Subthreshold opioid use disorder prevention (STOP) trial: a cluster randomized clinical trial: study design and methods.

BACKGROUND: Preventing progression to moderate or severe opioid use disorder (OUD) among people who exhibit risky opioid use behavior that does not meet criteria for treatment with opioid agonists or antagonists (subthreshold OUD) is poorly understood. The Subthreshold Opioid Use Disorder Prevention (STOP) Trial is designed to study the efficacy of a collaborative care intervention to reduce risky opioid use and to prevent progression to moderate or severe OUD in adult primary care patients with subthreshold OUD. METHODS: The STOP trial is a cluster randomized controlled trial, randomized at the PCP level, conducted in 5 distinct geographic sites. STOP tests the efficacy of the STOP intervention in comparison to enhanced usual care (EUC) in adult primary care patients with risky opioid use that does not meet criteria for moderate-severe OUD. The STOP intervention consists of (1) a practice-embedded nurse care manager (NCM) who provides patient participant education and supports primary care providers (PCPs) in engaging and monitoring patient-participants; (2) brief advice, delivered to patient participants by their PCP and/or prerecorded video message, about health risks of opioid misuse; and (3) up to 6 sessions of telephone health coaching to motivate and support behavior change. EUC consists of primary care treatment as usual, plus printed overdose prevention educational materials and an educational video on cancer screening. The primary outcome measure is self-reported number of days of risky (illicit or nonmedical) opioid use over 180 days, assessed monthly via text message using items from the Addiction Severity Index and the Current Opioid Misuse Measure. Secondary outcomes assess other substance use, mental health, quality of life, and healthcare utilization as well as PCP prescribing and monitoring behaviors. A mixed effects negative binomial model with a log link will be fit to estimate the difference in means between treatment and control groups using an intent-to-treat population. DISCUSSION: Given a growing interest in interventions for the management of patients with risky opioid use, and the need for primary care-based interventions, this study potentially offers a blueprint for a feasible and effective approach to improving outcomes in this population. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT04218201, January 6, 2020.

Using a health information technology survey to explore the availability of addiction treatment data in the electronic health records: A National Drug Abuse Treatment Clinical Trials Network study.

BACKGROUND: Healthcare data from electronic health records (EHRs) and related health information technology (IT) tools are critical data sources for pragmatic clinical trials and observational studies aimed at producing real-world evidence. To unlock the full potential of such data to advance science, the data must be complete and in structured formats to facilitate research use. METHODS: A Health IT survey was conducted within the National Drug Abuse Treatment Clinical Trials Network (CTN) to explore information related to data completeness and presence of unstructured data (e.g., clinical notes, free text) for conducting the EHR-based research for substance use disorders (SUDs). The analysis was based on 36 participants from 36 facilities located in 14 states and affiliated with the CTN. RESULTS: The mean age of the participants (n = 34) was 48.0 years (SD = 9.8). Of the participants enrolled, 50.0% were female and 82.4% were white. Participants' facilities were from four census-defined regions (South 35.3%, Northeast 29.4%, West 20.6%, Midwest 11.8%, Missing 2.9%) and represented diverse settings. The EHR was used by all surveyed facilities including 17 different kinds of EHR platforms or vendors, and 17.6% (n = 6) of surveyed facilities also used a separate EHR for behavioral health care (e.g., SUD care). Paper records were also used by 76.5% of surveyed facilities for clinical care (e.g., for health risk appraisal questionnaires, substance use screening or assessment, check-in screening, substance use specific intervention/treatment or referral, or labs/testing). The prevalence of using a patient portal, practice management system, and mHealth for patient care was 76.5%, 50.0%, and 29.4%, respectively. CONCLUSION: While results are descriptive in nature, they reveal the heterogeneity in the existing EHRs and frequent use of paper records to document patient care tasks, especially for SUD care. The use of a separate EHR for behavioral healthcare also suggests the challenge of obtaining complete EHR data to support research for SUDs. Much EHR development, integration, and standardization needs to be done especially in regard to SUD treatment to facilitate research across disparate healthcare systems.

Clinical Workflow and Substance Use Screening, Brief Intervention, and Referral to Treatment Data in the Electronic Health Records: A National Drug Abuse Treatment Clinical Trials Network Study.

INTRODUCTION: The use of electronic health records (EHR) data in research to inform recruitment and outcomes is considered a critical element for pragmatic studies. However, there is a lack of research on the availability of substance use disorder (SUD) treatment data in the EHR to inform research. METHODS: This study recruited providers who used an EHR for patient care and whose facilities were affiliated with the National Institute on Drug Abuse's National Drug Abuse Treatment Clinical Trials Network (NIDA CTN). Data about providers' use of an EHR and other methods to support and document clinical tasks for Substance use screening, Brief Intervention, and Referral to Treatment (SBIRT) were collected. RESULTS: Participants (n = 26) were from facilities across the country (South 46.2%, West 23.1%, Midwest 19.2 percent, Northeast 11.5 percent), representing 26 different health systems/facilities at various settings: primary care (30.8 percent), ambulatory other/specialty (26.9 percent), mixed setting (11.5 percent), hospital outpatient (11.5 percent), emergency department (7.7 percent), inpatient (3.8 percent), and other (7.7 percent). Validated tools were rarely used for substance use screen and SUD assessment. Structured and unstructured EHR fields were commonly used to document SBIRT. The following tasks had high proportions of using unstructured EHR fields: substance use screen, treatment exploration, brief intervention, referral, and follow-up. CONCLUSION: This study is the first of its kind to investigate the documentation of SBIRT in the EHR outside of unique settings (e.g., Veterans Health Administration). While results are descriptive, they emphasize the importance of developing EHR features to collect structured data for SBIRT to improve health care quality evaluation and SUD research.

Safety and efficacy of intralesional triamcinolone administration for treatment of mast cell tumors in dogs: 23 cases (2005-2011).

OBJECTIVE To evaluate the safety and efficacy of intralesional triamcinolone administration, as a sole or adjuvant treatment, in dogs with mast cell tumors. DESIGN Retrospective case series ANIMALS 23 dogs with mast cell tumors. PROCEDURES Medical records of dogs treated for a confirmed diagnosis of a mast cell tumor between 2005 and 2011 were reviewed. Patients with a confirmed diagnosis and measurable disease (tumor longest dimension ≥ 0.5 cm) that had received ≥ 1 intralesional treatment with triamcinolone, regardless of prior, concurrent, or adjuvant treatments, were eligible for inclusion. Data collected included patient characteristics, results of cytologic and histologic testing and tumor staging, triamcinolone dosage, treatment response, and adverse events. RESULTS 23 dogs with 24 tumors were included. Tumors were treated by means of intralesional triamcinolone administration alone (n = 5), intralesional triamcinolone administration with concurrent oral administration of glucocorticoids (6), and intralesional triamcinolone administration with concurrent cytotoxic chemotherapy, with or without oral administration of corticosteroids and radiation therapy (13). Of 5 dogs treated with intralesional triamcinolone administration alone, 1 achieved a complete response, 3 achieved a partial response, and 1 maintained stable disease. The response rate for all 24 tumors (23 dogs) was 67% (16/24), including 4 with a complete response and 12 with a partial response. The median time to progression was 63 days (range, 6 to 447 days). Three dogs experienced adverse events (local hemorrhage [n = 1]; suspected gastrointestinal ulceration [2]). CONCLUSIONS AND CLINICAL RELEVANCE Intralesional triamcinolone administration may be well tolerated and effective for treatment of nonresectable mast cell tumors in dogs.

Identification of prognostic collagen signatures and potential therapeutic stromal targets in canine mammary gland carcinoma.

Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic) recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS) and individual collagen fiber characteristics (width, length and straightness) in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal interactions in breast cancer.

Pregnancy-associated Breast Cancer.

Breast cancer is one of the most common malignancies affecting pregnancy. Pregnancy-associated breast cancer refers to breast cancer that is diagnosed during pregnancy or within the first postpartum year. The incidence is increasing as more women delay childbearing. Breast cancer can be safely diagnosed, staged, and treated during pregnancy while protecting the fetus and mother with excellent outcomes for both. Avoiding diagnostic delays is vital to prognosis. This article provides an overview of the diagnosis, staging, management, and prognosis of pregnancy-associated breast cancer. Relevant current literature is reviewed.

Abundance and Frequency of the Asiatic Oak Weevil (Coleoptera: Curculionidae) and Defoliation on American, Chinese, and Hybrid Chestnut (Castanea).

The Asiatic oak weevil, Cyrtepistomus castaneus Roelofs (Coleoptera: Curculionidae), is a nonnative defoliator of trees in the Fagaceae family in the United States but has not been studied on Castanea species in the southern Appalachian Mountains. Planted trees of Castanea dentata (Marsh.) Borkh. (Fagales: Fagaceae), Castanea mollissima Blume (Fagales: Fagaceae), and four hybrid breeding generations were evaluated in 2012 for insect defoliation and C. castaneus abundance and frequency. Defoliation was visually assessed throughout the growing season at two sites in the southern Appalachian Mountains (western North Carolina and eastern Tennessee). C. castaneus abundance and frequency were monitored on trees using beat sheets and emergence was recorded from ground traps. Asiatic oak weevils were more abundant and more frequently collected on American chestnut (Ca. dentata) and its most closely related BC3F3 hybrid generation than on the Asian species Ca. mollissima. In most months, C. castaneus colonization of hybrid generations was not significantly different than colonization of parental species. Frequency data for C. castaneus suggested that adults were distributed relatively evenly throughout the study sites rather than in dense clusters. Emergence of C. castaneus was significantly higher under a canopy dominated by Quercus species than under non-Quercus species or open sky. C. castaneus emergence began in May and peaked in late June and early July. These results may be useful for resource managers trying to restore blight-resistant chestnut to the Southern Appalachians while minimizing herbivory by insect pests.

Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer.

OBJECTIVE: We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. METHODS: Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m(2) day 1, topotecan 0.75 mg/m(2) days 1, 2 and 3 and bevacizumab 15 mg/kgday 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy. RESULTS: Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1-19). Median follow-up was 10 months (range, 1.7-33.4). The 6-month PFS was 59% (80% CI: 46-70%). In 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4-14%) and 8 PR (31%; 80% CI: 19-45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25-53%) with median duration of 2.2 months. Median PFS was 7.1 months (80% CI: 4.7-10.1) and median OS was 13.2 months (80% CI: 8.0-15.4). All patients were evaluated for toxicity. Grade 3-4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. CONCLUSION: The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.

The retinoblastoma tumor suppressor regulates a xenobiotic detoxification pathway.

The retinoblastoma tumor suppressor (pRb) regulates cell cycle entry, progression and exit by controlling the activity of the E2F-family of transcription factors. During cell cycle exit pRb acts as a transcriptional repressor by associating with E2F proteins and thereby inhibiting their ability to stimulate the expression of genes required for S phase. Indeed, many tumors harbor mutations in the RB gene and the pRb-E2F pathway is compromised in nearly all types of cancers. In this report we show that both pRb and its interacting partners, the transcriptional factors E2F1-2-3, act as positive modulators of detoxification pathways important for metabolizing and clearing xenobiotics--such as toxins and drugs--from the body. Using a combination of conventional molecular biology techniques and microarray analysis of specific cell populations, we have analyzed the detoxification pathway in murine samples in the presence or absence of pRb and/or E2F1-2-3. In this report, we show that both pRb and E2F1-2-3 act as positive modulators of detoxification pathways in mice, challenging the conventional view of E2F1-2-3 as transcriptional repressors negatively regulated by pRb. These results suggest that mutations altering the pRb-E2F axis may have consequences beyond loss of cell cycle control by altering the ability of tissues to remove toxins and to properly metabolize anticancer drugs, and might help to understand the formation and progression rates of different types of cancer, as well as to better design appropriate therapies based on the particular genetic composition of the tumors.

Wound complications after gynecologic cancer surgery.

OBJECTIVE: To explore clinical correlates of wound complications in high-risk women undergoing abdominal gynecologic surgery in a tertiary referral center. METHODS: Retrospective analysis of patient demographics, pre-operative and intra-operative information, and outcomes was performed in a cohort of patients who underwent abdominal surgery for suspected gynecologic malignancy between 1/2005 and 6/2008. The primary outcome was wound complication within 6 weeks of surgery. Univariate and multivariate logistic regression analyses were employed. A nomogram predicting post-operative wound complications was created and validated by receiver operating characteristic (ROC) curve analysis and 10-fold cross-validation. RESULTS: Median age of 373 women analyzed was 57years (range 25-88), median body mass index (BMI) 32.3kg/m(2) (range 14.0-70.7). A total of 150 patients (40%) had prior abdominal surgery; 40 (11%) had a pre-operative serum albumin <3.5g/dl; and 78 (21%) had pulmonary disease. Wound complications occurred in 125 patients (34%). In multivariate analysis wound complications were correlated with BMI of 30-39.9kg/m(2) (OR=5.62, 95% CI 2.08-15.19, p<0.0001) and BMI≥40kg/m(2) (OR=10.27, 95% CI 3.66-28.88, p<0.0001), prior abdominal surgery (OR 3.28, 95%CI1.89-5.70, p<0.0001), serum albumin≤3.5g/dl (OR 4.24, 95%CI 1.87-9.61, p=0.0005), pulmonary disease (OR 2.22, 95%CI 1.09-4.51, p=0.03), lysis of adhesions (OR 3.57, 95%CI 1.04-12.26, p=0.04), and length of surgery (OR 2.42, 95%CI 1.35-4.35, p=0.003). Risk for wound complication was lower with pelvic drain placement (OR 0.26, 95%CI 0.11-0.64, p=0.003). CONCLUSIONS: Wound complications are common in gynecologic oncology. Further studies should explore whether risk factor modification decreases complications.

Clinical and pathologic features of vulvar intraepithelial neoplasia in premenopausal and postmenopausal women.

OBJECTIVE: To explore the clinical and pathologic differences between vulvar intraepithelial neoplasia (VIN) in premenopausal and postmenopausal women cared for in a tertiary referral center. METHODS: Between January 1997 and June 2008, 145 women received care at our institution for VIN and VIN-associated squamous cell carcinoma (SCC). All patients' demographic characteristics and recurrence histories were recorded throughout the study period and were retrieved retrospectively. Menopausal status was self-reported at the time of initial diagnosis. χ, odds ratio, and logistic regression analyses were used. RESULTS: The median age was 50 years (range = 19-91 y) with 77% (111/145) of patients white, 20% (29/145) African American, and 3% (5/145) other ethnicity. Sixty percent of patients diagnosed with VIN were current smokers, 18% (26/145) were immunocompromised (positive for human immunodeficiency virus/transplant/steroids), and 30% (44/145) had concomitant or previous lower genital tract dysplasia. Vulvar intraepithelial neoplasia or VIN-related cancer recurred in 57 (39%) of 145 patients; of these, 40 (71%) had recurrence of VIN and 18 (29%) had recurrence of cancer. Fifty-one percent (74/145) of patients were menopausal at initial VIN diagnosis. Among women with VIN, the odds of initially presenting with a VIN-related SCC was 3.2 times greater in postmenopausal than in premenopausal women (confidence interval = 1.5-7.1, p < .01), and postmenopausal women were more likely to present with stage II to IV SCC (p = .021). Recurrence risk of SCC, but not VIN, was associated with menopause status (p < .05). CONCLUSIONS: Among women with VIN, the risk of SCC is higher in postmenopausal than in premenopausal women both initially and at recurrence. Excisional therapies to identify occult invasion are especially important for postmenopausal women with VIN.

Chemoradiation in locally advanced cervical carcinoma: an analysis of cisplatin dosing and other clinical prognostic factors.

OBJECTIVES: The aim of this study was to evaluate the effect of number of chemotherapy cycles and other clinical and pathologic factors on progression-free (PFS) and overall survival (OS) in patients with newly diagnosed cervical cancer. METHODS: We identified 118 patients with locally advanced cervical cancer (stages IB2-IVA) treated with combination weekly cisplatin (40 mg/m(2)) and radiation therapy (RT) between 2003 and 2007. Kaplan-Meier and Cox proportional hazard models were utilized to evaluate PFS and OS for associations with number of chemotherapy cycles and other factors. RESULTS: The majority of patients had stage IB2 or II disease (70%), squamous histology (91%), and size <6 cm (65%). Median RT duration was 50 days and 95% received brachytherapy. Thirty percent of patients completed <6 cycles of chemotherapy, and estimated PFS and OS were 63% and 75%, respectively. In multivariate analyses, the number of chemotherapy cycles was independently predictive of PFS and OS. Patients who received <6 cycles of cisplatin had a worse PFS (HR 2.65; 95% CI 1.35-5.17; p=0.0045) and OS (HR 4.47; 95% CI 1.83-10.9; p=0.001). Advanced stage, longer time to RT completion, and absence of brachytherapy were also associated with decreased OS and PFS (p<0.05). Similar results were found when analysis was conducted using a breakpoint of at least five but not less than five chemotherapy cycles. Higher grade was associated with decreased PFS (p=0.03) but not OS. Age, race, BMI, tumor size, smoking, histology, and IMRT were not statistically significant for OS or PFS. CONCLUSIONS: Aggressive supportive care to minimize missed chemotherapy treatments may improve survival after chemoradiation.

"Surgical Apgar Score" predicts postoperative complications after cytoreduction for advanced ovarian cancer.

OBJECTIVE: A 10-point "Surgical Apgar Score" (SAS) for predicting postoperative complications after general and vascular operations has recently been developed and validated. We sought to estimate the ability of this metric to predict major postoperative complications in women undergoing ovarian cancer cytoreductive procedures. METHODS: All eligible patients with stage III and IV epithelial ovarian, fallopian tube and primary peritoneal cancer undergoing surgical cytoreduction at our institution between 1999 and 2005 were included. Medical records were reviewed and demographic data, clinicopathologic characteristics, comorbidities and intra and postoperative complications were analyzed. The surgical score was calculated from intraoperative blood loss, lowest mean arterial pressure and lowest heart rate as previously described. Descriptive statistics, univariable and multivariable analyses were used as appropriate. Occurrence of major postoperative complications represented the primary outcome. RESULTS: A total of 232 cases were analyzed. Mean age was 62 years. Most patients were Caucasian (92%) and diagnosed with stage III disease (83%). Mean duration of surgical procedure was 171 (70-350) minutes. Median SAS was 6 points (range 1-9). On multivariable analyses, occurrence of major postoperative complications was associated with multiple comorbidities (OR 2.2; 95% CI:1.5-3.1; p<0.0001), stage IV disease (OR 2.5; 95% CI:1.1-5.7; p=0.03), ASA class (OR 2.4; 95% CI:1.2-4.7; p=0.01) and SAS

The value of perioperative imaging in patients with uterine sarcomas.

OBJECTIVE: To explore the yield and impact of perioperative imaging on management among patients undergoing surgical resection and treatment of uterine sarcomas. METHODS: A retrospective chart review was done for women with histologically confirmed uterine sarcomas treated at Barnes Jewish Hospital/Washington University from 2001 to 2007. Descriptive statistics, Cox multivariate models, and Kaplan-Meier plots were used to evaluate associations and survival. RESULTS: A total of 92 patients were identified and 55 (60%) were diagnosed with stage III-IV disease. Perioperative imaging was obtained in 84 (91%) cases, including chest X-ray in 66 (72%), computerized tomography (CT) of the abdomen and pelvis in 59 (64%), chest CT in 33 (36%), positron emission tomography (PET) in 8 (9%), and CT of the head, pelvic magnetic resonance imaging (MRI), or bone scan in a total of 2 (2.2%). Imaging identified abnormalities concerning for metastases in 30 (32%) studies. Thirty-four recurrences have been documented, and 21 (62%) of these treatment failures were extrapelvic. Multivariate analysis of this series noted that tomographic evidence of extrauterine disease predicted recurrence (p=0.028) and incomplete surgical resection (p=0.003, HR 6.0 95% CI 1.9-19.9) predicted disease-free survival. Imaging contributed to change in surgical and post-surgical treatment decisions in 8 (9%) patients. CONCLUSION: Pretreatment imaging studies change management in a minority of patients with newly diagnosed uterine sarcomas.

The role of PET/CT in the management of patients with cervical cancer: practice patterns of the members of the Society of Gynecologic Oncologists.

OBJECTIVES: Recent data has highlighted the role of PET/CT in the pretreatment evaluation and follow-up of patients with cervical cancer. The objective of our study was to assess the acceptance of PET/CT into the management of patients with cervical cancer. We also explored potential barriers to the use of these imaging modalities in patients with cervical cancer. METHODS: A 14-item electronic questionnaire was initially sent to all working addresses of members of the SGO (n=1048). An opt-out option was offered. For members who did not respond within 3 weeks, a second electronic invitation was sent. A third request was finally sent to further improve response rates. Data were collected and analyzed using a commercially available on-line survey database. RESULTS: A total of 305 responses were collected for an overall 30% response rate. PET/CT appears to be widely available (99%) and accessible (75%) in most practices. Although 83% of members order routine CT imaging for all newly diagnosed cervical cancer cases, only 28% routinely order a PET/CT. Conversely, 64% would order a PET/CT for newly diagnosed patients with advanced disease or those at high risk for distant metastatic disease. Most members (82%) do not routinely use PET/CT to assess response to treatment. Twenty percent of members believe that no useful prognostic information can be obtained from routine use of molecular imaging in patients with cervical cancer. The most common barriers for use of PET/CT cited by members were perceived lack of third-party payer coverage and lack of scientific evidence. CONCLUSIONS: Despite clear scientific data supporting the use of PET/CT in patients with cervical cancer and apparent widespread availability, this imaging modality remains highly underutilized in clinical practice. Clarifying insurance coverage early in the evaluation process and replicating studies that have shown effectiveness of PET/CT in multiple roles may improve adoption of this potentially useful imaging modality.

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair.

OBJECTIVES: We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. METHODS: A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. RESULTS: Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. CONCLUSIONS: We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

Diagnostic loop electrosurgical excisional procedure for discrepancy: do preoperative factors predict presence of significant cervical intraepithelial neoplasia?

OBJECTIVE: Although pathological discrepancy between Pap smear and biopsy is an accepted indication to perform a diagnostic loop electrosurgical excision procedure (LEEP), this procedure is not without complications. Our objective was to determine the incidence of cervical intraepithelial neoplasia (CIN) 2,3 and patient factors that increase the likelihood of detecting CIN 2,3. MATERIALS AND METHODS: We performed a retrospective chart review of patients who underwent a diagnostic LEEP for pathological discrepancy at a university-based colposcopy clinic. Pathological discrepancy is defined as a high-grade Pap smear with a colposcopically directed biopsy of CIN 1 or less. Demographic, cytological, and histological information were collected using a computerized database. The patients were divided into 2 groups (CIN 2,3 and CIN 1 or less) based on the pathology from the LEEP specimen. Patient factors were compared with final pathological results using chi(2) test, Student t test, Wilcoxon rank sum test, and multivariate analysis as indicated. RESULTS: A total of 102 patients were identified. Seven patients had normal specimens, 3 had HPV changes, 25 had CIN 1, 29 had CIN 2, and 38 had CIN 3. Thirty-five patients (34%) had CIN 1 or less, whereas 67 patients (66%) had CIN 2,3. The 2 groups were comparable in terms of age (30.4 vs 28.1 years), parity (2.2 vs 1.9), and age of coitarche (16.3 vs 16.4 years). No statistical difference existed between the groups regarding race, smoking status, Pap smear, history of previous cytological abnormality, contraception method, number of previous sexual partners, and HIV status. The majority of patients (75%) had not undergone previous treatment of CIN. The CIN 2,3 group were more likely than the CIN 1 or less group to have had previous treatment or biopsy for CIN (66% vs 34%; p = .004). Univariate (p = .004) and multivariate (p < .001) analysis demonstrated previous treatment of CIN as the only significant factor predicting CIN 2,3. CONCLUSION: Two thirds of women undergoing a LEEP for pathological discrepancy between Pap smear and cervical biopsy will have CIN 2,3. Women that have had previous treatment of CIN are more likely to have CIN 2,3 detected on their LEEP specimen.

A cost-effectiveness analysis of chemotherapy for patients with recurrent platinum-sensitive epithelial ovarian cancer.

OBJECTIVE: The majority of patients with advanced epithelial ovarian cancer (EOC) will experience a recurrence after primary chemotherapy and receive second-line chemotherapy. Patients who have a disease-free interval >6 months (platinum-sensitive) will often receive multiple chemotherapy regimens. Therefore, our goal was to assess the effectiveness and medical costs of chemotherapy for platinum-sensitive patients with advanced EOC. METHODS: A decision analysis model compared several chemotherapeutic strategies in a hypothetical cohort of 10,000 platinum-sensitive EOC patients with recurrent disease: (a) best supportive care (BSC); (b) second-line monotherapy; (c) second-line combination therapy; (d) third-line chemotherapy after disease progression on second-line monotherapy or combination therapy; (e) fourth-line chemotherapy after disease progression on second- and third-line chemotherapy. RESULTS: BSC and second-line therapies were cost-effective strategies. The cost-effectiveness ratios ranged from $2896 for second-line monotherapy to $4914 for fourth-line previous monotherapy. Compared to BSC, second-line monotherapy gained an additional 8 months of overall survival (OS) with a favorable incremental cost-effectiveness ratio (ICER) of $24,228 per life year saved (LYS). The ICER for second-line combination therapy compared to second-line monotherapy was also favorable ($46,068 per LYS). Although third- and fourth-line chemotherapy provided small improvements in OS, they were dominated by other strategies or had an unfavorable ICER (>$50,000 per LYS). CONCLUSIONS: Second-line chemotherapy is cost-effective for patients with platinum-sensitive recurrent EOC. Due to minimal improvements in overall survival, third- and fourth-line chemotherapy are not cost-effective strategies.