BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade.

Non-T-cell-inflamed immunologically "cold" tumor microenvironments (TME) are associated with poor responsiveness to immune checkpoint blockade (ICB) and can be sculpted by tumor cell genomics. Here, we evaluated how retinoblastoma (Rb) tumor-suppressor loss-of-function (LOF), one of the most frequent alterations in human cancer and associated with lineage plasticity, poor prognosis, and therapeutic outcomes, alters the TME, and whether therapeutic strategies targeting the molecular consequences of Rb loss enhance ICB efficacy. We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we used isogenic murine models of Rb-deficient prostate cancer for in vitro and in vivo mechanistic studies to examine how Rb loss and bromodomain and extraterminal (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in vivo therapeutic efficacy of BETi, singly and in combination with ICB and androgen deprivation therapy. Rb loss was enriched in non-T-cell-inflamed tumors, and Rb-deficient murine tumors demonstrated decreased immune infiltration in vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced tumor cell STING/NF-κB activation and type I IFN signaling within tumor cells, resulting in differential macrophage and T-cell-mediated tumor growth inhibition and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate cancer.

Outpatient Foley catheter induction protocol provides clinical and cost benefits.

BACKGROUND: Obstetric induction procedures are expensive, and little is known of the specific difference in cost between inpatient and outpatient protocols for these procedures. OBJECTIVE: The objective of this study was to examine the difference in health care costs, maternal and neonatal morbidity, and cesarean birth rates for inpatient versus outpatient Foley induction protocols. MATERIAL AND METHODS: We conducted a retrospective study using deliveries from 2013 to 2015 that received an outpatient or inpatient Foley catheter induction. Inductions were matched by race, parity, and maternal age. We used univariate and multivariate logistic regression to test the association between type of induction, length of stay, and cost. Maternal and neonatal factors and cesarean rates were also considered. RESULTS: A total of 163 outpatient Foley inductions were matched 1:1 to inpatient inductions. Outpatient inductions were more likely to have a shorter length of hospitalization from admission to discharge (a 7.17-hour difference, 95% CI, 71.00, 77.59) and lower costs of hospitalization ($408 per patient, 95% CI, 4305, 4714). In the univariate analysis, there was no difference in rate of cesarean birth (OR 0.95, 95% CI, 0.61, 1.48). However, in the multivariate analysis, there was a decreased rate of cesarean for outpatient inductions (OR 0.5, 95% CI, 0.26, 0.97). CONCLUSIONS: Outpatient Foley catheter induction appears to be a safe, cost-effective method for induction of labor. Generating protocols allowing patients to receive quality care in an outpatient setting is increasingly important in current health care environments.

Prevalence of Cervical Dysplasia in HIV-Positive and HIV-Negative Women at the Sihanouk Hospital Center of HOPE, Phnom Penh , Cambodia

Introduction: There is a high burden of cervical cancer in Cambodia, yet published data on the prevalence of cervical dysplasia and the risk factors contributing to the development of pre-cancerous lesions in Cambodian women is very limited. In addition, as it is well known that HIV positivity increases cervical cancer risk, it is important to quantify the prevalence of cervical dysplasia and carcinoma among Cambodian women living with HIV disease. Methods: A cross-sectional study was conducted with a sample of 499 HIV+ and 501 HIV- Cambodian women at the Sihanouk Hospital Center of HOPE. Visual inspection with 5% acetic acid was the method of screening. Colposcopy was performed on all VIA+ patients, and subsequent treatment followed WHO guidelines. Logistic regression models, stratified by both HIV+ and HIV- groups, were used to assess significant factors associated with having dysplasia. Results: VIA+ results were prevalent in both the HIV+ and HIV- arms of the study. The HIV+ patients were more likely to have a lower age at coitarche, lower weight, 2 or more lifetime sexual partners, two or greater pregnancies, or be unmarried. The estimated prevalence of VIA detected cervical dysplasia was 11% for the entire study sample, 13.4% in the HIV positive (HIV+) group and 8.6% in the HIV negative (HIV-) group (OR: 1.65; 95% CI: 1.10, 2.48; p=0.01). For the HIV+ group, having a history of 4 or more full-term pregnancies (OR: 3.42; 95% CI: 1.01-11.64; p=0.049) was found to be significantly associated with having an increased risk of developing cervical dysplasia in the multivariate model. Conclusion: Cervical dysplasia is prevalent in both HIV positive and negative Cambodian women and a VIA based national screening programs need to be developed and expanded to provide access to affordable and effective treatment for cervical dysplasia and cancers.

Performance of the cobas HPV Test for the Triage of Atypical Squamous Cells of Undetermined Significance Cytology in Cervical Specimens Collected in SurePath.

OBJECTIVES: Determine performance of the cobas human papillomavirus (HPV) test for triage of atypical squamous cells of undetermined significance (ASC-US) in SurePath. METHODS: Women presenting for routine screening had cervical specimens collected in SurePath and specimen transport medium (STM); those with ASC-US cytology underwent colposcopy. Performance of cobas HPV in SurePath specimens that had undergone a preanalytic procedure to reverse possible cross-linking of HPV DNA was compared with Hybrid Capture 2 (hc2) specimens in STM. RESULTS: Among 856 women, HPV prevalence was 45.8%; HPV 16 and HPV 18 prevalences were lower than expected in the 21- to 29-year-old group in this highly vaccinated population. cobas HPV performance in SurePath was comparable to hc2 in STM. Sensitivity and specificity for detection of cervical intraepithelial neoplasia grade 3 or worse were 87.5% (95% confidence interval [CI], 71.9%-95.2%) and 55.5% (95% CI, 52.1%-58.9%) for cobas and 85.3% (95% CI, 69.9%-93.6%) and 54.7% (95% CI, 51.4%-57.9%) for hc2. Sensitivity was negatively affected by random biopsies performed at colposcopy; comparable sensitivities were achieved in the nonvaccinated and vaccinated populations with disease determined by directed biopsy only. CONCLUSIONS: Performance of cobas HPV for ASC-US triage in pretreated SurePath specimens meets criteria for validation. Preliminary data indicate reliable performance of HPV testing in a highly vaccinated population.

Hysterectomy for benign conditions: Complications relative to surgical approach and other variables that lead to post-operative readmission within 90 days of surgery.

OBJECTIVE: To examine variables associated with hysterectomy-related complications, relative to surgical approach and other variables, that lead to readmission within 90 days of surgery. METHODS: We conducted an observational cohort study for which data were extracted from electronic health records. Data were extracted of all patients (n = 3106) who underwent hysterectomies at 10 Kaiser Permanente Southern California medical centers between June 2010 and September 2011. Patients who were pregnant or had a cancer diagnosis were excluded from the study. To identify univariate associations between examined variables and procedure type, chi-square tests for categorical variables and t-tests or analysis of variance for continuous variables were used. Generalized estimating equations methods were used to test associations between independent variables and primary outcomes of interest. Statistical significance was determined using a p-value <.05. RESULTS: Of 3106 patients, 109 experienced 168 post-operative complications. The most common post-operative complications were related to pelvic abscesses, bowel obstruction, or severe ileus, and the vaginal cuff. Pelvic abscesses were most frequent among total laparoscopic hysterectomy and total abdominal hysterectomy cases (p = .002), and vaginal cuff complications were most frequent among total laparoscopic hysterectomy cases (p = .015). Patients who underwent total vaginal hysterectomy (odds ratio = 2.13, confidence interval = 1.15-3.92), laparoscopic supracervical hysterectomy (odds ratio = 3.11, confidence interval = 1.13-8.57), and total laparoscopic hysterectomy (odds ratio = 5.60, confidence interval = 2.90-10.79) experienced increased occurrence of post-operative complications resulting in readmission. Other variables associated with an increased risk for readmission included high estimated blood loss (201-300 mL and 301+ mL, relative to 0-50 mL; odds ratio = 2.28, confidence interval = 1.24-4.18 and odds ratio = 2.63, confidence interval = 1.67-4.14) and long length of stay of 3 days or more (relative to 0 days; odds ratio = 2.93, confidence interval = 1.28-6.69). Pelvic specimen weight in the 151-300 g and 501+ g ranges appeared protective (odds ratio = 0.40, confidence interval = 0.25-0.64 and odds ratio = 0.54, confidence interval = 0.33-0.90). In a sub-analysis of 1294 patients, 74 hospital operative complications directly related to hysterectomy were identified among 59 patients. The most common hospital operative complications were excessive bleeding associated with surgery or injury to nearby structures. Among the sub-sample of 1294 patients, those with hospital operative complications were more likely to experience post-operative complications that lead to readmission (odds ratio = 3.82, confidence interval = 1.55-9.43, p = .004). CONCLUSION: The observed increased risk of complications among patients of Black race, who underwent laparoscopic supracervical hysterectomy or total laparoscopic hysterectomy, who experienced more than 300 mL surgical blood loss, who suffered hospital operative complications, and those whose hospitalization was 3 days or greater, offers an opportunity for higher scrutiny and preventive measures during usual hysterectomy care to prevent later readmission.

Physicians', Nurses', and Medical Assistants' Perceptions of the Human Papillomavirus Vaccine in a Large Integrated Health Care System.

CONTEXT: Vaccination against the human papillomavirus (HPV) decreases risks of cancer and genital warts and the need for gynecologic procedures, yet nationwide vaccination rates are low. Previous surveys exploring this phenomenon have not included input from nurses and medical assistants, who play integral roles in HPV vaccine delivery. OBJECTIVE: To understand perceptions of HPV vaccine delivery among physicians, nurses, and medical assistants in a large integrated health care system in Southern California. DESIGN: Online surveys were sent to 13 nurse administrators and 75 physicians. Physicians were instructed to forward the survey to nurses and medical assistants with whom they work. RESULTS: A total of 76 surveys were completed, consisting of 52 physicians, 16 clinical nurses and medical assistants, and 8 nurse administrators. Physicians' perceptions of vaccine safety or strength of recommendation did not differ by specialty department. Physicians reportedly perceived the HPV vaccine as safer than did clinical nurses and medical assistants (p < 0.001), who indicated they wanted more education on the safety and efficacy of the vaccine before being comfortable strongly recommending it. Respondents advised that all clinicians could improve in their roles as HPV vaccine advocates through patient counseling and providing informational literature and that workflow standardization was needed to minimize missed vaccination opportunities. CONCLUSION: Physicians reportedly perceive the HPV vaccine as safer compared with nurses and medical assistants. Both groups think that more education of nonphysician staff is needed. Having proper systems in place is also vital to improving vaccination compliance.

Validation of a patient decision aid for choosing between dabigatran and warfarin for atrial fibrillation.

BACKGROUND: Decision aids have been helpful to support patients in decision-making including anticoagulation. With the introduction of new oral anticoagulants (NOACs), it will be important to assist patients and physicians in shared decision-making about NOACs and warfarin. OBJECTIVES: To validate a patient decision aid (DA) for warfarin versus dabigatran, the first NOAC approved for atrial fibrillation (AF). METHODS: Participants without AF and not taking anticoagulants were recruited for the validation exercise. The decision aid described AF, stroke, and hemorrhagic events in terms of incidence, clinical presentation, and prognosis. Warfarin and dabigatran were then compared on multiple clinical and process outcomes as outlined in the pivotal clinical trial. Our primary outcome was confidence in making a treatment decision, using a decisional conflict scale. Secondary outcomes were change in knowledge scores and ratings of clarity, helpfulness and comprehensiveness. RESULTS: 35 patients (mean age 62.7 [SD 9.68], 37.1% female) participated. After use of the decision aid, the mean total decisional conflict score was low at 18.9 (SD: 14.2). Mean knowledge score improved significantly from 4.60 (SD 1.48) to 6.42 (SD 0.80) out of a total score of 7. Only one participant (2.9%) found the decision aid difficult to understand. All 35 participants rated the DA as helpful for making a decision about anticoagulant treatment for AF. Two participants (5.7%) requested more information on adverse effects of the two drugs. CONCLUSION: Our DA to allow patients to make an informed decision with their physician regarding dabigatran versus warfarin in AF, proved understandable, comprehensive and helpful.

Repetitively dosed docetaxel and ¹5³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer.

BACKGROUND: ß-emitting bone-seeking radiopharmaceuticals have historically been administered for pain palliation whereas docetaxel prolongs life in patients with metastatic castration-resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize antitumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established. METHODS: Patients with progressive mCRPC and ≥ 3 bone lesions received (153) Sm-EDTMP (samarium-153 ethylene diamine tetramethylene phosphonate) at a dose of 1.0 mCi/kg every 9 weeks and docetaxel at a dose of 75 mg/m(2) every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic disease progression. RESULTS: Of the 30 patients treated, approximately 50% were considered to be taxane-naive, 36.7% were taxane-refractory, and 13.3% had previously been exposed to taxanes but were not considered refractory. Patients received on average 2.5 cycles of treatment (6.5 doses of docetaxel and 2.5 doses of (153) Sm-EDTMP). Twelve patients (40%) demonstrated a decline in their prostate-specific antigen level of ≥ 50%. The median progression-free survival (biochemical or radiographic) was 7.0 months and the overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts >100 K/mm(3) after a median of 3 cycles to allow for additional treatment, with 4 patients experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity. CONCLUSIONS: The results of the current study indicate that (153) Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis in patients with mCRPC. Although thrombocytopenia limited therapy for some patients, preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, which is an appealing strategy given the anticipated availability of α emitters that can prolong survival.

Increased error-related brain activity in youth with obsessive-compulsive disorder and other anxiety disorders.

The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response that is thought to reflect activity in the anterior cingulate cortex (ACC) and is often increased in patients with anxiety disorders. This study measured the ERN and correct response negativity (CRN) during an Eriksen flanker task to assess performance monitoring in 26 youth with obsessive-compulsive disorder (OCD), 13 youth with a non-OCD anxiety disorder consisting of either generalized anxiety disorder or separation anxiety disorder, and 27 age-matched healthy controls ranging in age from 8 to 16 years. Compared to healthy controls, ERN amplitude was significantly increased in patients with either OCD or a non-OCD anxiety disorder. There were no significant group differences in CRN amplitude. Treatment with a serotonergic antidepressant or cognitive-behavior therapy had no effect on the ERN in patients. Scores from the Child Behavior Checklist DSM-oriented anxiety problems scale had a significant correlation with ERN amplitude in all subjects. The results provide further evidence that the pathophysiology of OCD and some non-OCD anxiety disorders involves increased ACC activity and that the ERN may serve as a quantitative phenotype in genetic and longitudinal studies of these complex traits.

Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.

PURPOSE: Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS: Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS: Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION: Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.

Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women.

OBJECTIVE: B-type natriuretic peptide (BNP) is synthesized in cardiac ventricles in response to volume expansion. This study evaluated BNP levels to determine trends during pregnancy, and to assess BNP as a diagnostic tool in preeclampsia. STUDY DESIGN: We studied 163 BNP levels in 118 pregnant women, ranging from first trimester to term. An additional 34 patients with preeclampsia were studied and compared to 25 normal control patients at term. Plasma BNP values were determined using a standard assay. RESULTS: The median BNP levels during the 1st, 2nd, 3rd trimester, and at term were equivalent (18.4, 17.9, 15.5, and 17.8 pg/mL, respectively, P = .796). The median BNP levels in normal patients, mild preeclamptics, and severe preeclamptics were 17.8, 21.1, and 101 pg/mL, respectively, with the severe group being significantly higher than the mild group (P = .003) and any phase of normal pregnancy (P < .001 in each case). A BNP cut-off of <40.6 pg/mL had a negative predictive value of 92% in excluding preeclampsia. CONCLUSION: In normal pregnancies, median BNP values are <20 pg/mL, and stable throughout gestation. In severe preeclampsia BNP levels are elevated. This may reflect ventricular stress and/or subclinical cardiac dysfunction associated with preeclampsia.