Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase.

BACKGROUND: Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed. METHODS: The CWR22 human tumour xenograft and its CRPC subline 22Rv1 and sera from lapatinib-treated CRPC patients from a previously reported Phase II trial were used to study lapatinib resistance. Mechanistic studies were conducted in LNCaP, C4-2 and 22Rv1 cell lines. RESULTS: Lapatinib increased intratumoral HER2 protein, which encouraged resistance to this treatment in mouse models. Sera from CRPC patients following lapatinib treatment demonstrated increased HER2 levels. Investigation of the mechanism of lapatinib-induced HER2 increase revealed that lapatinib promotes HER2 protein stability, leading to membrane localisation, EGFR/HER2 heterodimerisation and signalling, elevating cell viability. Knockdown of HER2 and ErbB3, but not EGFR, sensitised CRPC cells to lapatinib. At equimolar concentrations, the recently FDA-approved pan-ErbB inhibitor dacomitinib decreased HER2 protein stability, prevented ErbB membrane localisation (despite continued membrane integrity) and EGFR/HER2 heterodimerisation, thereby decreasing downstream signalling and increasing apoptosis. CONCLUSIONS: Targeting the EGFR axis using the irreversible pan-ErbB inhibitor dacomitinib is a viable therapeutic option for CRPC.

Psychometric Properties of the Preparedness Assessment for the Transition Home After Stroke Instrument.

PURPOSE: The aim of this study was to evaluate psychometric properties of the Preparedness Assessment for the Transition Home After Stroke (PATH-s), a novel instrument to assess stroke caregiver commitment and capacity. The PATH-s instrument can be obtained at www.rehabnurse.org/pathtool. DESIGN: The design of this study is cross-sectional. METHODS: The PATH-s, the Preparedness for Caregiving Scale (PCS), the Patient Health Questionnaire, the Perceived Stress Scale, and the Global Health Scale were self-reported from a convenience sample of caregiver-stroke survivor dyads (n = 183) during inpatient rehabilitation. RESULTS: Exploratory factor analysis revealed eight factors underlying the PATH-s structure. The PATH-s Cronbach's alpha of .90 demonstrated criterion-related validity with the PCS (r = .79, p < .01). Both the PATH-s and the PCS were negatively correlated with the Patient Health Questionnaire (r = -.26 and -.27, respectively; p < .01) and the Perceived Stress Scale (r = -.12 and -.15, respectively; p > .05) and positively correlated with the Global Health Scale (r = -.46 and .46, respectively; p < .01), indicating convergent validity. CONCLUSIONS: The PATH-s demonstrates excellent internal consistency and satisfactory criterion-related and convergent validity. CLINICAL RELEVANCE: The PATH-s may be used to assess the risk/needs of caregivers over time.

Feasibility of Colocating a Nutrition Education Program into a Medical Clinic Setting to Facilitate Pediatric Obesity Prevention.

PURPOSE: Within a medical clinic environment, pediatric obesity prevention education for families faces challenges. Existing long-term government-funded nutrition education programs have the expertise and staff to deliver. The purpose is to determine feasibility of colocating the Expanded Food and Nutrition Education Program (EFNEP) into a medical clinic setting to support pediatric obesity prevention. METHODS: Physicians from a large university teaching and research hospital (n = 73) and 4 small Medicaid-serving community clinics (n = 18) in the same geographic area in northern California were recruited and trained in the patient-referral protocol for a primary prevention intervention provided by EFNEP. The 8-week intervention deployed in the medical clinics, included general nutrition, physical activity and parenting topics anchored with guided goal setting and motivational modeling. Referral, enrollment, and attendance data were collected for 2 years. Parent and physician feasibility surveys, parent interviews and parent risk assessment tools were administered. Paired-sample t-test analysis was conducted. RESULTS: Twenty intervention series with parents of patients (n = 106) were conducted at 5 clinics. Physicians (n = 92) generated 686 referrals. Every 6 referrals generated 1 enrolled parent. Physicians (91%, n = 34) reported the intervention as useful to families. Parents (n = 82) reported improved child behaviors for sleep, screen time, physical activity, and food and beverage offerings (P < .0001) and at family mealtime (P < .001). Focus group interviews (n = 26) with 65 participants indicated that parents (97%) reacted positively to participating in the intervention with about a third indicating the classes were relevant to their needs. CONCLUSION: The intervention is a feasible strategy for the 5 medical clinics. Physicians referred and parents enrolled in the intervention with both physicians and parents indicating positive benefits. Feasibility is contingent upon physician awareness of the intervention and motivation to refer patients and additional EFNEP and clinic staff time to enroll and keep parents engaged.

Quality-of-life and surgical treatments for rectal cancer--a longitudinal analysis using the California Cancer Registry.

BACKGROUND: Heterogeneous results for research investigating health-related quality of life (HRQL) in patients undergoing sphincter-ablating procedures for rectal cancer are likely due to single institution experiences and measurement of HRQL. To address this heterogeneity, we evaluated HRQL in patients with rectal cancer by type of surgery, location of tumor, and receipt of adjuvant therapy using an HRQL instrument that has not been used to address rectal cancer patients in a population-based sample over time. METHODS: The Functional Assessment of Cancer Therapy-Colorectal instrument was administered at 9 and 19 months after diagnosis to a consecutive sample of 160 patients in Northern California identified by the California Cancer Registry. A broad multidimensional interpretation of HRQL was used to examine the impact of tumor location and treatment status, stage of disease, age, and gender. RESULTS: In general, men had lower social well-being scores, and younger patients had lower physical and emotional well-being scores and colorectal concerns scores. We found no differences in HRQL by either tumor location or type of surgery, at either 9 or 19 months after diagnosis. Lower physical well-being and greater adverse colorectal concerns were reported at 9 months among patients who received adjuvant therapy; however, only adverse colorectal concerns persisted over time. CONCLUSIONS: This study provides additional evidence that sphincter-ablating procedures do not necessarily reduce quality of life in patients with rectal cancer. Distinctive features of this study include a broad multidimensional interpretation of HRQL, the 19 months of longitudinal follow-up, and a prospective population-based study design.

Extent of diagnostic inquiry among a population-based cohort of patients with cancer of unknown primary.

PURPOSE: Current cancer registry data cannot distinguish a justified cancer of unknown primary (CUP) diagnosis, where the patient received a complete diagnostic evaluation that was unable to identify the primary tumor, from potentially misclassified patients, documented as CUP but not based on a complete diagnostic evaluation. This misclassification may skew population-based cancer registry surveillance research used to frame and guide translational CUP research. We identified characteristics of patients who received justified vs. potentially misclassified CUP diagnoses in cancer registry data. METHODS: We developed a conceptual definition of a complete diagnostic evaluation from professional society-recommended guidelines. We translated this definition into procedure codes in the Medicare encounter data. We assessed age, gender, comorbidities, urban or rural residence, income, race, and tumor pathology by receipt of a complete diagnostic evaluation and palliative therapy among 10,575 elderly CUP patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset. We calculated odds ratios and adjusted probabilities using marginal standardization. RESULTS: Only 35% of elderly CUP patients identified in the cancer registry received a complete diagnostic evaluation. After adjustment for age and comorbidities, socioeconomic barriers to a complete diagnostic evaluation persisted: adjusted odds ratio and 95% confidence interval (AOR) for rural vs. urban 0.8(0.8,0.9) and for highest income vs. lowest income 1.2(1.1,1.4). Patients with vague or undocumented tumor pathology in SEER had 80% lower odds of receiving a complete diagnostic evaluation AOR(95%CI)=0.2(0.2,0.2). Although patients with a complete diagnostic evaluation were twice as likely to receive palliative therapy than those without a complete evaluation, AOR(95%CI)=2.0(1.7,2.3), they only had a 46.7% probability of receiving therapy, 95%CI=(44.4,49.1). CONCLUSION: Patients without a complete diagnostic evaluation are not limited to the frail and underserved. For accurate assessment of the CUP burden and disparities in utilization of diagnostic care, we recommend that the SEER definition of CUP include the extent of diagnostic inquiry.

Risk factors for first-time homelessness in low-income women.

Determinants of first-time homelessness were evaluated in Sacramento, California and Lehigh Valley, Pennsylvania. First-time homeless women had more cumulative risks for homelessness than low-income never-homeless women, even with the putative advantage of higher levels of education. Solutions to homelessness should address more than one dimension of risk.

Sensitivity and specificity of on-farm scoring systems and nasal culture to detect bovine respiratory disease complex in preweaned dairy calves.

The California (CA) and Wisconsin (WI) clinical scoring systems have been proposed for bovine respiratory disease complex (BRDC) detection in preweaned dairy calves. The screening sensitivity (SSe), for estimating BRDC prevalence in a cohort of calves, diagnostic sensitivity (DSe), for confirming BRDC in ill calves, and specificity (Sp) were estimated for each of the scoring systems, as well as for nasal swab cultures for aerobic bacteria and mycoplasma species. Thoracic ultrasound and auscultation were used as the reference standard tests interpreted in parallel. A total of 536 calves (221 with BRDC and 315 healthy) were sampled from 5 premises in California. The SSe of 46.8%, DSe of 72.6%, and Sp of 87.4% was determined for the CA system. The SSe of 46.0%, DSe of 71.1%, and Sp of 91.2% was determined for the WI system. For aerobic culture, the SSe was 43.4%, DSe was 52.6%, and Sp was 71.3%; for Mycoplasma spp. culture, the SSe was 57.5%, DSe was 68.9%, and Sp was 59.7%. The screening and diagnostic sensitivities of the scoring systems were not significantly different but the Sp of the WI system was greater by 3.8%. Scoring systems can serve as rapid on-farm tools to determine the burden of BRDC in preweaned dairy calves. However, users may expect the SSe to be less than the DSe when confirming BRDC in an ill calf.

In vitro investigation of the effects of nonsteroidal anti-inflammatory drugs, prostaglandin E2, and prostaglandin F2alpha on contractile activity of the third compartment of the stomach of llamas.

OBJECTIVE: To determine the in vitro effect of prostaglandin (PG) E2, PGF2alpha, and the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin, ketoprofen, and nabumetone on the contractile strength of the circular smooth muscle layer of the third compartment of the stomach of llamas. SAMPLE POPULATION: Specimens of the third compartment obtained from 5 healthy adult llamas. PROCEDURE: Full-thickness tissue samples were collected from the third compartment immediately after euthanasia. Specimens were cut into strips oriented along the circular muscle layer and mounted in a tissue bath system. Incremental amounts of ketoprofen, nabumetone, indomethacin, PGE2, and PGF2alpha were added, and contractile strength (amplitude of contractions) was recorded. RESULTS: Generally, PGE2 reduced contractile strength of the circular smooth layer of the third compartment, whereas PGF2alpha, increased the strength of contractions. The activity of the NSAIDs was generally excitatory in a concentration-dependent manner, although significant changes were induced only by administration of indomethacin. CONCLUSIONS AND CLINICAL RELEVANCE: On isolated smooth muscle strips of the third compartment of llamas, exogenous PGE2 and PGF2alpha had a variable effect on contractile strength. Administration of the NSAIDs did not inhibit contractility and would not be likely to induce stasis of the third compartment in the absence of an underlying disease process.

Factors associated with time to availability for cases reported to population-based cancer registries.

OBJECTIVE: Population-based cancer registries provide an excellent source of data for cancer surveillance and research. However, delays in reporting and processing can affect the accuracy of incidence rates and the availability of cases for research. This study was designed to describe factors related to delays in availability of cancer cases for epidemiologic analysis. METHODS: We identified all cancer cases diagnosed in 2000 and reported to the California Cancer Registry by August 2004. We analyzed factors associated with time to availability, defined as the time from diagnosis until the time the case was available for research. RESULTS: A total of 137,270 cancer cases were reported during the study period. The median time to availability for all cases was 382 days. Forty-five percent of cases were available within the first 12 months and 96% were available within 24 months after diagnosis. Cases reported by hospitals had the shortest time to availability (373 days) followed by doctors' offices and laboratories. Melanoma and prostate cancers had longer times to be available than other types of cancer. Time to availability varied by geographic region, but differences by age, gender, race and stage at diagnosis were minimal or non-significant. CONCLUSION: Strategies are needed to improve timeliness without sacrificing quality and completeness.