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Background and AimMacrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1.Methods and ResultsAcute administration of a CSF1-Fc fusion protein led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilisation of body fat. The impacts of CSF1 on macrophage abundance, liver size and body composition were rapidly reversed to restore homeostasis. CSF1’s effects on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake.ConclusionThese results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, metabolic regulation and homeostatic control of liver:body weight ratio.

Supplementary Figure 2 from Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis

Supplementary Figure 1 from Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis

Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease. [Cancer Res 2007;67(18):8504–10]

Background. Non-alcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver as a consequence of metabolic perturbations associated with obesity, type 2 diabetes, dyslipidemia and insulin resistance. People with NAFLD may develop metabolic and cardiovascular complications, and/or liver-related complications, especially fibrosis and hepatocellular carcinoma, associated with high morbidity and mortality. Due to the high and increasing prevalence of NAFLD there is an urgent need to identify people at risk of developing liver fibrosis and complications. CC-chemokine ligand 2 (CCL2) is chemokine that attracts inflammatory monocytes to stressed or injured tissues. Infiltrating inflammatory monocytes, and CCL2, are strongly implicated in the pathogenesis of liver disease in animal models, however evidence in patient cohorts is conflicting. Methods. We investigated associations between circulating CCL2 and clinical parameters, including fibrosis assessed by liver stiffness measurement, in a cohort of 250 NAFLD patients. We also measured Fatty Acid Binding Protein 2 (FABP2), a putative biomarker of intestinal permeability in patients with liver disease, since pro-inflammatory gut-derived microbial products may induce inflammatory chemokines such as CCL2. Results. Serum CCL2 levels were weakly associated with liver stiffness, but the association was no longer significant after accounting for age, diabetes and BMI in a multivariable model. Consistent with this, girth and BMI were the strongest predictors of elevated circulating CCL2. Serum FABP2 was weakly, but significantly, correlated with CCL2, and negatively correlated with estimated Glomerular Filtration Rate (eGFR). Conclusion. Circulating CCL2 and FABP2 are associated with NAFLD co-morbidities, but not liver disease progression in patients with NAFLD.

Background Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation. Methods We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay. Results CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48−CD150+ HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48−CD150+ HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment. Conclusion These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.

Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.Summary statementMacrophages contribute to both progression and resolution of chronic tissue injury and fibrogenesis. Administration of a macrophage growth factor promoted liver regeneration and resolution of advanced liver fibrosis in mice.

Macrophages are present in large numbers in every tissue in the body where they play critical roles in development and homeostasis. They exhibit remarkable phenotypic and functional diversity, underpinning their adaptation to specialized roles in each tissue niche. CSF1, signaling through the CSF1 receptor, which is restricted to monocyte-macrophage lineage cells in adults, is a critical growth factor controlling macrophage proliferation, differentiation, and many aspects of mature macrophage function. We have generated a macrophage reporter rat, utilizing a construct containing elements of the mouse Csf1r promoter and the highly conserved Fms intronic regulatory element to drive mApple fluorescent protein expression. Csf1r-mApple was robustly expressed in monocyte-macrophage lineage cells in rat bone marrow (BM), peripheral blood, and tissues, with detectable expression in granulocytes and B cells and no evidence of expression in hematopoietic precursors or non-hematopoietic cells. Here, we use the Csf1r-mApple transgene to highlight and dissect the abundance and heterogeneity of rat tissue macrophage populations, and to demonstrate parallel increases in blood monocytes and multiple tissue macrophage populations, including BM, liver, spleen, and lung, in response to CSF1 treatment in vivo. The Csf1r-mApple rat is a novel tool enabling analysis of rat macrophages in situ by direct imaging and providing an additional phenotypic marker to facilitate exploration of rat tissue macrophage phenotypic and functional heterogeneity.

Mϕ proliferation, differentiation, and survival are controlled by signals from the Mϕ CSF receptor (CSF1R). Mono-allelic gain-of-function mutations in CSF1R in humans are associated with an autosomal-dominant leukodystrophy and bi-allelic loss-of-function mutations with recessive skeletal dysplasia, brain disorders, and developmental anomalies. Most of the phenotypes observed in these human disease states are also observed in mice and rats with loss-of-function mutations in Csf1r or in Csf1 encoding one of its two ligands. Studies in rodent models also highlight the importance of genetic background and likely epistatic interactions between Csf1r and other loci. The impacts of Csf1r mutations on the brain are usually attributed solely to direct impacts on microglial number and function. However, analysis of hypomorphic Csf1r mutants in mice and several other lines of evidence suggest that primary hydrocephalus and loss of the physiological functions of Mϕs in the periphery contribute to the development of brain pathology. In this review, we outline the evidence that CSF1R is expressed exclusively in mononuclear phagocytes and explore the mechanisms linking CSF1R mutations to pleiotropic impacts on postnatal growth and development.

Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with colony stimulating factor-1 (CSF1) to modify the BM niche and expand the potential HSC pool for autologous transplantation. We administrated CSF1 Fc fusion protein (CSF1-Fc) to naive C57Bl/6 mice and assessed the impacts on HSC number and function and overall haematopoiesis. Outcomes were assessed by in situ imaging and ex vivo flow cytometry with functional validation by colony formation and competitive transplantation assay. CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of haematopoiesis was accompanied by an increase in the total available HSPC pool. In the spleen, increased HSC was associated with expression of the BM niche marker CD169 in red pulp macrophages. Pre-treatment with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of granulocyte colony stimulating factor (G-CSF) treatment. These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve autologous or heterologous HSC transplantation outcomes.Key points1) Recovery from Fc-modified colony stimulating factor-1 (CSF1-Fc) treatment was accompanied by an increase in total haematopoietic stem cells. 2) Pre-conditioning with CSF1-Fc increased the reconstitution potential of blood after haematopoietic stem cell mobilisation.

Background The population-based assessment of patient-centered outcomes (PCOs) has been limited by the efficient and accurate collection of these data. Natural language processing (NLP) pipelines can determine whether a clinical note within an electronic medical record contains evidence on these data. We present and demonstrate the accuracy of an NLP pipeline that targets to assess the presence, absence, or risk discussion of two important PCOs following prostate cancer treatment: urinary incontinence (UI) and bowel dysfunction (BD). Methods We propose a weakly supervised NLP approach which annotates electronic medical record clinical notes without requiring manual chart review. A weighted function of neural word embedding was used to create a sentence-level vector representation of relevant expressions extracted from the clinical notes. Sentence vectors were used as input for a multinomial logistic model, with output being either presence, absence or risk discussion of UI/BD. The classifier was trained based on automated sentence annotation depending only on domain-specific dictionaries (weak supervision). Results The model achieved an average F1 score of 0.86 for the sentence-level, three-tier classification task (presence/absence/risk) in both UI and BD. The model also outperformed a pre-existing rule-based model for note-level annotation of UI with significant margin. Conclusions We demonstrate a machine learning method to categorize clinical notes based on important PCOs that trains a classifier on sentence vector representations labeled with a domain-specific dictionary, which eliminates the need for manual engineering of linguistic rules or manual chart review for extracting the PCOs. The weakly supervised NLP pipeline showed promising sensitivity and specificity for identifying important PCOs in unstructured clinical text notes compared to rule-based algorithms. Trial registration This is a chart review study and approved by Institutional Review Board (IRB).

Background It can be challenging to predict the risk of biochemical recurrence (BR) during follow-up after radical prostatectomy (RP) in men who have undetectable prostate-specific antigen (PSA), even years after surgery. Objective To establish and validate a contemporary nomogram that predicts the absolute risk of BR every year after RP in men with undetectable PSA while accounting for competing risks of death. Design, setting, and participants A total of 3746 patients from Rigshospitalet (Copenhagen, Denmark) and Stanford Urology (Stanford, CA, USA) who underwent RP between 1995 and 2013 were included. Outcome measurements and statistical analysis Time to BR was defined as the first PSA result ≥0.2 ng/ml. BR risk was computed using multiple cause-specific Cox regression including preoperative PSA, pT category, RP Gleason score (GS), and surgical margin (R) status. Death without BR was considered a competing event. The nomogram presents the future risk of BR for a man who is alive and without BR at the time of follow-up. Validation assessed the discrimination and accuracy using time-dependent area under the curve and Brier scores. Results and limitations The nomogram predicts risk of BR up to 12 yr after RP at an individual level. As example, the risk of BR for a man with pT3a, R−, GS 3 + 4, and preoperative PSA ≤10 ng/ml followed for 5 yr with undetectable PSA is 18% for the next 5 yr. External validation demonstrated both high accuracy and discrimination. The CPC Risk Calculator is available as a free Android and iOS App. Declining discrimination and accuracy after 7 yr of follow-up is the main limitation. Conclusions This nomogram can be used as a tool to inform men with undetectable PSA during follow-up after RP about their future risk of BR, and may aid in decisions on the necessity for further follow-up. The nomogram is the first to be available as a free app. Patient summary We developed an easily interpretable nomogram to evaluate the risk of prostate-specific antigen elevation (cancer recurrence) following complete removal of the prostate (radical prostatectomy). The tool can aid both physicians and patients in evaluating the future risk of cancer recurrence during follow-up after surgery. The model is available as a free mobile app that can be downloaded from the App Store.

Objective: To assess documentation of urinary incontinence (UI) in prostatectomy patients using unstructured clinical notes from Electronic Health Records (EHRs).Methods: We developed a weakly-supervised natural language processing tool to extract assessments, as recorded in unstructured text notes, of UI before and after radical prostatectomy in a single academic practice across multiple clinicians. Validation was carried out using a subset of patients who completed EPIC-26 surveys before and after surgery. The prevalence of UI as assessed by EHR and EPIC-26 was compared using repeated-measures ANOVA. The agreement of reported UI between EHR and EPIC-26 was evaluated using Cohen’s Kappa coefficient.Results: A total of 4870 patients and 716 surveys were included. Preoperative prevalence of UI was 12.7 percent. Postoperative prevalence was 71.8 percent at 3 months, 50.2 percent at 6 months and 34.4 and 41.8 at 12 and 24 months, respectively. Similar rates were recorded by physicians in the EHR, particularly for early follow-up. For all time points, the agreement between EPIC-26 and the EHR was moderate (all p < 0.001) and ranged from 86.7 percent agreement at baseline (Kappa = 0.48) to 76.4 percent agreement at 24 months postoperative (Kappa = 0.047).Conclusions: We have developed a tool to assess documentation of UI after prostatectomy using EHR clinical notes. Our results suggest such a tool can facilitate unbiased measurement of important PCOs using real-word data, which are routinely recorded in EHR unstructured clinician notes. Integrating PCO information into clinical decision support can help guide shared treatment decisions and promote patient-valued care.

The clinical, granular data in electronic health record (EHR) systems provide opportunities to improve patient care using informatics retrieval methods. However, it is well known that many methodological obstacles exist in accessing data within EHRs. In particular, clinical notes routinely stored in EHR are composed from narrative, highly unstructured and heterogeneous biomedical text. This inherent complexity hinders the ability to perform automated large-scale medical knowledge extraction tasks without the use of computational linguistics methods. The aim of this work was to develop and validate a Natural Language Processing (NLP) pipeline to detect important patient-centered outcomes (PCOs) as interpreted and documented by clinicians in their dictated notes for male patients receiving treatment for localized prostate cancer at an academic medical center.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log 10 (CFU/ml) [IQR, 5.43 to 6.46 log 10 (CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.)

Purpose To investigate the impact of race on the risk of pathological upgrading and upstaging at radical prostatectomy (RP) in an Asian (Korean) and Western (Caucasian) cohort eligible for active surveillance (AS). Materials and methods We performed a retrospective cohort study of 854 patients eligible for AS who underwent RP in United States (n = 261) and Korea (n = 593) between 2006 and 2015. After adjusting for age, PSA level, and prostate volume, we utilized multivariate logistic regression analysis to assess the effect of race on upgrading or upstaging. Results There were significant differences between Caucasian and Korean patients in terms of age at surgery (60.2 yr. vs. 64.1 yr.), PSA density (0.115 ng/mL/mL vs. 0.165 ng/mL/mL) and mean number of positive cores (3.5 vs. 2.4), but not in preoperative PSA values (5.11 ng/mL vs. 5.05 ng/mL). The rate of upstaging from cT1 or cT2 to pT3 or higher was not significantly different between the two cohorts (8.8% vs. 11.0%, P = 0.341). However, there were higher rates of upgrading to high-grade cancer (Gleason 4+3 or higher) in Korean patients (9.1%) when compared to Caucasian counterparts (2.7%) (P = 0.003). Multivariate logistic regression analysis showed that age (OR 1.07, P < 0.001) and smaller prostate volume (OR 0.97, P < 0.001), but not race, were significantly associated with upstaging or upgrading. Conclusions There were no differences in rates of upgrading or upstaging between Caucasian and Korean men eligible for active surveillance.

Einleitung: Die Behandlung von Patienten mit einem high risk Prostatakarzinom (PCa) bleibt hinsichtlich der Wahl des geeigneten operative Verfahrens der radikalen Prostatektomie (RP) kontrovers: offene retropubisch RP (RRP), laparoskopisch RP (LRP) oder Roboter-assistiert (RARP). Ziel dieser Arbeit war es, den Einfluss der unterschiedlichen Techniken auf das histopathologische Ergebnis sowie auf die biochemischen Rezidivraten zu untersuchen. Patienten und Methoden: Insgesamt wurden 805 Patienten mit einem high risk PCa (PSA >20 ng/mL, Gleason Score ≥8, oder klinisches Stadium ≥cT2c) identifiziert. Der Vergleich von 407 RRP Patienten mit 398 Fallen, die minimal invasiv operiert wurden (LRP+RARP) ergab deutliche Storgrosen. Dementsprechend wurden alle 110 RARP Falle mit dem Propensity Score (PS) 1:1 gegen LRP und RRP Falle gematched. Der PS beinhaltete Alter, klinisches Tumorstadium, praoperativer PSA, Gleason Score der Biopsie, die Erfahrung des Operateurs sowie die Anwendung einer nerverhaltenden Operationstechnik. Die Patientencharakteristika wurden mit geeigneten Testverfahren verglichen. Vergleich von Gesamtuberleben (OS) und Rezidiv-freiem Uberleben (RFS) mit dem log rank Test. Die RFS Pradiktoranalyse erfolgte mithilfe von Cox Regressionsmodellen. Ergebnisse: Innerhalb der post-matching Kohorte von 330 Patienten lag der Anteil an Patienten mit einem pathologischen Gleason Score 7 bei 1,8, 55,5 und 42,7% fur RARP, 8,2, 36,4, 55,5% fur LRP sowie 0, 60,9 und 39,1% fur RRP (p=0,004 fur RARP vs. LRP und p=0,398 fur RARP vs. RRP). Unterschiede bei den histopathologischen Stadien waren statistisch nicht signifikant. Die Gesamtrate an positiven Schnittrandern (PSM) sowie die PSM Rate fur ≥pT3 waren nicht unterschiedlich. PSM bei pT2 betrug 15,7, 14,0 und 20,0% fur RARP, LRP und RRP (statistisch nicht signifikant). Das mittlere 3-Jahres RFS lag bei jeweils 41,4, 77,9, 54,1% (p Schlussfolgerung: RARP kann bei high risk PCa Patienten mit der LRP und RRP vergleichbaren pathologischen sowie onkologischen Ergebnissen angewendet werden.

Objective To determine pathological and oncological outcomes of patients diagnosed with low-risk prostate cancer in two age cohorts who underwent radical prostatectomy (RP) and qualified for active surveillance (AS) according to Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, as AS for low-risk prostate cancer represents an acceptable management strategy especially for older patients. Patients and Methods In all, 320 patients aged ≥65 years who underwent RP and were eligible for AS according to PRIAS criteria were propensity score matched 1:1 to patients aged

Tumor volume and percent cancer (ratio of tumor volume/prostate volume) have been proposed as predictors of biochemical recurrence and cancer specific survival after radical prostatectomy. However, their relative merits as prognosticators have not been tested. We therefore evaluated and compared tumor volume and percent cancer as independent predictors of biochemical recurrence and prostate cancer specific death after radical prostatectomy.A retrospective review of 739 patients who underwent radical prostatectomy for prostate cancer between 1984 and 2004 was conducted. Median follow-up was 91.7 months, and 22 patients died of prostate cancer. Univariate and multivariate analysis evaluated the following factors in predicting biochemical recurrence and prostate cancer specific death: tumor volume, prostate volume, percent cancer, Gleason score, percentage of Gleason grade 4/5, margin status, capsular invasion status, seminal vesicle invasion status, preoperative PSA, and lymph node status.In univariate analysis, both tumor volume (P0.001) and percent cancer (P0.001) significantly correlated with biochemical recurrence. Since they are highly correlated, they did not predict outcome independently when included in the same model; however, both were highly predictive for biochemical recurrence in separate multivariate models (P=0.01 for both). Both also correlated with cancer specific survival as single variables; however, in separate multivariate models, only tumor volume (P=0.03) predicted death, while percent cancer did not (P=0.09).Tumor volume and percent cancer are independent predictors of recurrence after radical prostatectomy. However, in our series, tumor volume predicted cancer specific death better than percent cancer. Therefore, accurate determination of tumor volume, along with other accepted pathologic indices, is sufficient and preferred over percent cancer for prognostication after radical prostatectomy.

Objectives: Positive surgical margins (PSM) have been associated with biochemical recurrence (BCR) after radical prostatectomy, but the significance of PSM length and location are debated. We assessed the impact of PSM lengths at specific locations for BCR in an open radical prostatectomy series. Methods: Detailed clinical and pathological data were collected from 117 post-prostatectomy patients with PSM from 1984 to 2004 at our institution. PSM locations were classified as apex, mid-gland, base, bladder neck, and anterior fibromuscular region with lengths measured at each site. Aggregate PSM length was obtained by summing lengths of all PSM areas in contact with the inked surface. BCR was defined as serum prostate specific antigen level 0.2 ng/mL or greater. Cox proportional hazards regression analyses of PSM lengths were conducted either as a continuous or categorical variable relative to location as a predictor of BCR. Results: Multivariate analyses demonstrated that as a continuous variable, PSM length at the anterior fibromuscular region (Hazard ratio [HR] = 1.17; P = 0.027) and bladder neck (HR = 1.29; P = 0.046) were significant predictors for BCR. As a categorical variable, PSM length ≥ 2 mm at the anterior fibromuscular area was significant for BCR (HR = 3.02; P = 0.036). Increasing Gleason grade and positive lymph node status were also found to be significant independent predictors for BCR. Conclusion: PSM length at the anterior fibromuscular region (continuous and categorical) and the bladder neck (continuous) was significantly associated with BCR. Site-specific PSM length, along with Gleason grade and lymph node status, can be predictive of BCR and assist in risk stratification of patients with PSM following radical prostatectomy.

Background Fecal contamination is a major challenge in patients in acute/critical care settings that is associated with increased cost of care and supplies and with development of pressure ulcers, incontinence dermatitis, skin and soft tissue infections, and urinary tract infections. Objectives To assess the economic impact of fecal containment in bedridden patients using 2 different indwelling bowel catheters and to compare infection rates between groups. Methods A multicenter, observational study was done at 12 US sites (7 that use catheter A, 5 that use catheter B). Patients were followed from insertion of an indwelling bowel catheter system until the patient left the acute/critical care unit or until 29 days after enrollment, whichever came first. Demographic data, frequency of bedding/dressing changes, incidence of infection, and Braden scores (risk of pressure ulcers) were recorded. Results The study included 146 bedridden patients (76 with catheter A, 70 with catheter B) who had similar Braden scores at enrollment. The rate of bedding/dressing changes per day differed significantly between groups (1.20 for catheter A vs 1.71 for catheter B; P = .004). According to a formula that accounted for personnel resources and laundry cycle costs, catheter A cost $13.94 less per patient per day to use than did catheter B. Catheter A was less likely than was catheter B to be removed during the observational period (P = .03). Observed infection rates were low. Conclusion Catheter A may be more cost-effective than catheter B because it requires fewer unscheduled linen changes per patient day.

Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease. [Cancer Res 2007;67(18):8504–10]

232 Background: Electronic health records (EHRs) are a widely adopted but underutilized source of data for systematic assessment of healthcare quality. Barriers for use of this data source include its vast complexity, lack of structure, and the lack of use of standardized vocabulary and terminology by clinicians. This project aims to develop generalizable algorithms to extract useful knowledge regarding prostate cancer quality metrics from EHRs. Methods: We used EHR ICD-9/10 codes to identify prostate cancer patients receiving care at our academic medical center. Patients were confirmed in the California Cancer Registry (CCR), which provided data on tumor characteristics, treatment data, treatment outcomes and survival. We focused on three potential pretreatment process quality measures, which included documentation within 6 months prior to initial treatment of prostate-specific antigen (PSA), digital rectal exam (DRE) performance, and Gleason score. Each quality metric was defined using target terms and concepts to extract from the EHRs. Terms were mapped to a standardized medical vocabulary or ontology, enabling us to represent the metric elements by a concept domain and its permissible values. The structured representation of the quality metric included rules that accounted for the temporal order of the metric components. Our algorithms used natural language processing for free text annotation and negation, to ensure terms such as ‘DRE deferred’ are appropriately categorized. Results: We identified 2,123 patients receiving prostate cancer treatment between 2008-2016, of whom 1413 (67%) were matched in the CCR. We compared accuracy of our data mining algorithm, a random sample of manual chart review, and the CCR. (See Table.) Conclusions: EHR systems can be used to assess and report quality metrics systematically, efficiently, and with high accuracy. The development of such systems can improve and reduce the burden of quality reporting and potentially reduce costs of measuring quality metrics through automation. [Table: see text]

Aims and objectives The aim of this study was to explore the experiences and concerns of individuals with type 2 diabetes mellitus, in a predominantly low socio-economic setting. Background Currently, approximately 1 million Australians have diabetes and rates have more than doubled since 1989. Type 2 diabetes mellitus accounts for approximately 85% of diabetes cases. Risk factors include obesity, older age, low socio-economic status, sedentary lifestyle and ethnicity. Older individuals from low socio-economic backgrounds are particularly at risk of both developing and of mismanaging their condition. Design Exploratory qualitative design. Methods Focus groups were used to collect data from 22 individuals, aged 40 to more than 70 years, with type 2 diabetes mellitus, who were attending local health services for their diabetes care. Focus groups ranged in size from four to eight individuals and all were recorded, transcribed and analysed. Data were analysed using a thematic analysis approach. Results Participants described their experiences of managing their diabetes as emotionally, physically and socially challenging. Data analysis revealed four main themes including: (1) diabetes the silent disease; (2) a personal journey (3) the work of managing diabetes; and (4) access to resources and services. Throughout, participants highlighted the impact of diabetes on the family, and the importance of family members in providing support and encouragement to assist their self-management efforts. Conclusions Participants in this study were generally satisfied with their diabetes care but identified a need for clear simple instruction immediately post-diagnosis, followed by a need for additional informal information when they had gained some understanding of their condition. Relevance to clinical practice Findings reveal a number of unmet information and support needs for individuals with type 2 diabetes mellitus. In particular, it is important for healthcare professionals and family members to recognise the significant emotional burden that diabetes imposes, and the type and quantity of information individuals with diabetes prefer. It is also important to consider levels of health literacy in the community when developing diabetes-related information or programmes.

Prostate cancer arises in the transition zone (TZ) in approximately 20-25% of cases. Modern biopsy and surveillance protocols, and advances in prostate cancer imaging, have renewed interest in TZ prostate cancers. We compared TZ and PZ prostate cancer to determine if cancer location is independently associated with better outcomes.We evaluated an expanded cohort of 1354 men who underwent radical prostatectomy between 1983 and 2003 with updated long-term clinical follow-up. Regression models were used to compare the volume of high-grade (Gleason 4 or 5) cancer and total cancer volume by location. Uni- and multi-variable logistic regression models tested the associations between cancer location and adverse pathologic features. Multivariable proportional hazard models were fit to examine cancer recurrence.Patients with TZ cancer presented with higher pre-operative serum PSA values (11.07 vs. 7.86 ng/ml) and larger total cancer volume (7.1 vs. 3.8 cc). Patients with TZ cancer had decreased odds of seminal vesicle invasion (OR 0.08, 95% CI 0.03, 0.21), extra-capsular extension (OR 0.56, 95% CI 0.35, 0.92), and lymphovascular invasion (OR 0.48, 95% CI 0.27, 0.87) in multivariable models. TZ cancers were independently associated with decreased hazard of tumor recurrence (HR 0.62, 95% CI 0.43, 0.90).TZ cancer prostate is associated with favorable pathologic features and better recurrence-free survival despite being diagnosed with larger cancers and higher PSA values. Tumor location should be taken into account when stratifying patient risk before and after prostatectomy, particularly with the evolving role of imaging in prostate cancer management.

To investigate pathological and oncological outcomes of obese patients who underwent robot-assisted radical prostatectomy (RARP) compared with laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (RRP) since limited comparative data exist with regard to oncological and survival outcomes.A total of 869 patients with body mass index ≥ 30 from two academic centers were identified. A total of 194 patients who underwent RARP were propensity score (PS) matched 1:1 to LRP or RRP cases. PS-matching variables included prostate-specific antigen (PSA), biopsy Gleason score, clinical stage, surgeon experience, and nerve-sparing technique. Predictors of positive surgical margins (PSMs) were analyzed using logistic regression. Predictors of recurrence-free survival (RFS) were analyzed within Cox regression models. Overall survival was compared with RFS using the log-rank test.Pathologic Gleason scores7, =7, and7 were found in 24.2, 63.6, and 11.7 % of patients, respectively. There were no statistically significant differences related to pathologic stage or lymph node metastases between surgical techniques. PSM for pT2 disease were observed in 22.9, 17.4, and 19.3 % of patients undergoing RARP, LRP, and RRP, respectively (not significantly different). Preoperative PSA and clinical stage cT2 disease were independently associated with PSM. There were no significant differences in mean 3-year RFS for RARP, LRP, and RRP (87.4, 91.0, and 85.7 %). Biopsy Gleason score7, PSM, and clinical stage two were independent predictors of decreased RFS.RARP demonstrates similar pathological and oncological results compared with LRP or RRP for obese patients.

We evaluate the efficacy of the male bulbourethral sling procedure in the treatment of post-radical prostatectomy urinary incontinence.We reviewed the records of 64 consecutive men with severe post-prostatectomy incontinence who underwent the male bulbourethral sling procedure at Northwestern Memorial Hospital and Stanford University Hospital. Preoperatively 50% of the patients were completely incontinent (diapers, clamps or condom catheter), and the remainder required a mean of 4.7 pads per day. Data were collected by chart review, patient interviews at followup appointments and telephone interviews. Median followup was 18.1 months (mean 22.4, range 6.5 to 53.8).Following a single sling procedure 36 patients (56%) became dry, and 5 (8%) were significantly improved. In 17 patients 23 retightening procedures were performed, which decreased the median followup to 16 months and increased the success rate to 75% (67% cured, 8% improved). The revision, erosion and infection rates were 27, 6 and 3%, respectively.The male bulbourethral sling procedure is effective treatment for post-radical prostatectomy urinary incontinence. Patients who had received adjuvant radiation therapy demonstrated a lower continence rate than those who had not. Further followup is needed to assess long-term efficacy.

To determine pathological and oncological outcomes of patients diagnosed with low-risk prostate cancer in two age cohorts who underwent radical prostatectomy (RP) and qualified for active surveillance (AS) according to Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, as AS for low-risk prostate cancer represents an acceptable management strategy especially for older patients.In all, 320 patients aged ≥65 years who underwent RP and were eligible for AS according to PRIAS criteria were propensity score matched 1:1 to patients aged65 years. Patient characteristics were compared with chi-square, Kruskal-Wallis, and one-way anova tests. Predictors of RP pathological upgrading or upstaging were analysed using logistic regression. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Predictors of RFS were analysed within Cox regression models.Pathological upgrading and upstaging were significantly higher among older (≥65 years) vs younger (65 years) patients (53.1% vs 44.1% and 12.2% vs 7.2%, respectively). Higher prostate-specific antigen levels and increasing age were independent predictors of upgrading among patients aged65 years. There were no differences in RFS or OS between the two age groups. Positive surgical margin status was the only independent predictor of shorter RFS.Patients aged ≥65 years who are eligible for AS by PRIAS criteria have a higher risk of being upgraded and upstaged at RP than those aged65 years. These findings should be taken into consideration when discussing treatment options for patients diagnosed with prostate cancer.

Comparative data related to the use of open and minimally invasive surgical approaches for the treatment of high-risk prostate cancer (PCa) remain limited. We determined outcomes of open radical prostatectomy (RRP), laparoscopic RP (LRP), and robot-assisted RP (RARP) in matched cohorts of patients with high-risk prostate cancer.A total of 805 patients with high-risk PCa [prostate-specific antigen (PSA)20 ng/mL, Gleason score ≥8, or clinical stage ≥cT2c] were identified. A total of 407 RRP cases were propensity score (PS) matched 1:1 to 398 LRP or RARP cases to yield 3 cohorts (RARP, LRP, and RRP) of 110 patients each for analysis. PS matching variables included the following: age, clinical stage, preoperative PSA, biopsy Gleason score, surgeon experience, and nerve-sparing technique. Overall survival (OS) and recurrence-free survival (RFS) were compared with log-rank test. RFS predictor analysis was calculated within Cox regression models.Pathological Gleason scores7, =7, and7 were found in 3.3, 50.9, and 45.8 % of patients. There were no statistically significant differences for pathological stage and positive surgical margins between surgical techniques. Mean 3-year RFS was 41.4, 77.9, and 54.1 %, for RARP, LRP, and RRP, respectively (p0.0001 for RARP vs. LRP). There were no significant differences for mean estimated 3-year OS for patients treated with RARP, LRP, or RRP (95.4, 98.1, and 100 %).RARP demonstrated similar oncologic outcomes compared to RRP and LRP in a PS-matched cohort of patients with high-risk prostate cancer.

Tissue microarrays provide unique resources for rapid evaluation and validation of tissue biomarkers. The Canary Foundation Retrospective Prostate Tissue Microarray Resource used a rigorous statistical design, quota sampling, a variation of the case-cohort study, to select patients for inclusion in a multicenter, retrospective prostate cancer tissue microarray cohort. The study is designed to definitively validate tissue biomarkers of prostate cancer recurrence after radical prostatectomy. Tissue samples from over 1,000 participants treated for prostate cancer with radical prostatectomy between 1995 and 2004 were selected at six participating institutions in the United States and Canada. This design captured the heterogeneity of screening and clinical practices in the contemporary North American population. Standardized clinical data were collected in a centralized database. The project has been informative in several respects. The scale and complexity of assembling tissue microarrays (TMAs) with over 200 cases at each of six sites involved unanticipated levels of effort and time. Our statistical design promises to provide a model for outcome-based studies where tissue localization methods are applied to high-density tissue microarrays.

Objective To assess the performance characteristics of prostate-specific antigen (PSA) for predicting the volume of total or high-grade cancer in men undergoing radical prostatectomy. It is known that the performance characteristics of PSA are improved for predicting the presence of high-grade prostate cancer. Methods We identified 1459 patients from the Stanford Radical Prostatectomy Database with clinical Stage T1c (n = 783) and T2 (n = 676) disease who underwent surgery from 1988 to 2003 with detailed morphometric mapping. We generated receiver operating characteristic curves for PSA levels according to the total and high-grade (Gleason score 4 or 5) cancer volume and compared the areas under the curve (AUC) for the various total and high-grade cancer volumes. Results For patients with Stage T1c disease, the AUC for the PSA ROC curve increased in a stepwise fashion as both the total cancer volume and the high-grade cancer volume increased. Significant differences between the AUCs for low and high volumes of total and high-grade disease were observed. For T2 disease, the AUCs for predicting high-grade cancer volume were generally greater than the corresponding AUCs for T1c disease, although no incremental increase was observed. Conclusion In patients with Stage T1c disease, in whom the PSA level was the driving force for biopsy, the PSA performance improved in a stepwise fashion with greater total and high-grade cancer volumes as evidenced by improved ROC. Previous studies have shown that PSA performs better for detecting the presence of high-grade disease. We have shown that PSA performs better in predicting greater volumes of high-grade disease in radical prostatectomy specimens.

Positive surgical margins (PSM) have been associated with biochemical recurrence (BCR) after radical prostatectomy, but the significance of PSM length and location are debated. We assessed the impact of PSM lengths at specific locations for BCR in an open radical prostatectomy series.Detailed clinical and pathological data were collected from 117 post-prostatectomy patients with PSM from 1984 to 2004 at our institution. PSM locations were classified as apex, mid-gland, base, bladder neck, and anterior fibromuscular region with lengths measured at each site. Aggregate PSM length was obtained by summing lengths of all PSM areas in contact with the inked surface. BCR was defined as serum prostate specific antigen level 0.2 ng/mL or greater. Cox proportional hazards regression analyses of PSM lengths were conducted either as a continuous or categorical variable relative to location as a predictor of BCR.Multivariate analyses demonstrated that as a continuous variable, PSM length at the anterior fibromuscular region (Hazard ratio [HR] = 1.17; P = 0.027) and bladder neck (HR = 1.29; P = 0.046) were significant predictors for BCR. As a categorical variable, PSM length ≥ 2 mm at the anterior fibromuscular area was significant for BCR (HR = 3.02; P = 0.036). Increasing Gleason grade and positive lymph node status were also found to be significant independent predictors for BCR.PSM length at the anterior fibromuscular region (continuous and categorical) and the bladder neck (continuous) was significantly associated with BCR. Site-specific PSM length, along with Gleason grade and lymph node status, can be predictive of BCR and assist in risk stratification of patients with PSM following radical prostatectomy.

We evaluated the usefulness of an ultrasensitive immunoassay for prostate specific antigen (PSA), modified from the standard Yang Pros-Check PSA test and with a biological detection limit for PSA in serum of 0.07 ng./ml., to detect residual prostate cancer at an earlier date. We studied retrospectively serial frozen serum samples from 22 prostate cancer patients after radical prostatectomy who later had residual cancer with detectable PSA levels of 0.3 ng./ml. or more by the standard PSA test. As controls we studied 33 cystoprostatectomy patients (for bladder cancer) without histological evidence of prostate cancer and 23 patients after radical prostatectomy who had the highest probability of cure of the cancer. All control patients without cancer had PSA values (282 of 283 samples, 99.6%) of less than 0.1 ng./ml. This value was called the residual cancer detection limit. In the 22 patients with recurrent cancer the ultrasensitive assay detected cancer recurrence (PSA 0.1 ng./ml. or more) much earlier (median 202 and mean 310 days) than the standard assay (PSA 0.3 ng./ml. or more). On screening 187 current post-radical prostatectomy patients without evidence of cancer by the standard assay the ultrasensitive assay detected 21 (11.2%) with evidence of residual cancer, that is PSA level of 0.1 ng./ml. or more. We conclude that an ultrasensitive assay for PSA can detect residual cancer after radical prostatectomy much earlier than current immunoassays for PSA. Earlier detection of residual cancer may improve long-term survival by allowing for earlier institution of adjuvant therapy.

Prior radical prostatectomy series have shown an inverse association between prostate size and high grade cancer. It has been suggested that smaller size prostates arise in a low androgen environment, enabling development of more aggressive cancer. We propose that this observation is the result of ascertainment bias driven by prostate specific antigen performance.We identified 1,404 patients from the Stanford Radical Prostatectomy Database with clinical stage T1c (723) and T2 (681) disease who underwent surgery between 1988 and 2002, and underwent detailed morphometric mapping by a single pathologist. Multivariate linear regression was performed to assess for the effects of age, prostate weight and prostate specific antigen on total and high grade (Gleason grade 4/5) cancer volume and percentage of high grade disease.In patients who underwent biopsy due to abnormal prostate specific antigen (stage T1c), prostate weight was negatively associated (p = 0.0002) with total cancer volume, volume of high grade disease and percentage of high grade disease. For patients who underwent biopsy based on abnormal digital rectal examination (stage T2) these associations were not observed.Improved prostate specific antigen performance for high grade disease results in ascertainment bias in patients with T1c disease. Thus, the association between prostate size and high grade disease may be a consequence of grade dependent performance of prostate specific antigen rather than true tumor biology.