotherapy may be useful to consolidate complete responses following therapy multiagent chemotherapy, particularly with the upper abdominal dose escalation provided by intensity modulated radiation therapy and possibly in conjunction with chemotherapy.

Insulin-like growth factors, insulin-like growth factor-binding proteins, and endometrial cancer in postmenopausal women: results from a U.S. case-control study.

OBJECTIVE: To assess whether circulating insulin-like growth factor-1 (IGF-1), IGF-2, insulin-like growth factor-binding protein-1 (IGFBP-1), or IGFBP-3 were associated with endometrial cancer in postmenopausal women. STUDY DESIGN: Between 1987 and 1990, we conducted a case-control study of 405 women with endometrial cancer and 297 matched population-based controls. This analysis included 174 postmenopausal cases and 136 controls. RESULTS: In logistic regression models adjusted for potential confounders, higher IGF-1 levels were not positively associated with endometrial cancer: odds ratio (OR) for the highest tertile versus the lowest tertile = 0.63, 95% confidence interval (CI) = 0.30-1.32. Endometrial cancer was inversely associated with IGF-2 (OR for the highest tertile = 0.35, 95% CI = 0.18-0.69) and IGFBP-3 (OR for the highest tertile = 0.40, 95% CI = 0.21-0.77), and not associated with IGFBP-1. CONCLUSION: Serum IGF-1, IGF-2, and IGFBP-3, but not IGFBP-1, were inversely associated with endometrial cancer in postmenopausal women. These associations and the potential role of the IGF system in endometrial proliferation and carcinogenesis warrant further research.

Evidence supporting the current management guidelines for high-grade squamous intraepithelial lesion cytology.

OBJECTIVE: The study was undertaken to provide consensus guidelines for the management of women with a cytologic interpretation of high-grade squamous intraepithelial lesion (HSIL) on cytologic examination. This review article presents relevant literature supporting the proposed guidelines. PARTICIPANTS: An independent panel of 121 experts in various aspects of the diagnosis and management of cervical cancer precursors, including representatives from 29 participating professional organizations, federal agencies, national and international health organizations, and others were invited by the American Society for Colposcopy and Cervical Pathology. CONSENSUS PROCESS: Guidelines for the management of women with HSIL cytologic results were developed through a multistep process. Draft management guidelines were developed by the HSIL working group after formal literature reviews and obtained input from the professional community at large by way of an interactive internet-based bulletin board. At the American Society for Colposcopy and Cervical Pathology Consensus Conference, September 6 through 8, 2001, in Bethesda, Maryland, the guidelines were discussed, revised, and adopted by formal vote. CONCLUSIONS: Evidence-based guidelines have been developed for the management of women with HSIL cytologic results.

Home study course: spring 2004.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia.

OBJECTIVE: The study was undertaken to provide consensus guidelines for the management of women with histologically confirmed cervical intraepithelial neoplasia (CIN) that can act as a precursor to invasive cervical cancer and represents one of the most common significant gynecologic diseases of women of reproductive age. PARTICIPANTS: An independent panel of 121 experts in various aspects of the diagnosis and management of cervical cancer precursors, including representatives from 29 participating professional organizations, federal agencies, national and international health organizations, and others were invited by the American Society for Colposcopy and Cervical Pathology (ASCCP). CONSENSUS PROCESS: Guidelines for the management of women with CIN were developed through a multistep process. Draft management guidelines were developed by working groups who performed formal literature reviews and obtained input from the professional community at large by way of an interactive internet-based bulletin board. At the ASCCP Consensus Conference, September 6 through 8, 2001, in Bethesda, Md, all guidelines were discussed, revised, and adopted by formal vote. CONCLUSION: Evidence-based guidelines have been developed for the management of women with biopsy-confirmed CIN.