Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone.

The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.

Waiting for definitive care: An analysis of elapsed time from decision to surgery or transfer in a rural centre.

OBJECTIVE: To examine the timing of operative management and interhospital transfer of emergency general surgical patients in a regional setting. DESIGN: Retrospective cohort study. SETTING: The surgical unit at a major rural referral centre for North-Eastern Victoria servicing a population of 90 000. PARTICIPANTS: General surgical patients (n = 649) admitted via the emergency department at Northeast Health Wangaratta between January 2011 and March 2013 undergoing operative management (n = 608) or transfer to a tertiary centre (n = 44). MAIN OUTCOME MEASURES: Timing of operative management, using appendicectomy as a benchmark operation, was measured as time from presentation to decision to operate, time from decision to surgery, percentage after-hours operating and length of stay (LOS). Time to interhospital transfer was calculated and reasons for delay were sought. RESULTS: Two hundred forty-six appendicectomies were performed. Median time from decision to operate to theatre was 3 hours (interquartile range (IQR) 2-8), and total LOS was 43 hours (IQR: 28-56). Two hundred seventy-two procedures (43%) were performed out-of-hours, including 48% of appendicectomies. Median time from decision making to transfer was 10.3 hours (IQR: 4.7-25). Transfer was less likely to be delayed in trauma patients when compared with urgent non-trauma patients (5.3 versus 10.6 hours; P = 0.04). CONCLUSION: Even in the absence of a strict four-hour rule program and a dedicated emergency surgical unit, main outcome measures appear to be comparatively efficient. However, the duration for transfer of patients is suboptimal because of the lack of established pathways for urgent non-trauma transfer from rural centres and bed availability in tertiary hospitals.

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array.

BACKGROUND: The Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues. RESULTS: We comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation. CONCLUSIONS: Our method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer.

Presence or absence of a positive pathological margin outperforms any other margin-associated variable in predicting clinically relevant biochemical recurrence in Gleason 7 prostate cancer.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The presence of a positive pathological margin is an independent risk factor for clinically significant disease recurrence only in intermediate-risk disease when the a priori risk of micrometastatic disease is accounted for. The study examines patients with Gleason 7 prostate cancer to assess the relative importance of various margin-related variables (focality, linear length, tumour grade at margin, presence of diathermy artifact and plane of tumour) with regard to biochemical recurrence. We found that the presence or absence of a positive pathological margin outperforms any other margin-associated variable in predicting significant disease recurrence. OBJECTIVE: To determine the influence of pathological margin variables on the risk of clinically significant biochemical recurrence in Gleason 7 prostate cancer. MATERIALS AND METHODS: Patients with Gleason 7 prostate cancer with complete clinical and pathological data and detailed follow-up were identified from a prospectively recorded prostatectomy database. Slides from all patients with positive pathological margins were reviewed by a single expert uropathologist and the following information recorded: multifocality, linear length, predominant Gleason grade at the margin, diathermy artifact and margin plane. Cox regression models were generated to determine the impact of positive pathological margins on the risk of biochemical recurrence (using various definitions thereof). RESULTS: Of 1048 patients with Gleason 7 prostate cancer, 238 (23%) patients had positive margins. With a median follow-up of 11 months, biochemical recurrence occurred in 9.7% of patients with negative surgical margins and 28.4% of patients with positive margins. Positive margins were significantly associated with higher serum prostate-specific antigen (PSA) level, tumour grade, stage and volume. In patients with positive pathological margins, controlling for other factors, no margin-derived variable (focality, linear length, tumour grade at margin, diathermy artifact or plane of tumour) was a consistent predictor of biochemical recurrence, although the presence of Gleason score 4 or tertiary Gleason score 5 tumour at the margin edge was an independent predictor of recurrence with PSA doubling times ≤ 6 and ≤9 months. Similarly, in the cohort as a whole, the pathological margin status was a more important predictor of recurrence than any other margin-derived variable. CONCLUSIONS: In Gleason 7 prostate cancer, positive pathological margin status was the only consistent margin-derived variable determining biochemical failure. The presence of high-grade disease at the margin may also have an impact on the development of clinically significant biochemical recurrence.

Are transrectal prostate biopsies routinely indicated in patients with incidentally diagnosed prostate cancer following transurethral resection of the prostate for benign disease?

OBJECTIVE: To determine the indication of routine transrectal ultrasound-guided needle biopsy (TRUSBx) of the prostate gland following incidental cancer diagnosis after transurethral resection of the prostate (TURP) for benign prostatic hyperplasia. MATERIALS AND METHODS: A multi-institutional search identified 63 patients with incidental TURP-diagnosed prostate cancer from 2001 to 2010, who underwent subsequent TRUSBx or radical prostatectomy (RP). The Gleason scores from TURP were compared to those from TRUSBx or RP. Whole mount maps from RP were analysed to provide an anatomical basis for the correlation observed. To determine the clinical impact of this problem, the incidence of TURP-diagnosed prostate cancer in the population was also determined. RESULTS: Of 22 patients who underwent TRUSBx, the rates of Gleason score concordance, upgrading and downgrading were 32, 14 and 54% respectively (Spearman correlation coefficient 0.20). Most cases of pathological downgrading consisted of benign cores at biopsy. Therefore, TRUSBx did not give additional Gleason score (GS) information in 86% of patients. Of 41 RP patients, the respective rates were 61, 22 and 17% (Spearman correlation coefficient 0.15). The majority of them retained a similar or lower GS between TURP and RP. Of 13 whole mount maps analysed, 6 (46%) were found with anterior/transitional zone (AZ/TZ) tumours, 6 (46%) with multifocal tumours and 1 (8%) with a large peripheral zone (PZ) tumour extending into the TZ. Regional population data show that despite a gradual reduction in the proportion of TURP-diagnosed cases over the past decade, they still account for 8.5-13% of all new cases. CONCLUSION: TURP-diagnosed prostate cancers represent predominantly AZ tumours. A TRUSBx does not give additional GS information in a majority of cases, and therefore is not routinely indicated. It may be selectively useful prior to active surveillance, but not in all pursuing radical treatment. These findings may help reduce unnecessary TRUSBx in the population.

Re-evaluating the biological significance of seminal vesicle invasion (SVI) in locally advanced prostate cancer.

OBJECTIVE: • To examine the impact of seminal vesicle invasion (SVI) in patients with locally advanced (pT3) prostate cancer on clinical outcome. • To explore the clinical association of SVI with metastatic disease. • To distinguish between the possibilities that either seminal vesicles possess their own biological significance and represent a privileged staging site for systemic tumour cell dissemination, or that their invasion is a surrogate marker for an aggressive large-volume poorly differentiated cancer. PATIENTS AND METHODS: • Patients with extraprostatic extension (EPE) and/or SVI were identified from a prospectively recorded and maintained prostate cancer database. • Patients were categorised according to the presence of SVI as determined by routine pathological assessment. Tumour volumes were measured routinely by computed planimetry at the time of histological assessment. • The impact of SVI on biochemical recurrence with a definition of a prostate-specific antigen (PSA) level of ≥0.2 ng/mL, as well as a clinically significant recurrence defined as failure with a PSA doubling time of <6 months, was determined by univariable and multivariable Cox regression analysis. RESULTS: • Of 249 patients with pT3 disease, 46 (18%) had SVI, 40 (87%) by direct extension and six (13%) metastatic. • Tumours with SVI had significantly greater tumour burden as determined by total tumour volume (7.2 vs 3.7 mL, P < 0.001), index tumour volume (6.8 vs. 3.4 mL, P < 0.001) and percentage tumour volume (21.8 vs 12.4 %, P= 0.001). • After controlling for tumour volume and Gleason score, the presence of SVI did not significantly predict for the development of a significant PSA recurrence. CONCLUSIONS: • Our results suggest that SVI is a surrogate marker of larger and more aggressive tumours with higher Gleason scores rather than a privileged site of tumour cell dissemination.

The ability of prostate-specific antigen (PSA) density to predict an upgrade in Gleason score between initial prostate biopsy and prostatectomy diminishes with increasing tumour grade due to reduced PSA secretion per unit tumour volume.

UNLABELLED: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Due to sampling error, the Gleason score of clinically localized prostate cancer is frequently underestimated at the time of initial biopsy. Given that this may lead to inappropriate surveillance of patients with high-risk disease, there is considerable interest in identifying predictors of significant undergrading. Recently PSAD has been proposed to be an accurate predictor of subsequent upgrading in patients diagnosed with Gleason 6 disease on biopsy. We examined the predictive characteristics of PSAD in patients with low- and intermediate-risk disease on biopsy subsequently treated with radical prostatectomy. We found that although PSAD was a significant predictor of upgrade of biopsy Gleason 6 and 3 + 4 = 7 tumours, it failed to predict upgrading in patients with Gleason 7 tumours taken as a whole. When we explored reasons for this discrepancy, we found that the amount of PSA produced per unit tumour volume decreased with increasing Gleason score, thereby diminishing the predictive value of PSAD. OBJECTIVES: To analyse the performance of PSA density (PSAD) as a predictor of Gleason score upgrade in a large cohort stratified by Gleason score. We and others have shown that an upgrade in Gleason score between initial prostate biopsy and final radical prostatectomy (RP) pathology is a significant risk factor for recurrence after local therapy. PATIENTS AND METHODS: Patients undergoing RP with matching biopsy information were identified from two prospective databases. Patients were analysed according to the concordance between biopsy and final pathology Gleason score in three paired groups: 6/>6, 3 + 4/>3 + 4, 7/>7. Receiver-operating characteristic (ROC) curves were generated stratified by Gleason score, and the area under the curve (AUC) calculated. Logistic regression models were fitted to identify significant predictors of tumour upgrade. RESULTS: From 1516 patients, 435 (29%) had an upgrade in Gleason score. ROC analysis showed a decline in AUC with increasing biopsy Gleason score, from 0.64 for biopsy Gleason score 6, to 0.57 for Gleason score 7. In logistic regression models containing pretreatment variables, e.g. clinical stage and number of positive cores, for Gleason score 6 and 3 + 4, PSAD was the strongest predictor of subsequent tumour upgrade (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 1.18-1.83, P= 0.001 and OR 1.37, 95% CI 1.14-1.67, P= 0.002, respectively). Surprisingly, in tumours upgraded from Gleason score 7 to >7, PSAD was not predictive even on univariable analysis, whereas clinical stage and number of positive cores were significant independent predictors. To explore the relationship between serum PSA and Gleason score, tumour volume was calculated in 669 patients. There was a strong association between Gleason score and tumour volume, with the median volume of Gleason score 7 and Gleason score >7 tumours being approximately twice and four-times that of Gleason score 6 tumours, respectively (P < 0.001). In contrast, the median serum PSA level per millilitre tumour volume decreased significantly with increasing grade, from 5.4 ng/mL for Gleason score 6 to 2.1 ng/mL for >7 (P < 0.001). CONCLUSIONS: There is a strong correlation between Gleason score and tumour volume in well/intermediate differentiated tumours, and as they produce relatively high amounts of PSA per unit volume of cancer, high PSAD is the strongest single predictor of tumour undergrading. However, as higher grade tumours produce less PSA per unit volume, PSAD loses its predictive ability, and other clinical markers of tumour volume such as palpable disease and numbers of positive cores become more predictive.

Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours.

OBJECTIVE: • To determine the influence of tumour and prostate gland volumes on the underestimation of prostate cancer Gleason score in diagnostic core biopsies. PATIENTS AND METHODS: • Patients undergoing radical prostatectomy with matched diagnostic biopsies were identified from a prospectively recorded database. • Tumour volumes were measured in serial whole-mount sections with image analysis software as part of routine histological assessment. • Differences in various metrics of tumour and prostate volume between upgraded tumours and tumours concordant for the lower or higher grade were analysed. RESULTS: • In all, 684 consecutive patients with Gleason score 6 or 7 prostate cancer on diagnostic biopsy were identified. • Of 298 patients diagnosed with Gleason 6 tumour on biopsy, 201 (67.4%) were upgraded to Gleason 7 or higher on final pathology. Similarly, of 262 patients diagnosed with Gleason 3 + 4 = 7 prostate cancer on initial biopsy, 60 (22.9%) were upgraded to Gleason score 4 + 3 = 7 or higher. • Tumours upgraded from Gleason 6 to 7 had a significantly lower index tumour volume (1.73 vs 2 mL, P= 0.029), higher calculated prostate volume (41.6 vs 39 mL, P= 0.017) and lower relative percentage of tumour to benign glandular tissue (4.3% vs 5.9%, P= 0.001) than tumours concordant for the higher grade. • Similarly, tumours that were Gleason score 3 + 4 on biopsy and upgraded on final pathology to 4 + 3 were significantly smaller as measured by both total tumour volume (2.3 vs 3.3 mL, P= 0.005) and index tumour volume (2.2 vs 3, P= 0.027) and occupied a smaller percentage of the gland volume (6.3% vs 8.9%, P= 0.017) compared with tumours concordant for the higher grade. • On multivariate analysis, lower prostate weight (hazard ratio 0.97, 95% confidence interval 0.96-0.99, P < 0.001) and larger total tumour volume (hazard ratio 1.87, 95% confidence interval 1.4-2.6, P < 0.001) independently predicted an upgrade in Gleason score from 6 to 7. In tumours upgraded from biopsy Gleason 3 + 4, only higher index tumour volume (hazard ratio 3.1, 95% confidence interval 1.01-9.3, P= 0.048) was a significant predictor of upgrading on multivariate analysis. CONCLUSIONS: • Under-graded tumours are significantly smaller than tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error. • Surrogate measures of tumour volume may predict those at greatest risk of Gleason score upgrade.

Prostate weight is the preferred measure of prostate size in radical prostatectomy cohorts.

OBJECTIVE: To evaluate the accuracy of calculated prostate volume variables in a radical prostatectomy (RP) cohort, as many recent studies use these measures of prostate size instead of prostate weight. To determine whether this accuracy could be improved by modifying the mathematical model used in the volume estimation. PATIENTS AND METHODS: Patients who underwent RP for prostate cancer at our associated institutions had calculated specimen volumes and weights from RP specimens determined at one pathology institution and transrectal ultrasonography (TRUS) volumes were recorded preoperatively (n= 236). Correlation analysis was performed and errors were determined for calculated volume variables when compared with prostate weight. Bland-Altman plots were drawn and concordance coefficients calculated. Analysis was repeated with smaller prostates mathematically modelled as bullet-shaped rather than ellipsoid (n= 165). RESULTS: Although correlation was good for both TRUS and specimen volumes, they equally underestimated prostate weight with a large range of errors and poor concordance coefficients. Only 22% of TRUS volumes and 11% of calculated specimen volumes were within 10% of weight measurements. Application of a bullet-shaped mathematical model for prostates <55 g did not correct the large individual variation seen within these values. CONCLUSION: Calculated prostate volume variables are prone to a large range of individual error regardless of the mathematical model used and should be avoided in statistical studies involving RP cohorts, and the more accurate prostate weight variable should instead be used as a size variable or correction factor.

Positive surgical margins are a risk factor for significant biochemical recurrence only in intermediate-risk disease.

UNLABELLED: What's known on the subject? and What does the study add? Positive surgical margins (PSMs) after radical prostatectomy are common, although their impact on the risk of disease recurrence is unknown. We examined the impact of PSMs on the risk of 'significant' biochemical recurrence stratified by their risk of occult metastatic disease. We find that only in intermediate-risk disease does the presence of a PSM have a significant impact on the risk of recurrence, and this represents a failure of technique. By contrast, for high- and low-risk disease, the risk of recurrence is driven by intrinsic tumour biology, and the presence of a PSM has little impact on outcome. OBJECTIVE: To determine the impact of surgical margin status on the risk of significant biochemical recurrence (prostate-specific antigen [PSA] doubling time <3, <6 or <9 months) after prostatectomy. MATERIALS AND METHODS: Patients undergoing radical prostatectomy with complete clinical and pathological data and detailed PSA follow-up were identified from two prospectively recorded databases. Patients were stratified according to their risk of occult systemic disease (low risk: PSA < 10 ng/dL, pT2 stage and Gleason score ≤6; intermediate risk: PSA 10-20 ng/dL, pT2 stage and/or Gleason score 7; high: PSA > 20 ng/dL or pT3-4 stage or Gleason score 8-10) and the impact of a positive surgical margin (PSM) within each stratum determined by univariable and multivariable analysis. RESULTS: Of 1514 patients identified, 276 (18.2%), 761 (50.3%) and 477 (31.5%) were classified as having low-, intermediate- and high-risk disease respectively. A total of 370 (24.4%) patients had a PSM and with a median follow-up of 22.2 months, and 165 (7%) patients had a biochemical recurrence. Sufficient PSA data was available to calculate PSA doubling times in 151/165 patients (91.5%). The PSM rate rose significantly, from 11% in low-risk to 43% in high-risk disease (P < 0.001), with similar positive associations noted with tumour grade, stage and serum PSA (P < 0.001). Patients with low-risk disease had essentially identical risks of significant biochemical recurrence over the study period, regardless of surgical margin status. By contrast, in patients with both intermediate- and high-risk disease, a PSM was a strong predictor of significant biochemical recurrence on univariable analysis. On multivariable analysis, howver, PSM predicted significant disease recurrence in intermediate-risk disease only. CONCLUSIONS: PSM is a risk factor for significant biochemical recurrence only in intermediate risk disease.

Upgrade in Gleason score between prostate biopsies and pathology following radical prostatectomy significantly impacts upon the risk of biochemical recurrence.

OBJECTIVE: •To determine the effect of an upgrade in Gleason score between initial prostate biopsy and final prostatectomy specimen on the risk of postoperative biochemical recurrence. PATIENTS AND METHODS: •A total of 1629 patients with paired biopsy and radical prostatectomy histology were identified from two prospectively recorded prostate cancer databases. •Information on key clinical and pathological characteristics as well as prostate-specific antigen follow-up was recorded. •Patients who experienced an upgrade in their Gleason score were compared with corresponding patients with concordant tumours of the lower and higher grade. •Kaplan-Meier curves and multivariate models were generated to examine the impact of Gleason score upgrade on the risk of postoperative biochemical recurrence. RESULTS: •Overall, 466 patients (28.6%) experienced an upgrade in their Gleason score post radical prostatectomy, in 88.4% of cases involving a change in a single Gleason score point. •Patients upgraded from Gleason 6 (3 + 3) to Gleason 7 (3 + 4) had pathological characteristics that were very similar to Gleason 7 (3 + 4) concordant tumours, with an identical risk of biochemical recurrence. In contrast, patients upgraded from Gleason score 6 (3 + 3) to Gleason 7 (4 + 3) had tumours with pathological characteristics intermediate between the two concordant groups, which was mirrored by their risk of biochemical recurrence. •Patients with Gleason 7 tumours who experienced a change in the predominant pattern from 3 + 4 to 4 + 3 had tumours that resembled Gleason 7 (4 + 3) concordant tumours, with a similar risk of biochemical recurrence. In contrast, patients upgraded from Gleason 7 to Gleason >7 had tumours with intermediate pathological characteristics, and a risk of biochemical recurrence that was significantly different to concordant tumours of the lower and higher grade. •In multivariate models, a change in Gleason score was an independent predictor of biochemical recurrence in the preoperative setting only. •Although a difference in Gleason score was an independent predictor of recurrence in concordant tumours in models based on postoperative variables, an upgrade in Gleason score in discordant tumours was not, with differences in co-segregated adverse pathological characteristics being more predictive. CONCLUSIONS: •Patients experiencing an upgrade in their Gleason score between biopsy and final specimen exhibit significantly more aggressive pathological features than corresponding concordant tumours, and a higher risk of biochemical recurrence post radical prostatectomy. •As Gleason score can be more accurately assessed preoperatively than other prognostic tumour features, continued effort is required to identify those most at risk of upgrading, and to refine biopsy strategies to reduce sampling error.

MSH2-deficient prostate tumours have a distinct immune response and clinical outcome compared to MSH2-deficient colorectal or endometrial cancer.

BACKGROUND: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes. METHODS AND RESULTS: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours. CONCLUSIONS: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.

Male urethral stricture disease in a regional centre: 10 years of experience.

BACKGROUND: Male urethral stricture disease is a challenging condition with a propensity for recurrence following endoscopic management. In recent years, earlier definitive urethral reconstruction has been advocated through international guidelines, prompted by series suggesting the underutilization of urethroplasty at rates of 0.6-0.8%. However, little local data exists to characterize our urethral stricture patients and we aimed to characterize the management of patients with urethral stricture disease presenting over a 10-year period to a single regional centre. METHODS: Patients with urethral stricture disease and admitted to a regional health service were identified. Retrospective chart review was undertaken for patients detailing basic demographics, stricture characteristics, clinical management and follow up. RESULTS: We identified 360 patients with median age 69 years (interquartile range 56-77). A total of 191 (53%) presented with lower urinary tract symptoms, 122 (34%) urethral strictures were incidental, and 13% presented in urinary retention. Bulbar urethral strictures were the commonest strictures at 40% with most being spontaneous or idiopathic (67%). A total of 339 patients had treatment during their first admission, 48% of patients had subsequent treatment on a second episode, and over 20% had a third or subsequent treatment. Only 21 (5.8%) underwent urethroplasty. Urethral dilatation and optical urethrotomy were most commonly performed (54%). With follow up 19 months (interquartile range 2-56), 205 (57%) were voiding, 38 (11%) were performing intermittent catheterization, and 59 were catheterized permanently. CONCLUSION: Definitive urethral reconstruction appears underutilized in our cohort of patients. A high proportion of incidentally presenting urethral strictures emphasizes the importance of wider education to optimize patient outcomes.

The angiosome territories of the spinal cord: exploring the issue of preoperative spinal angiography. Laboratory investigation.

OBJECT: The angiosome concept has been the subject of extensive research by the senior author (G.I.T.), but its specific applicability to the spinal cord was hitherto unknown. The aim of this study was to see if the spinal cord vasculature followed the angiosome concept and to review the usefulness of preoperative spinal angiography in surgery for spinal disorders. Spinal cord infarction and permanent paraplegia may result from inadvertent interruption of the artery of Adamkiewicz. Spinal angiography, which may enable avoidance of this catastrophic complication, is still not commonly used. METHODS: Two fresh cadavers were injected with a gelatin-lead oxide mixture for detailed comparative study of spinal cord vasculature. One cadaver had insignificant vascular disease, whereas the other had extensive aortic atherosclerosis, presenting a unique opportunity for study. After removal from each cadaver, radiographs of the spinal cords were obtained, then photographed, and the vascular territories of the cords were defined. RESULTS: Four angiosome territories were defined: vertebral, subclavian, posterior intercostal, and lumbar. These vascular territories were joined longitudinally by true anastomotic channels along the anterior and posterior spinal cord. Anastomosis between the anterior and posterior vasculature was poor in the thoracolumbar region. The anterior cord relied on fewer feeder arteries than the posterior, and the anterior thoracolumbar cord depended on the artery of Adamkiewicz for its supply. In chronic aortic disease with intercostal artery occlusion at multiple levels, a rich collateral circulation supporting the spinal cord was found. CONCLUSIONS: The arterial supply of the spinal cord follows the angiosome concept. The atherosclerotic specimen supports the suggestion that the blood supply is able to adapt to gradual vascular occlusion through development of a collateral circulation. Nevertheless, the spinal cord is susceptible to ischemia when faced with acute vascular occlusion. This includes inadvertent interruption of the artery of Adamkiewicz. The authors recommend the use of preoperative spinal angiography to prevent possible paraplegia in removal of thoracolumbar spinal tumors.

Variability in adolescent portal privacy features: how the unique privacy needs of the adolescent patient create a complex decision-making process.

Objective: Medical privacy policies, which are clear-cut for adults and young children, become ambiguous during adolescence. Yet medical organizations must establish unambiguous rules about patient and parental access to electronic patient portals. We conducted a national interview study to characterize the diversity in adolescent portal policies across a range of institutions and determine the factors influencing decisions about these policies. Methods: Within a sampling framework that ensured diversity of geography and medical organization type, we used purposive and snowball sampling to identify key informants. Semi-structured interviews were conducted and analyzed with inductive thematic analysis, followed by a member check. Results: We interviewed informants from 25 medical organizations. Policies established different degrees of adolescent access (from none to partial to complete), access ages (from 10 to 18 years), degrees of parental access, and types of information considered sensitive. Federal and state law did not dominate policy decisions. Other factors in the decision process were: technology capabilities; differing patient population needs; resources; community expectations; balance between information access and privacy; balance between promoting autonomy and promoting family shared decision-making; and tension between teen privacy and parental preferences. Some informants believed that clearer standards would simplify policy-making; others worried that standards could restrict high-quality polices. Conclusions: In the absence of universally accepted standards, medical organizations typically undergo an arduous decision-making process to develop teen portal policies, weighing legal, economic, social, clinical, and technological factors. As a result, portal access policies are highly inconsistent across the United States and within individual states.

Supporting Families in Reviewing and Communicating about Radiology Imaging Studies.

Diagnostic radiology reports are increasingly being made available to patients and their family members. However, these reports are not typically comprehensible to lay recipients, impeding effective communication about report findings. In this paper, we present three studies informing the design of a prototype to foster patient-clinician communication about radiology report content. First, analysis of questions posted in online health forums helped us identify patients' information needs. Findings from an elicitation study with seven radiologists provided necessary domain knowledge to guide prototype design. Finally, a clinical field study with 14 pediatric patients, their parents and clinicians, revealed positive responses of each stakeholder when using the prototype to interact with and discuss the patient's current CT or MRI report and allowed us to distill three use cases: co-located communication, preparing for the consultation, and reviewing radiology data. We draw on our findings to discuss design considerations for supporting each of these use cases.

3D modelling of radical prostatectomy specimens: Developing a method to quantify tumor morphometry for prostate cancer risk prediction.

Prostate cancer displays a wide spectrum of clinical behaviour from biological indolence to rapidly lethal disease, but we remain unable to accurately predict an individual tumor's future clinical course at an early curable stage. Beyond basic dimensions and volume calculations, tumor morphometry is an area that has received little attention, as it requires the analysis of the prostate gland and tumor foci in three-dimensions. Previous efforts to generate three-dimensional prostate models have required specialised graphics units and focused on the spatial distribution of tumors for optimisation of biopsy strategies rather than to generate novel morphometric variables such as tumor surface area. Here, we aimed to develop a method of creating three-dimensional models of a prostate's pathological state post radical prostatectomy that allowed the derivation of surface areas and volumes of both prostate and tumors, to assess the method's accuracy to known clinical data, and to perform initial investigation into the utility of morphometric variables in prostate cancer prognostication. Serial histology slides from 21 prostatectomy specimens covering a range of tumor sizes and pathologies were digitised. Computer generated three-dimensional models of tumor and prostate space filling models were reconstructed from these scanned images using Rhinoceros 4.0 spatial reconstruction software. Analysis of three-dimensional modelled prostate volume correlated only moderately with weak concordance to that from the clinical data (r=0.552, θ=0.405), but tumor volume correlated well with strong concordance (r=0.949, θ=0.876). We divided the cohort of 21 patients into those with features of aggressive tumor versus those without and found that larger tumor surface area (32.7 vs 3.4cc, p=0.008) and a lower tumor surface area to volume ratio (4.7 vs 15.4, p=0.008) were associated with aggressive tumor biology.

Holmium Laser Enucleation of the Prostate in a 400 cc Prostate: Case Report.

The modality of choice in the surgical management of benign prostatic hyperplasia for large prostates has traditionally been open prostatectomy. Advances in minimally invasive techniques have begun to challenge this notion with advantages such as lower bleeding and transfusion rates and shorter hospital stay. In this case report, we illustrate the use of holmium laser enucleation of the prostate (HoLEP) in a gland measuring more than 400 cc. We describe the case of a 71-year-old man with persistent voiding urinary symptoms despite two previous transurethral resections of his prostate. With greater experience in HoLEP and declining experience in open prostatectomy, there may be a shift toward HoLEP as the preferred treatment choice for large prostate glands.

Care Partnerships: Toward Technology to Support Teens' Participation in Their Health Care.

Adolescents with complex chronic illnesses, such as cancer and blood disorders, must partner with family and clinical caregivers to navigate risky procedures with life-altering implications, burdensome symptoms and lifelong treatments. Yet, there has been little investigation into how technology can support these partnerships. We conducted 38 in-depth interviews (15 with teenage adolescents with chronic forms of cancer and blood disorders, 15 with their parents, and eight with clinical caregivers) along with nine non-participant observations of clinical consultations to better understand common challenges and needs that could be supported through design. Participants faced challenges primarily concerning: 1) teens' limited participation in their care, 2) communicating emotionally-sensitive information, and 3) managing physical and emotional responses. We draw on these findings to propose design goals for sociotechnical systems to support teens in partnering in their care, highlighting the need for design to support gradually evolving partnerships in care.

Adolescent and Caregiver use of a Tethered Personal Health Record System.

Supporting adolescent patient engagement in care is an important yet underexplored topic in consumer health informatics. Personal Health Records (PHRs) show potential, but designing PHR systems to accommodate both emerging adults and their parents is challenging. We conducted a mixed-methods study with teenage adolescent patients (ages 13-17) with cancer and blood disorders, and their parents, to investigate their experiences with My-Chart, a tethered PHR system. Through analyses of usage logs and independently-conducted surveys and interviews, we found that patients and parents both valued MyChart, but had different views about the role of the PHR for care communication and management, and different attitudes about its impact on the patient's ability to manage care. Specific motivations for using MyChart included patient-parent coordination of care activities, communication around hospital encounters, and support for transitioning to adult care. Finally, some parents had concerns about certain diagnostic test results being made available to their children.