The Impact of Positron Emission Tomography Imaging and Tumor Molecular Profiling on Risk Stratification, Treatment Choice, and Oncological Outcomes of Patients with Primary or Relapsed Prostate Cancer: An International Collaborative Review of the Existing Literature.

CONTEXT: The clinical introduction of next-generation imaging methods and molecular biomarkers ("radiogenomics") has revolutionized the field of prostate cancer (PCa). While the clinical validity of these tests has thoroughly been vetted, their clinical utility remains a matter of investigation. OBJECTIVE: To systematically review the evidence to date on the impact of positron emission tomography (PET) imaging and tissue-based prognostic biomarkers, including Decipher, Prolaris, and Oncotype Dx, on the risk stratification, treatment choice, and oncological outcomes of men with newly diagnosed PCa or those with biochemical failure (BCF). EVIDENCE ACQUISITION: We performed a quantitative systematic review of the literature using the MEDLINE, EMBASE, and Web of Science databases (2010-2022) following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. The validated Quality Assessment of Diagnostic Accuracy Studies 2 scoring system was used to assess the risk of bias. EVIDENCE SYNTHESIS: A total of 148 studies (130 on PET and 18 on biomarkers) were included. In the primary PCa setting, prostate-specific membrane antigen (PSMA) PET imaging was not useful in improving T staging, moderately useful in improving N staging, but consistently useful in improving M staging in patients with National Comprehensive Cancer Network (NCCN) unfavorable intermediate- to very-high-risk PCa. Its use led to a management change in 20-30% of patients. However, the effect of these treatment changes on survival outcomes was not clear. Similarly, biomarkers in the pretherapy primary PCa setting increased and decreased the risk, respectively, in 7-30% and 32-36% of NCCN low-risk and 31-65% and 4-15% of NCCN favorable intermediate-risk patients being considered for active surveillance. A change in management was noted in up to 65% of patients, with the change being in line with the molecular risk-based reclassification, but again, the impact of these changes on survival outcomes remained unclear. Notably, in the postsurgical primary PCa setting, biomarker-guided adjuvant radiation therapy (RT) was associated with improved oncological control: Δ↓ 2-yr BCF by 22% (level 2b). In the BCF setting, the data were more mature. PSMA PET was consistently useful in improving disease localization-Δ↑ detection for T, N, and M staging was 13-32%, 19-58%, and 9-29%, respectively. Between 29% and 73% of patients had a change in management. Most importantly, these management changes were associated with improved survival outcomes in three trials: Δ↑ 4-yr disease-free survival by 24.3%, Δ↑ 6-mo metastasis-free survival (MFS) by 46.7%, and Δ↑ androgen deprivation therapy-free survival by 8 mo in patients who received PET-concordant RT (level 1b-2b). Biomarker testing in these patients also appeared to be helpful in risk stratifying and guiding the use of early salvage RT (sRT) and concomitant hormonal therapy. Patients with high-genomic-risk scores benefitted from treatment intensification: Δ↑ 8-yr MFS by 20% with the use of early sRT and Δ↑ 12-yr MFS by 11.2% with the use of hormonal therapy alongside early sRT, while low-genomic-risk score patients did equally well with initial conservative management (level 3). CONCLUSIONS: Both PSMA PET imaging and tumor molecular profiling provide actionable information in the management of men with primary PCa and those with BCF. Emerging data suggest that radiogenomics-guided treatments translate into direct survival benefits for patients, however, additional prospective data are awaited. PATIENT SUMMARY: In this review, we evaluated the utility of prostate-specific membrane antigen positron emission tomography and tumor molecular profiling in guiding the care of men with prostate cancer (PCa). We found that these tests augmented risk stratification, altered management, and improved cancer control in men with a new diagnosis of PCa or for those experiencing a relapse.

Effects of a multicomponent resistance-based exercise program with protein, vitamin D and calcium supplementation on cognition in men with prostate cancer treated with ADT: secondary analysis of a 12-month randomised controlled trial.

OBJECTIVES: The aim of this preplanned secondary analysis of a 12-month randomised controlled trial was to investigate the effects of a multicomponent exercise programme combined with daily whey protein, calcium and vitamin D supplementation on cognition in men with prostate cancer treated with androgen deprivation therapy (ADT). DESIGN: 12-month, two-arm, randomised controlled trial. SETTING: University clinical exercise centre. PARTICIPANTS: 70 ADT-treated men were randomised to exercise-training plus supplementation (Ex+ Suppl, n=34) or usual care (control, n=36). INTERVENTION: Men allocated to Ex + Suppl undertook thrice weekly resistance training with weight-bearing exercise training plus daily whey protein (25 g), calcium (1200 mg) and vitamin D (2000 IU) supplementation. PRIMARY AND SECONDARY OUTCOME MEASURES: Cognition was assessed at baseline, 6 and 12 months via a computerised battery (CogState), Trail-making test, Rey auditory-verbal learning test and Digit span. Data were analysed with linear mixed models and an intention-to-treat and prespecified per-protocol approach (exercise-training: ≥66%, nutritional supplement: ≥80%). RESULTS: Sixty (86%) men completed the trial (Ex + Suppl, n=31; control, n=29). Five (7.1%) men were classified as having mild cognitive impairment at baseline. Median (IQR) adherence to the exercise and supplement was 56% (37%-82%) and 91% (66%-97%), respectively. Ex + Suppl had no effect on cognition at any time. CONCLUSIONS: A 12-month multicomponent exercise training and supplementation intervention had no significant effect on cognition in men treated with ADT for prostate cancer compared with usual care. Exercise training adherence below recommended guidelines does not support cognitive health in men treated with ADT for prostate cancer. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry (ACTRN12614000317695, registered 25/03/2014) and acknowledged under the Therapeutic Goods Administration Clinical Trial Notification Scheme (CT-2015-CTN-03372-1 v1).

The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.

Musculoskeletal Responses to Exercise Plus Nutrition in Men with Prostate Cancer on Androgen Deprivation: A 12-Month RCT.

PURPOSE: Androgen deprivation therapy (ADT) for prostate cancer has multiple adverse effects on musculoskeletal health. This 12-month randomized controlled trial aimed to assess the effects of multicomponent exercise training combined with whey protein, calcium and vitamin D supplementation on bone mineral density (BMD), structure and strength, body composition, muscle strength, and physical function in ADT-treated men. METHODS: Seventy ADT-treated men were randomized to exercise plus supplementation (Ex + Suppl; n = 34) or usual care (control; n = 36). Ex + Suppl involved thrice weekly progressive resistance training plus weight-bearing impact exercise with daily multinutrient supplementation. Primary outcomes were DXA hip and spine areal BMD. Secondary outcomes included the following: tibia and radius pQCT volumetric BMD, bone structure and strength, DXA body composition, pQCT muscle and fat cross-sectional area and muscle density, and muscle strength and physical function. RESULTS: Sixty men (86%) completed the study. Mean exercise and supplement adherence were 56% and 77%, respectively. There were no effects of the intervention on bone or body composition outcomes. Ex + Suppl improved leg muscle strength (net difference, (95% confidence interval, or CI), 14.5% (-0.2 to 29.2); P = 0.007) and dynamic mobility (four-square-step test time, -9.3% (-17.3 to -1.3), P = 0.014) relative to controls. Per-protocol analysis of adherent participants (≥66% exercise, ≥80% supplement) showed Ex + Suppl preserved femoral neck aBMD (1.9% (0.1 to 3.8), P = 0.026) and improved total body lean mass (1.0 kg (-0.23 to 2.22), P = 0.044) relative to controls. CONCLUSIONS: Exercise training combined with multinutrient supplementation had a limited effect on ameliorating the adverse musculoskeletal consequences of ADT, likely related to the modest intervention adherence.

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Current management of radiation cystitis: a review and practical guide to clinical management.

INTRODUCTION: Haemorrhage is a frequent complication of radiation cystitis leading to emergency presentations in patients with prior pelvic radiation therapy. Standard initial patient management strategies involve resuscitation, bladder washout with clot evacuation and continuous bladder irrigation. Beyond this, definitive surgical treatment is associated with significant morbidity and mortality. Alternative less invasive management options for non-emergent haemorrhagic cystitis include systemic medical therapies, hyperbaric oxygen (HBO), intravesical therapies and laser ablation. However, evidence to support and compare treatment for haemorrhagic radiation cystitis is limited. METHODS: Herein, a literature search pertaining to the current management of haemorrhagic cystitis was conducted. RESULTS: In total, 23 studies were included in this review with 2 studies reviewing systemic therapy, 7 studies evaluating HBO therapy, 10 studies investigating a variety of intravesical therapies and the remaining 4 were relating to ablative therapies. Across these studies, the patient groups were heterogenous with small numbers and variable follow up periods. CONCLUSION: With evaluation of existing literature, this narrative review also provides a stepwise clinical algorithm to aid the urologist in treating patients presenting with complications associated with radiation cystitis.

Interpolation to define clinical tumor stage in prostate cancer using clinical description of digital rectal examination.

AIM: This study aims to assess characteristics of patients with prostate cancer for whom clinical T stage category (cT) was not documented in the medical record and assess whether specialists had concordant conclusions regarding cT based on digital rectal examination (DRE) notes. METHODS: Data from the Prostate Cancer Outcome Registry - Victoria (PCOR-Vic) were interrogated. Four specialists independently assigned cT to DRE notes. Words, or part thereof, associated with agreement between clinicians were identified. RESULTS: Of the 10 587 men, cT was documented in 8758 (82.7%) cases. Multivariate analysis indicated that poor cT documentation was associated with older patient age (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.66-0.99 if 75.1-85 years; OR 0.50, 95%CI 0.36-0.72 if >85 years); diagnosis via transperineal compared to transrectal ultrasound-guided biopsy (TRUS) (OR 0.68, 95%CI 0.51-0.91); diagnosed in a private hospital (OR 0.85, 95%CI 0.75-0.96); and a diagnostic Gleason score of >8 compared to ≤6 (OR 0.59, 95%CI = 0.48-0.73). cT was more likely documented in men diagnosed via transurethral resection of prostate (OR 2.06, 95%CI 1.64-2.58) compared to TRUS and/or if receiving treatment in a radiotherapy center (OR 3.44, 95%CI 2.80-4.23 for external beam radiotherapy; OR 3.57 95%CI 2.44-5.23 for brachytherapy and OR 1.34, 95%CI 1.06-1.69 for combination surgery and radiotherapy) compared to those undergoing radical prostatectomy. Agreement in cT assignment ranged from kappa of 0.158 to 0.582. Stem word components in DRE notes associated with poorest level of agreement were "abnorm," "hard," "nodul" and those with highest level of agreement were terms "benign" and "smooth." CONCLUSIONS: Mode of diagnosis/subsequent treatment, and cancer characteristics were associated with cT documentation. Third party interpretation of clinical notes is problematic.

Stimulation of the Neurovascular Bundle Results in Rhabdosphincter Contraction in a Proportion of Men Undergoing Radical Prostatectomy.

OBJECTIVE: To use nerve conduction studies to clarify the functional innervation of the male urethral rhabdosphincter (RS). In particular, to test the hypothesis that in some men, fibers of the neurovascular bundle supply the RS. These fibers may be at risk during radical prostatectomy. MATERIALS AND METHODS: Men undergoing robot-assisted radical prostatectomy for clinically localized prostate cancer were included. Men with a history of pelvic surgery and/or radiation and/or trauma, obesity, or neurological diseases were excluded. Nerve conduction studies were performed before and after prostate removal. The St. Mark's pudendal electrode was used for pudendal (control) stimulation. The ProPep Nerve-Monitoring System (ProPep Surgical, Austin, TX) was used to stimulate the neurovascular bundle at the level of the prostate base, mid, and apex. ProPep needle electrodes inserted into the RS were used to measure evoked compound motor action potential response. Results were only included if a valid pudendal control was elicited. RESULTS: Seventeen men in total underwent investigation. Valid measurements were obtained after initial quality control in seven. In two cases, evidence of sphincteric activation was observed, providing evidence to support neurovascular bundle innervation of the RS. In the other five patients, no intrapelvic nerve supply was demonstrated. CONCLUSION: Somatic nerve supply to the RS is variable. Direct intrapelvic supply to the RS may exist in some men. This may be one explanation as to why some patients unexpectedly develop severe urinary incontinence postoperatively despite technically satisfactory surgery. Further research is required to validate our findings.

Comparison of oncological and health-related quality of life outcomes between open and robot-assisted radical prostatectomy for localised prostate cancer - findings from the population-based Victorian Prostate Cancer Registry.

OBJECTIVE: To compare the short-term oncological and health-related quality of life (HRQOL) outcomes between open (ORP) and robot-assisted (RARP) radical prostatectomy in the population-based Victorian Prostate Cancer Registry. PATIENTS AND METHODS: This is a prospective cohort of patients with prostate cancer who had RP (1117 ORP and 885 RARP) between January 2009 and June 2012. The oncological outcomes of interest were: positive surgical margin (PSM) and biochemical recurrence (BCR), defined as postoperative PSA level of >0.2 ng/mL. The HRQOL outcomes were: sexual and urinary bother, assessed using the Expanded Prostate Cancer Index Composite at 1- and 2-years after diagnosis. For univariate comparison of continuous variables the Student's t-test or Mann-Whitney U-test were used, and the Pearson's chi-squared test was used for categorical variables. Bonferroni correction was applied to account for multiple testing, with a threshold for significance of P < 0.003 for univariate analyses. The inverse-probability-treatment-weighting (IPTW) approach was used to adjust for differences in baseline characteristics between ORP and RARP patients [including age, National Comprehensive Cancer Network (NCCN) risk categories, hospitals, and year of RP] in all multivariate analyses. Logistic regressions were used to analyse for PSM, Cox regressions for BCR, and ordinal logistic regressions for HRQOL outcomes. All multivariate analyses also adjusted for surgeons' average annual caseload, and employed the robust standard errors for clustering by surgeon. RESULTS: ORP and RARP patients were followed for a median of 19 and 17 months, respectively. The proportion of patients with NCCN low-risk prostate cancer was significantly higher among RARP patients (21% vs 26%; P = 0.002). Most RPs was done in private hospitals (77% ORP, and 85% RARP, P < 0.001). A higher proportion of RARP patients were operated by surgeons with higher annual caseloads (65% RARP and 53% ORP operated by surgeons with >20 case/year; P < 0.001). In the IPTW-adjusted multivariate analyses, RARP patients had a lower risk of PSM (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.38-0.81), and BCR (hazard ratio [HR] 0.73, 95% CI 0.55-0.99). In the sensitivity analyses (excluding public hospital patients), the lower PSM risk with RARP remained (OR 0.63, 95% CI 0.38-0.81), but the lower BCR risk with RARP was no longer statistically significant (HR 0.79, 95% CI 0.57-1.12). At 1-year follow-up, 61% of ORP and 59% of RARP patients reported 'moderate-big' sexual bother (P = 0.2), while 14% of ORP and 11% of RARP patients reported 'moderate-big' urinary bother (P = 0.08). The sexual and urinary bothers at 2 years were similar between ORP and RARP. In multivariate analyses, there were no statistically significant differences in the HRQOL outcomes between ORP and RARP. CONCLUSIONS: We report on a large population-based comparative study of ORP and RARP with better short-term oncological outcomes favouring RARP, but no significant differences in HRQOL outcomes. The results have to be interpreted taking into account significant surgeon heterogeneity in a population-based study.

Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay.

In humans, both language and fine motor skills are associated with left-hemisphere specialization, whereas visuospatial skills are associated with right-hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC.

Atypical processing of voice sounds in infants at risk for autism spectrum disorder.

Adults diagnosed with autism spectrum disorder (ASD) show a reduced sensitivity (degree of selective response) to social stimuli such as human voices. In order to determine whether this reduced sensitivity is a consequence of years of poor social interaction and communication or is present prior to significant experience, we used functional MRI to examine cortical sensitivity to auditory stimuli in infants at high familial risk for later emerging ASD (HR group, N = 15), and compared this to infants with no family history of ASD (LR group, N = 18). The infants (aged between 4 and 7 months) were presented with voice and environmental sounds while asleep in the scanner and their behaviour was also examined in the context of observed parent-infant interaction. Whereas LR infants showed early specialisation for human voice processing in right temporal and medial frontal regions, the HR infants did not. Similarly, LR infants showed stronger sensitivity than HR infants to sad vocalisations in the right fusiform gyrus and left hippocampus. Also, in the HR group only, there was an association between each infant's degree of engagement during social interaction and the degree of voice sensitivity in key cortical regions. These results suggest that at least some infants at high-risk for ASD have atypical neural responses to human voice with and without emotional valence. Further exploration of the relationship between behaviour during social interaction and voice processing may help better understand the mechanisms that lead to different outcomes in at risk populations.

The current use of active surveillance in an Australian cohort of men: a pattern of care analysis from the Victorian Prostate Cancer Registry.

OBJECTIVES: To ascertain the treatment trends and patterns of care, for men with prostate cancer on active surveillance (AS) in Victoria, Australia. PATIENTS AND METHODS: De-identified data was obtained for 6424 men from the Victorian Prostate Cancer Registry. Men included in this study were diagnosed with prostate cancer from 2008 to August 2012 with ≥ 12-months of follow-up. Patients were stratified using the National Comprehensive Cancer Network (NCCN) risk grouping system and those who were not actively treated were identified. Data was acquired to describe the trends and uptake of AS according to public vs private hospital sector, and regional vs metropolitan regions. RESULTS: In all, 1603/6424 (24.9%) men received no treatment with curative intent at 12-months follow-up. This cohort included patients in whom the chosen management plan was recorded as AS (980/1603, 61.1%), watchful waiting (341/1603, 21.3%), or no management plan (282/1603, 17.6%). From this, 980/6424(15.3%) of the patients were recorded as being on AS across all NCCN categories at 12 months after diagnosis. This included 653/1816 (35.9%) of very low- and low-risk men, and 251/2820 (8.9%) of intermediate-risk men. Of our patients on AS, 169/980 (17.2%) progressed onto active treatment after 12 months. This active treatment included radical prostatectomy in 116 (68.6%), 32 (18.9%) undergoing external beam radiation therapy, 12 (7.1%) undergoingt brachytherapy and nine (5.3%) undergoing androgen-deprivation therapy. Overall, 629/979 (64.2%) of the AS patients were notified from a private hospital, with 350/979 (35.7%) of the patients notified from a public hospital (one patient unclassified). Of these, 202/652 (30.9%) of the AS patients with very low-/low-risk disease were managed in the public sector, vs 450/652 (69%) of very low-/low-risk AS patients being managed in the private sector. In our cohort, patients with very low- and low-risk disease, managed in a private hospital, were more likely to be on AS (P = 0.005). AS patients in the private sector were also a median of 2.8 years younger (median 65.6 vs 68.4 years, P < 0.001); had a lower median PSA level (5.3 vs 6.7 ng/mL, P < 0.001); and had lower biopsy Gleason score and clinical staging. There was no significant difference in the uptake of AS demographically, in our cohort of men between metropolitan and regional areas. CONCLUSION: In this contemporary registry-based population, AS is being used in a significant proportion of patients. The proportion of men progressing to intervention is lower than that reported in the current literature. Patients are more likely to be on AS if they are managed in a private hospital, with no differences in the uptake of AS, from metropolitan to regional areas.

Abnormal functional activation and maturation of fronto-striato-temporal and cerebellar regions during sustained attention in autism spectrum disorder.

OBJECTIVE: Sustained attention problems are common in people with autism spectrum disorder (ASD) and may have significant implications for the diagnosis and management of ASD and associated comorbidities. Furthermore, ASD has been associated with atypical structural brain development. The authors used functional MRI to investigate the functional brain maturation of attention between childhood and adulthood in people with ASD. METHOD: Using a parametrically modulated sustained attention/vigilance task, the authors examined brain activation and its linear correlation with age between childhood and adulthood in 46 healthy male adolescents and adults (ages 11-35 years) with ASD and 44 age- and IQ-matched typically developing comparison subjects. RESULTS: Relative to the comparison group, the ASD group had significantly poorer task performance and significantly lower activation in inferior prefrontal cortical, medial prefrontal cortical, striato-thalamic, and lateral cerebellar regions. A conjunction analysis of this analysis with group differences in brain-age correlations showed that the comparison group, but not the ASD group, had significantly progressively increased activation with age in these regions between childhood and adulthood, suggesting abnormal functional brain maturation in ASD. Several regions that showed both abnormal activation and functional maturation were associated with poorer task performance and clinical measures of ASD and inattention. CONCLUSIONS: The results provide first evidence that abnormalities in sustained attention networks in individuals with ASD are associated with underlying abnormalities in the functional brain maturation of these networks between late childhood and adulthood.

Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011.

OBJECTIVE: To describe patterns of care for men diagnosed with prostate cancer in Victoria, Australia, between 2008 and 2011. DESIGN, SETTING AND PATIENTS: Men who were diagnosed with prostate cancer at 11 public and six private hospitals in Victoria from August 2008 to February 2011, and for whom prostate cancer notifications were received by the Prostate Cancer Registry. MAIN OUTCOME MEASURES: Characteristics of men diagnosed with prostate cancer; details of treatment provided within 12 months of diagnosis, according to National Comprehensive Cancer Network risk categories; and characteristics of men who did not receive active treatment within 12 months of diagnosis. RESULTS: Treatment details were collected for 98.1% of men who were assessed as eligible to participate in the study (2724/2776) and were confirmed by telephone 12 months after diagnosis for 74.4% of them (2027/2724). Most patients (2531/2724 [92.9%]) were diagnosed with clinically localised disease, of whom 1201 (47.5%) were at intermediate risk of disease progression. Within 12 months of diagnosis, 299 of the 736 patients (40.6%) who had been diagnosed as having disease that was at low risk of progression had received no active treatment, and 72 of 594 patients (12.1%) who had been diagnosed as having disease that was at high risk of progression had received no active treatment. Of those diagnosed as having intermediate risk of disease progression, 54.5% (655/1201) had undergone radical prostatectomy. Those who received no active treatment were more likely than those who received active treatment to be older (odds ratio [95% CI], 2.96 [2.01-4.38], 10.94 [6.96-17.21] and 32.76 [15.84-67.89], respectively, for age 65-74 2013s, 75-84 2013s and ≥ 85 2013s, compared with < 55 2013s), to have less advanced disease (odds ratio [95% CI], 0.20 [0.16-0.26], 0.09 [0.06-0.12] and 0.05 [0.02-0.90], respectively, for intermediate, high and very high-risk [locally advanced] or metastatic disease, compared with low-risk disease) and to have had their prostate cancer notified by a private hospital (odds ratio [95% CI], 1.35 [1.10-1.66], compared with public hospital). CONCLUSION: Our data reveal a considerable "stage migration" towards earlier diagnosis of prostate cancer in Victoria and a large increase in the use of radical prostatectomy among men with clinically localised disease.

Early specialization for voice and emotion processing in the infant brain.

Human voices play a fundamental role in social communication, and areas of the adult "social brain" show specialization for processing voices and their emotional content (superior temporal sulcus, inferior prefrontal cortex, premotor cortical regions, amygdala, and insula). However, it is unclear when this specialization develops. Functional magnetic resonance (fMRI) studies suggest that the infant temporal cortex does not differentiate speech from music or backward speech, but a prior study with functional near-infrared spectroscopy revealed preferential activation for human voices in 7-month-olds, in a more posterior location of the temporal cortex than in adults. However, the brain networks involved in processing nonspeech human vocalizations in early development are still unknown. To address this issue, in the present fMRI study, 3- to 7-month-olds were presented with adult nonspeech vocalizations (emotionally neutral, emotionally positive, and emotionally negative) and nonvocal environmental sounds. Infants displayed significant differential activation in the anterior portion of the temporal cortex, similarly to adults. Moreover, sad vocalizations modulated the activity of brain regions involved in processing affective stimuli such as the orbitofrontal cortex and insula. These results suggest remarkably early functional specialization for processing human voice and negative emotions.