Brachytherapy for high grade prostate cancer induces distinct changes in circulating CD4 and CD8 T cells - Implications for systemic control.

This exploratory study is a follow up to our previous investigation of immune response in the circulation of high-grade Gleason 9 prostate cancer patients treated with EBRT + BT compared to EBRT alone. Notably, EBRT + BT demonstrates the potential to elicit an effect on CD4/CD8 ratio which may have attributed to improved clinical response to therapy. Our findings show promise for leveraging circulating immune cells as predictive biomarkers for radiotherapy response.

Executive function in children with sickle cell anemia on transfusion: NIH toolbox utility in the clinical context.

Objective: The aim of this study was to establish the utility of the NIH Toolbox as a cognitive screener of executive functions in the clinical context. Additionally, we aimed to investigate whether age and time on transfusion were related to executive function performance. Method: Twenty-eight children and adolescents with sickle cell anemia (SCA) between 8 and 18 years (M = 13.28, SD = 3.05) on transfusion treatment were included. Participants completed five NIH Toolbox tasks (three executive function tasks and two non-executive function control tasks). Results: Mean scores on one of the three executive function measures (inhibitory control) fell below the average range (M = 81.36, SD = 14.01) with approximately 70% of children from both groups below the average range. Scores for processing speed (M = 86.82, SD = 22.01) and cognitive flexibility (M = 85.75, SD = 12.67) were low averages. As expected, scores on non-executive measures (language and memory) fell within the average range. No significant differences were observed between children with silent stroke and no stroke on executive function measures. Older age (p < .01) and length of time on transfusion (p < .05) predicted lower inhibitory control scores. Conclusions: Findings provide evidence for poor development of inhibitory control with age in this patient population. As the NIH Toolbox successfully highlighted expected deficits in this patient population, this study supports the use of this tool as a brief screening measure for children with SCD. The clinical and theoretical implications of the findings are discussed.

Sensory modulation and negative affect in children at familial risk of ADHD.

BACKGROUND/AIMS: Sensory modulation difficulties are commonly reported in patients with ADHD, however there has been little focus on the development of these difficulties in young children at a higher risk of later ADHD diagnosis. This study investigated whether children with a familial history of ADHD show greater sensory modulation difficulties. We also explored whether sensory modulation was linked to negative affectivity, which has been highlighted as a potential early marker of ADHD. METHODS: Parents of children under 6 years with a family history of ADHD (n = 65) and no family history (n = 122) completed questionnaires on sensory modulation and temperament. RESULTS: Children from families with ADHD were reported to display extreme patterns of hyperresponsiveness and hyporesponsiveness, relative to controls. No differences emerged for the sensory seeking domain. Some children within the high-risk group reported high scores across all three sensory modulation patterns. Regression analysis revealed that hyperresponsiveness predicted higher levels of negative affect. CONCLUSIONS/IMPLICATIONS: This study is the first to report greater sensory modulation difficulties in children at familial risk of ADHD. Future research should establish whether children with sensory modulation and temperament difficulties in early childhood are more vulnerable to developing ADHD.

An Exploration of Sleep and Family Factors in Young Children at Familial Risk for ADHD.

Objective: The aim of the current study was to examine relations between sleep problems and family factors and early markers of ADHD in young children with and without a familial risk for ADHD.Methods: Differences in sleep behavior and family functioning in children under 6 years with (n = 72) and without (n = 139) a familial risk for ADHD were investigated. The influence of family and sleep factors on the development of early temperament markers of ADHD (effortful control and negative affect) was explored. Parents/caregivers completed questionnaires on family functioning, child sleep behavior, and general regulatory behaviors.Results: A significant difference was observed between high-risk and low-risk groups for family functioning in the infant/toddler (<3 years) and preschool (>3 years) cohorts. Parents of infants/toddlers in the high-risk group reported poorer infant sleep. However, there were no sleep differences reported for the preschool cohort. Family functioning was found to predict effortful control, while sleep quality predicted negative affect.Conclusion: The results of this study highlight potential family and sleep issues for young children with a familial history of ADHD and the potential influence of these factors on early temperament markers of ADHD. Future research should explore these relations further in order to better establish whether early sleep and family interventions could mitigate later ADHD symptomatology.

Immune cell profiling in Gleason 9 prostate cancer patients treated with brachytherapy versus external beam radiotherapy: An exploratory study.

This exploratory study evaluates immunological changes in high-risk Gleason 9 prostate cancer patients treated with EBRT+BT compared to EBRT alone. Notably, BT demonstrates the potential to elicit a T cell response which may support further investigation using circulating immune cells as predictive and prognostic biomarkers for radiotherapy response.

A Canadian guideline on the use of next-generation sequencing in oncology.

Rapid advancements in next-generation sequencing (ngs) technology have created an unprecedented opportunity to decipher the molecular profile of tumours to more effectively prevent, diagnose, and treat cancer. Oncologists now have the option to order molecular tests that can guide treatment decisions. However, to date, most oncologists have received limited training in genomics, and they are now faced with the challenge of understanding how such tests and their interpretation align with patient management. Guidance on how to effectively use ngs technology is therefore needed to aid oncologists in applying the results of genomic tests. The Canadian guideline presented here describes best practices and unmet needs related to ngs-based testing for somatic variants in oncology, including clinical application, assay and sample selection, bioinformatics and interpretation of reports performed by laboratories, patient communication, and clinical trials.

Harmonization of PD-L1 testing in oncology: a Canadian pathology perspective.

Checkpoint inhibitors targeting the programmed cell death 1 protein (PD-1) and programmed cell death ligand 1 (PD-L1) are demonstrating promising efficacy and appear to be well tolerated in a number of tumour types. In non-small-cell lung cancer, head-and-neck squamous cell carcinoma, and urothelial carcinoma, outcomes appear particularly favourable in patients with high PD-L1 expression. However, assays for PD-L1 have been developed for individual agents, and they use different antibody clones, immunohistochemistry staining protocols, scoring algorithms, and cut-offs. Given that laboratories are unlikely to use multiple testing platforms, use of one PD-L1 assay in conjunction with a specific therapy will become impractical and could compromise treatment options. Methods to harmonize testing methods are therefore crucial to ensuring appropriate treatment selection. This paper focuses on lung, bladder, and head-and-neck cancer. It reviews and compares available PD-L1 testing methodologies, summarizes the literature about comparability studies to date, discusses future directions in personalized diagnostics, and provides a pathologist's perspective on PD-L1 testing in the Canadian laboratory setting.

Stress in new graduates: can the profession do more to help?

Richard Halliwell and colleagues believe that it can, on the basis of a survey they conducted to assess the incidence of poor mental health and wellbeing in recent veterinary graduates, and workplace factors that might be associated with this.

Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases.

The vitamin D receptor (VDR) is a ligand-activated transcription factor that regulates gene expression in many cell types, including immune cells. It requires binding of 1,25 dihydroxy vitamin D3 (1,25D3) for activation. Many autoimmune diseases show latitude-dependent prevalence and/or association with vitamin D deficiency, and vitamin D supplementation is commonly used in their clinical management. 1,25D3 is regulated by genes associated with the risk of autoimmune diseases and predominantly expressed in myeloid cells. We determined the VDR cistrome in monocytes and monocyte-derived inflammatory (DC1) and tolerogenic dendritic cells (DC2). VDR motifs were highly overrepresented in ChIP-Seq peaks in stimulated monocyte (40%), DC1 (21%) and DC2 (47%), P

A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer.

BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies METHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. CONCLUSIONS: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.

Reduced-dose fractionated stereotactic radiotherapy for acoustic neuromas: maintenance of tumor control with improved hearing preservation.

BACKGROUND: Fractionated stereotactic radiotherapy (FSRT) is a noninvasive treatment for acoustic neuromas (ANs). Initial reports from our institution demonstrated that the reduction of treatment dose to 46.8 Gy resulted in improved preservation of functional hearing status. OBJECTIVE: We now report the tumor control (TC), symptomatic outcome, and hearing preservation (HP) rate in patients treated with reduced-dose FSRT. METHODS: We analyzed all patients with AN treated from 2002 to 2011. All patients received 46.8 Gy in 1.8-Gy fractions. Follow-up audiogram and magnetic resonance imaging were performed in ≤ 1-year intervals. TC and HP were calculated by the Kaplan-Meier method. Analysis of HP, defined as Gardner-Robertson value ≤ 2, was determined by audiometric data. Non-hearing-related symptoms were defined by Common Terminology Criteria for Adverse Events version 4. RESULTS: In total, 154 patients were analyzed. At a median follow-up of 35 months (range, 4-108), TC was achieved in 96% of patients (n = 148/154) and at 3 and 5 years was 99% and 93%. Eighty-seven patients had serviceable hearing at the time of FSRT and evaluable audiometric follow-up. Overall HP was 67% and at 3 and 5 years was 66% and 54%. Pure tone average decreased by a median of 13 dB in all patients. Nineteen percent (n = 31) of patients experienced symptom improvement, and 8% (n = 13) had worsening of symptoms. Cranial nerve dysfunction occurred in 3.8% of patients (n = 6). CONCLUSION: Reduced-dose FSRT to 46.8 Gy for AN achieves excellent functional HP rates and limited toxicity without compromising long-term TC. Based on these promising outcomes, further attempts at dose deescalation may be warranted.

Secular trends in nosocomial bloodstream infections: antibiotic-resistant bacteria increase the total burden of infection.

BACKGROUND: It is unknown whether rising incidence rates of nosocomial bloodstream infections (BSIs) caused by antibiotic-resistant bacteria (ARB) replace antibiotic-susceptible bacteria (ASB), leaving the total BSI rate unaffected. METHODS: We investigated temporal trends in annual incidence densities (events per 100 000 patient-days) of nosocomial BSIs caused by methicillin-resistant Staphylococcus aureus (MRSA), ARB other than MRSA, and ASB in 7 ARB-endemic and 7 ARB-nonendemic hospitals between 1998 and 2007. RESULTS: 33 130 nosocomial BSIs (14% caused by ARB) yielded 36 679 microorganisms. From 1998 to 2007, the MRSA incidence density increased from 0.2 to 0.7 (annual increase, 22%) in ARB-nonendemic hospitals, and from 3.1 to 11.7 (annual increase, 10%) in ARB-endemic hospitals (P = .2), increasing the incidence density difference between ARB-endemic and ARB-nonendemic hospitals from 2.9 to 11.0. The non-MRSA ARB incidence density increased from 2.8 to 4.1 (annual increase, 5%) in ARB-nonendemic hospitals, and from 1.5 to 17.4 (annual increase, 22%) in ARB-endemic hospitals (P < .001), changing the incidence density difference from -1.3 to 13.3. Trends in ASB incidence densities were similar in both groups (P = .7). With annual increases of 3.8% and 5.4% of all nosocomial BSIs in ARB-nonendemic and ARB-endemic hospitals, respectively (P < .001), the overall incidence density difference of 3.8 increased to 24.4. CONCLUSIONS: Increased nosocomial BSI rates due to ARB occur in addition to infections caused by ASB, increasing the total burden of disease. Hospitals with high ARB infection rates in 2005 had an excess burden of BSI of 20.6 per 100 000 patient-days in a 10-year period, mainly caused by infections with ARB.

Monitoring Clostridium difficile infection in an acute hospital: prevalence or incidence studies?

BACKGROUND: Surveillance of Clostridium difficile infection (CDI) is an essential component of a CDI preventative programme. AIMS: The aim of this study was to evaluate two methods of CDI surveillance. METHODS: Prevalence of CDI, antibiotic use and associated co-morbidity was assessed weekly on two wards over 6 weeks. In addition, CDI incidence surveillance was performed on all new CDI cases over a 13-week period. Cases were assessed for CDI risk factors, disease severity, response to treatment and outcome at 6 months. RESULTS: Clostridium difficile infection prevalence was 3.5% (range 2.9-6.1%) on the medical ward and 1.1% (range 0-3.5%) on the surgical ward. Patients on the medical ward were older and more likely to be colonised with MRSA; however, recent antibiotic use was more prevalent among surgical patients. Sixty-one new CDI cases were audited. Patients were elderly (mean age 71 years) with significant co-morbidity (median age adjusted Charlson co-morbidity score 5). CDI ribotypes included 027 (29 cases) 078 (5) and 106 (4). Eight patients developed severe CDI, seven due to 027. Antibiotic use was common with 56% receiving three or more antibiotics in the preceding 8 weeks. Twenty-four patients had died at 6 months, five due to CDI. CONCLUSION: Clostridium difficile infection prevalence gives a broad overview of CDI and points to areas that require more detailed surveillance and requires little time. However, patient-based CDI incidence surveillance provides a more useful analysis of CDI risk factors, disease and outcome for planning preventative programmes and focusing antibiotic stewardship efforts.

A 12-year review of Staphylococcus aureus bloodstream infections in haemodialysis patients: more work to be done.

Staphylococcus aureus bloodstream infections (BSI) are a significant cause of morbidity and mortality in haemodialysis patients. This study describes a 12-year retrospective review of S. aureus BSI in a large haemodialysis centre in a tertiary referral hospital. The overall rate of S. aureus BSI was 17.9 per 100 patient-years (range 9.7-36.8). The rate of meticillin-resistant S. aureus (MRSA) BSI was 5.6 per 100 patient-years (range 0.9-13.8). Infective complications occurred in 11% of episodes, the most common being infective endocarditis (7.6%). Ten percent of patients died within 30 days of S. aureus being isolated from blood. Most cases of S. aureus BSI (83%) were related to vascular catheters. The provision of lower-risk vascular access, such as arteriovenous fistulae, and reduced use of intravascular catheters should be priorities in all haemodialysis units. Where alternative vascular access cannot be established, interventions to reduce the risk of catheter-related infections should be implemented to reduce morbidity and mortality in this vulnerable patient group.

Cutaneous reactions to adalimumab administration.

Patients receiving antitumour necrosis factor-alpha treatment may develop cutaneous reactions. This human monoclonal antibody is used in the treatment of chronic inflammatory diseases, including arthritis and inflammatory bowel disease. A variety of side effects have been documented ranging from infection and vasculitis through to systemic lupus erythematosus and psoriasis. We report on two arthritic patients treated with adalimumab (Humira, Abbot Laboratories, IL, USA) who developed new onset rashes that resolved with discontinuation of therapy. The frequency of these cutaneous reactions has not been fully established and may benefit from a centralised registry.

Analysis of trends and seasonal variation in primary cutaneous melanoma: an Irish study.

A seasonal variation in the presentation of cutaneous melanoma has been documented in several studies. We performed a retrospective review of primary cutaneous melanomas (n = 263) from our institution to examine whether the seasonal patterns of presentation noted in the literature would be similar in Ireland, a climate with low ambient sunshine. A summer : winter ratio was determined for age, gender, subtype, location and Breslow thickness. We found an increase in total numbers of melanomas, particularly in men. The summer : winter ratio was 2.39 for all patients (95% CI 1.60-3.57, P < 0.001), with seasonal variations noted for location, thickness and subtype (excluding lentigo). Melanomas presenting over the summer tended towards a greater Breslow thickness than did those presenting in winter. This subclassification of primary cutaneous melanoma with summer : winter ratios based on patient and tumour characteristics gave remarkably similar results to previously published reports, notwithstanding the low levels of annual ambient sunshine in Ireland.

Nuclear receptors and AMPK: resetting metabolism.

Obesity, and in particular central adiposity, is a key feature of metabolic syndrome, which includes trends toward increased triglycerides, insulin resistance, high blood pressure, hypercholesterolemia, and heart disease. It has a prevalence of 25% or more and is a dominant component of the health care budgets in Western societies. In addition to genetic causes, high-fat diets and disrupted sleep patterns have major influences on the development of metabolic syndrome. Recent studies have demonstrated active roles for the nuclear receptor superfamily and the energy-sensing kinase adenosine monophosphate (AMP)-activated protein kinase (AMPK) in regulating metabolism and circadian rhythm. In this chapter, we review these findings and attempt to develop a better understanding of the interplay between metabolism and circadian rhythm and their coordinated regulation by nuclear receptors and AMPK. This supraregulatory network may be considered a target for novel therapeutic applications against metabolic syndrome.

Infection due to C. difficile ribotype 078: first report of cases in the Republic of Ireland.

Clostridium difficile is an important healthcare-associated pathogen. Hypervirulent strains such as those belonging to ribotype 027 have been widely reported in recent years. A second strain associated with hypervirulence is ribotype 078 and the prevalence of Clostridium difficile infection (CDI) due to this ribotype appears to be increasing. This report describes an outbreak, in which 15cases of CDI due to ribotype 078 were detected in an Irish hospital and from a nursing home in the hospital's catchment area. C. difficile ribotype 078 accounted for 15% of total isolates submitted for ribotyping. The average age of patients with CDI due to ribotype 078 was 76 years. Forty-six percent of patients experienced recurrence of symptoms within eight weeks of diagnosis and CDI was felt to have directly contributed to five of the eight deaths. Use of enhanced DNA fingerprinting identified clusters within the 15 cases and suggested hitherto unrecognised links between some patients with CDI. Such approaches offer the promise to delineate common sources and transmission routes for C. difficile.

Profile of sudden death in an adult population (1999-2008).

Sudden death is the sudden and unexpected death of an individual within 24 hours of symptom onset. The vast majority of these cases are found, at autopsy, to be due to underlying ischaemic cardiac disease. We retrospectively reviewed all adult post mortems performed at Beaumont Hospital over a decade (1999-2008). Our aim was to identify all sudden death cases (natural and accidental) and subclassify them according to age profile and organ system involved. We identified 1230 sudden death cases in the review period with 775 (63%) deaths attributable to ischaemic heart disease. The rate of sudden death remained constant over the decade with 663 (54%) deaths occurring in the first five years. Our negative autopsy rate was 2.8% corresponding to 35 cases. This is the first Irish study to retrospectively review all adult sudden deaths within a defined catchment area and analyse them as outlined above.

Detecting soluble clusterin in in-vitro and in-vivo models of prostate cancer.

PSA, the only relevant marker for prostate cancer, has a low predictive value; moreover its low threshold leads to unnecessary biopsies with associated complications. Identification of prognostic factors is an important goal in prostate cancer. In the search for new markers, clusterin, has some potential as it is closely linked with cancer progression and resistance to apoptosis. We looked at the expression of secreted clusterin (sCLU) in prostate cells to determine correlations with progression and drug resistance. The plasmatic expression of sCLU was also investigated in order to use it as a potential marker for prostate cancer. sCLU expression was studied using Western blotting on cultured prostate cells, PWR-1E, PC3 and PC3 Docetaxel resistant cells in the cytosol and culture medium. An inhouse ELISA test was developed to determine sCLU expression in culture media and plasma samples. A patient cohort was identified from the Prostate Cancer Research Consortium Bio-Resource and plasmatic expression of sCLU was studied using western blotting and the inhouse ELISA test. Only the fully processed form of sCLU was identified in the medium of cells with increased expression associated with increased progression of disease and resistance to docetaxel. Plasmatic expression of sCLU was significantly higher in the plasma of patients with high grade prostate cancer with extracapsular extension than in the plasma of prostate cancer patients without extracapsular extension. Plasmatic sCLU may be an effective prognostic marker of prostate cancer and needs to be tested in a multimarker approach.