BACKGROUND: Serine-threonine inhibitors, such as vemurafenib, are being used increasingly in cancer treatment, and the toxicity and therapeutic benefit need to be balanced carefully both before and during treatment. CASE PRESENTATION: A patient with metastatic melanoma and end stage renal failure who was on peritoneal dialysis was treated with the serine-threonine kinase inhibitor, vemurafenib. After 5 months of treatment, a substantial response to vemurafenib was observed using imaging, but when he developed a prolonged QTc interval (common toxicity criteria (CTC) grade 3), treatment was interrupted. Vemurafenib was restarted at a reduced dose when the QTc interval returned to normal. The patient has had a significant response to vemurafenib and continued on treatment for 12 months after beginning the therapy. CONCLUSION: This is the first reported case of end stage renal failure in a patient who is taking vemurafenib. Although the patient developed QTc prolongation, it appears to be asymptomatic, and was managed with dose reduction. This case highlights the need for closer QTc monitoring at the start and during treatment.

OBJECTIVES: Our objectives were to analyze the effectiveness of epidural anesthesia in patients who underwent open retropubic radical prostatectomy (RRP) at our institution over the past decade, and to examine subsequent oncologic outcomes, comparing those receiving with those not receiving epidural anesthesia. METHODS: A comprehensive database of all patients undergoing RRP from November 1996 to December 2006 was analyzed; 354 patients underwent RRP at our institution and were divided into those receiving or not receiving an epidural. An independent pain management team scoring technical success found epidural technique to be consistent. Oncological outcome was an endpoint of our study, comparing both analysis groups. We classed prostate-specific antigen (PSA) recurrence after RRP as a serum PSA ≥ 0.2 ng/mL at any stage of postoperative follow-up. Complications were recorded to 30 days using the modified Clavien system, and full statistical analyses were undertaken. RESULTS: Records were available for 239 men; we observed a decreased trend in the use of epidural for pain management, along with a decrease in average hospital stay and an overall epidural success rate of 64%. When dividing data into RRP with and without epidural, we found a median hospital stay of 7 days for patients receiving an epidural compared with 6 days for those not receiving an epidural. The differences were statistically significant (P < 0.048) and remained so after adjusting for complications (P < 0.0001). Regarding oncological outcome, PSA recurrence was further analyzed in this cohort. Percentage of recurrence was higher (14.8%) for patients receiving an epidural than for the non-epidural group (4.8%). The differences were statistically significant (P = 0.012). CONCLUSION: Epidural analgesia increased length of hospital stay and technical problems related to the epidural. Furthermore, men receiving an epidural showed an increased recurrence of PSA. In light of our findings, epidurals are probably not indicated for men undergoing RRP. However, as minimally invasive techniques are becoming more widespread, and epidural analgesia is being used less frequently, large randomized controlled trials to definitively support our hypotheses are unlikely to be undertaken.

Urological involvement of hepatocellular carcinoma (HCC) is rare; HCC arising in an orthotopic liver transplant (OLT) is exceptionally rare. Here we report the case of a 70-year-old man who was incidentally found to have metastatic HCC in the right kidney arising from his OLT undertaken for cryptogenic cirrhosis 10 years previously. Adding to the complexity of this case was the lack of an obvious liver primary HCC at the time of the radical nephrectomy, thus making the final diagnosis all but impossible. We believe this report represents the first report of HCC metastasizing to the kidney after OLT and adds to the few reports in the literature of HCC arising in transplanted livers.

G protein-coupled receptors (GPCRs) are critical for cardiovascular physiology. Cardiac cells express >100 nonchemosensory GPCRs, indicating that important physiological and potential therapeutic targets remain to be discovered. Moreover, there is a growing appreciation that members of the large, distinct taste and odorant GPCR families have specific functions in tissues beyond the oronasal cavity, including in the brain, gastrointestinal tract and respiratory system. To date, these chemosensory GPCRs have not been systematically studied in the heart. We performed RT-qPCR taste receptor screens in rodent and human heart tissues that revealed discrete subsets of type 2 taste receptors (TAS2/Tas2) as well as Tas1r1 and Tas1r3 (comprising the umami receptor) are expressed. These taste GPCRs are present in cultured cardiac myocytes and fibroblasts, and by in situ hybridization can be visualized across the myocardium in isolated cardiac cells. Tas1r1 gene-targeted mice (Tas1r1(Cre)/Rosa26(tdRFP)) strikingly recapitulated these data. In vivo taste receptor expression levels were developmentally regulated in the postnatal period. Intriguingly, several Tas2rs were upregulated in cultured rat myocytes and in mouse heart in vivo following starvation. The discovery of taste GPCRs in the heart opens an exciting new field of cardiac research. We predict that these taste receptors may function as nutrient sensors in the heart.

BACKGROUND: Burnout is a mental condition defined as a result of continuous and long-term stress exposure, particularly related to psychosocial factors at work. This paper seeks to examine the psychometric properties of the Shirom-Melamed Burnout Questionnaire (SMBQ) for validation of use in a clinical setting. METHODS: Data from both a clinical (319) and general population (319) samples of health care and social insurance workers were included in the study. Data were analysed using both classical and modern test theory approaches, including Confirmatory Factor Analysis (CFA) and Rasch analysis. RESULTS: Of the 638 people recruited into the study 416 (65%) persons were working full or part time. Data from the SMBQ failed a CFA, and initially failed to satisfy Rasch model expectations. After the removal of 4 of the original items measuring tension, and accommodating local dependency in the data, model expectations were met. As such, the total score from the revised scale is a sufficient statistic for ascertaining burnout and an interval scale transformation is available. The scale as a whole was perfectly targeted to the joint sample. A cut point of 4.4 for severe burnout was chosen at the intersection of the distributions of the clinical and general population. CONCLUSION: A revised 18 item version of the SMBQ satisfies modern measurement standards. Using its cut point it offers the opportunity to identify potential clinical cases of burnout.

BACKGROUND: While it is recognised that depression is prevalent in Rheumatoid Arthritis (RA), recent studies have also highlighted significant levels of anxiety in RA patients. This study compared two commonly used scales, the Depression Anxiety and Stress Scale (DASS) and the Hospital Anxiety and Depression Scale (HADS), in relation to their measurement range and cut points to consider the relative prevalence of both constructs, and if prevalence rates may be due to scale-specific case definition. METHODS: Patients meeting the criteria for RA were recruited in Leeds, UK and Sydney, Australia and asked to complete a survey that included both scales. The data was analysed using the Rasch measurement model. RESULTS: A total of 169 RA patients were assessed, with a repeat subsample, resulting in 323 cases for analysis. Both scales met Rasch model expectations. Using the 'possible+probable' cut point from the HADS, 58.3% had neither anxiety nor depression; 13.5% had anxiety only; 6.4% depression only and 21.8% had both 'possible+probable' anxiety and depression. Cut points for depression were comparable across the two scales while a lower cut point for anxiety in the DASS was required to equate prevalence. CONCLUSIONS: This study provides further support for high prevalence of depression and anxiety in RA. It also shows that while these two scales provide a good indication of possible depression and anxiety, the estimates of prevalence so derived could vary, particularly for anxiety. These findings are discussed in terms of comparisons across studies and selection of scales for clinical use.

BACKGROUND: The mini-Mental Adjustment to Cancer Scale (mini-MAC) is a well-recognised, popular measure of coping in psycho-oncology and assesses five cancer-specific coping strategies. It has been suggested that these five subscales could be grouped to form the over-arching adaptive and maladptive coping subscales to facilitate the interpretation and clinical application of the scale. Despite the popularity of the mini-MAC, few studies have examined its psychometric properties among long-term cancer survivors, and further validation of the mini-MAC is needed to substantiate its use with the growing population of survivors. Therefore, this study examined the psychometric properties and dimensionality of the mini-MAC in a sample of long-term cancer survivors using Rasch analysis. METHODS: RUMM 2030 was used to analyse the mini-MAC data (n=851). Separate Rasch analyses were conducted for each of the original mini-MAC subscales as well as the over-arching adaptive and maladaptive coping subscales to examine summary and individual model fit statistics, person separation index (PSI), response format, local dependency, targeting, item bias (or differential item functioning -DIF), and dimensionality. RESULTS: For the fighting spirit, fatalism, and helplessness-hopelessness subscales, a revised three-point response format seemed more optimal than the original four-point response. To achieve model fit, items were deleted from four of the five subscales - Anxious Preoccupation items 7, 25, and 29; Cognitive Avoidance items 11 and 17; Fighting Spirit item 18; and Helplessness-Hopelessness items 16 and 20. For those subscales with sufficient items, analyses supported unidimensionality. Combining items to form the adaptive and maladaptive subscales was partially supported. CONCLUSIONS: The original five subscales required item deletion and/or rescaling to improve goodness of fit to the Rasch model. While evidence was found for overarching subscales of adaptive and maladaptive coping, extensive modifications were necessary to achieve this result. Further exploration and validation of over-arching subscales assessing adaptive and maladaptive coping is necessary with cancer survivors.

BACKGROUND AND PURPOSE: Urinary dysfunction is associated with significant morbidity in persons with Guillain-Barré Syndrome (GBS). The aim of this study was to describe prevalence and long-term impact of bladder dysfunction on daily activities and quality of life (QoL) in persons in chronic phase of GBS and to examine the relationships between commonly used continence measures in this cohort. METHODS: Prospective cohort (n=66) following GBS treatment (1996-2009) was recruited from a tertiary hospital and assessed using standardised measures for bladder dysfunction: American Urological Association (AUA) Symptom Index, Incontinence Impact Questionnaire, Urogenital Distress Inventory. RESULTS: Sixty-six participants (64% male, mean age 56 years, median disease duration of 6.1 years) completed the study. Of these more than half reported nocturia and one-third reported urinary urgency and frequency. Urinary problems impacted on participants' daily activities: physical recreation (21%), emotional health and mood (17%), entertainment (14%), participation and mobility (>30 min) (12%), and performance of household chores (8%). Since GBS, 49% reported interference of urinary symptoms with daily life to some extent; and adverse impact on QoL (10.6%). Significant relationship between bladder symptoms; and the level of urogenital distress (p<0.001) and the impact of urinary problems (p<0.001), was noted. Higher scores on the bladder scales showed significant correlations with psychological, functional and participation scales. The single QoL item (AUA scale) correlated significantly with all other bladder scales (rho=0.63-0.86). This can be a potential 'screening tool' to identify patients for further assessment. CONCLUSIONS: Bladder dysfunction in chronic phase of GBS is not well studied. More research in longer-term screening and outcomes for bladder intervention are needed for integrated care and to guide treating clinicians.

Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63(-/-) mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC.

BACKGROUND: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response. METHODS: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion. RESULTS: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes. CONCLUSION: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.

BACKGROUND: Women's fears and attitudes to childbirth may influence the maternity care they receive and the outcomes of birth. This study aimed to develop profiles of women according to their attitudes regarding birth and their levels of childbirth related fear. The association of these profiles with mode and outcomes of birth was explored. METHODS: Prospective longitudinal cohort design with self report questionnaires containing a set of attitudinal statements regarding birth (Birth Attitudes Profile Scale) and a fear of birth scale (FOBS). Pregnant women responded at 18-20 weeks gestation and two months after birth from a regional area of Sweden (n = 386) and a regional area of Australia (n = 123). Cluster analysis was used to identify a set of profiles. Odds ratios (95% CI) were calculated, comparing cluster membership for country of care, pregnancy characteristics, birth experience and outcomes. RESULTS: Three clusters were identified - 'Self determiners' (clear attitudes about birth including seeing it as a natural process and no childbirth fear), 'Take it as it comes' (no fear of birth and low levels of agreement with any of the attitude statements) and 'Fearful' (afraid of birth, with concerns for the personal impact of birth including pain and control, safety concerns and low levels of agreement with attitudes relating to women's freedom of choice or birth as a natural process). At 18 -20 weeks gestation, when compared to the 'Self determiners', women in the 'Fearful' cluster were more likely to: prefer a caesarean (OR = 3.3 CI: 1.6-6.8), hold less than positive feelings about being pregnant (OR = 3.6 CI: 1.4-9.0), report less than positive feelings about the approaching birth (OR = 7.2 CI: 4.4-12.0) and less than positive feelings about the first weeks with a newborn (OR = 2.0 CI 1.2-3.6). At two months post partum the 'Fearful' cluster had a greater likelihood of having had an elective caesarean (OR = 5.4 CI 2.1-14.2); they were more likely to have had an epidural if they laboured (OR = 1.9 CI 1.1-3.2) and to experience their labour pain as more intense than women in the other clusters. The 'Fearful' cluster were more likely to report a negative experience of birth (OR = 1.7 CI 1.02- 2.9). The 'Take it as it comes' cluster had a higher likelihood of an elective caesarean (OR 3.0 CI 1.1-8.0). CONCLUSIONS: In this study three clusters of women were identified. Belonging to the 'Fearful' cluster had a negative effect on women's emotional health during pregnancy and increased the likelihood of a negative birth experience. Both women in the 'Take it as it comes' and the 'Fearful' cluster had higher odds of having an elective caesarean compared to women in the 'Self determiners'. Understanding women's attitudes and level of fear may help midwives and doctors to tailor their interactions with women.