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Premedical students typically pursue undergraduate specialization in basic biological and other sciences, learning to understand living systems at a microscopic, genetic, or molecular level. However, curricula in the basic sciences do not traditionally include courses that enable students to learn about living systems at the macro level-understanding individuals within their environment, as well as understanding and managing the health of populations, especially those with underlying conditions or the underserved. This disconnect can be bridged by creating novel curricular programs intersecting medicine and business. Population health management is a multidisciplinary field that aims to improve the patient experience, reduce health care costs, and improve treatment outcomes. Though related to public health, the 2 fields differ in significant ways. Population health management emphasizes health outcomes and their measurements and seeks to improve health outcomes based on a full understanding of risk, behaviors, lifestyle, environment, and all social determinants of health. A shift in premedical education that connects the medical sciences with business requires curricular reform with the emerging field of population health management at their intersection, allowing students to be better prepared for future medical practices and to understand expectations, benchmarks, business, and economics in a new value-based health care system.

Supplementary Data from A Novel DNMT3B Splice Variant Expressed in Tumor and Pluripotent Cells Modulates Genomic DNA Methylation Patterns and Displays Altered DNA Binding

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PDF file - 70K, CCR8+ myeloid cells induce FoxP3 expression in T cells

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Purpose: Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas.Experimental Design: We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function.Results: We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b+CCR8+ cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b+CCR8+ cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1.Conclusions: This study provides the first evidence that CCR8+ myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8+ myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers. Clin Cancer Res; 19(7); 1670–80. ©2013 AACR.

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The integration of medical schools and clinical partners is effectively established through the formation of academic medical centers (AMCs). The tripartite mission of AMCs emphasizes the importance of providing critical clinical services, medical innovation through research, and the education of future health care leaders. Although AMCs represent only 5% of all hospitals, they contribute substantially to serving disadvantaged populations of patients, including an estimated 37% of all charity care and 26% of all Medicaid hospitalizations. Currently, most AMCs use a business model centered upon revenue generated from hospital services and/or practice plans. In the last decade, mounting financial demands have placed significant pressure on AMC finances because of the rising costs associated with complex clinical care and operating diverse graduate medical education programs. A shift toward population health-centric health care management strategies will profoundly influence the predominant forms of health care delivery in the United States in the foreseeable future. Health systems are increasingly pursuing new strategies to manage financial risk, such as forming Accountable Care Organizations and provider-sponsored plans to provide value-based care. Refocusing research and operational capacity toward population health management fosters collaboration and enables reintegration with hospital and clinical partners across care networks, and can potentially create new revenue streams for AMCs. Despite the benefits of population health integration, current literature lacks a blueprint to guide AMCs in the transformation toward sustainable population health management models. The purpose of this paper is to propose a modern conceptual framework that can be operationalized by AMCs in order to achieve a sustainable future.

BACKGROUND: In Florida, 2.4 million people have diabetes and 5.8 million are pre-diabetic. Not only has the prevalence of diabetes doubled over the past 20 years from 5.2 in 1992 to 11.2 in 2014, but the Centers for Disease Control and Prevention expects 1 out of every 3 adults will have diabetes by the year 2050. In addition, in every year since 1996, Florida well exceeds the national levels in terms of prevalence of diabetes, and the gap is getting wider. A study was conducted to gather information from key physician stakeholders as to how to address unmet needs of patients at risk for, or whom already have, diabetes in a tri-county region of South Florida where the prevalence of diabetes is very high. OBJECTIVE: The goal was to catalyze innovation and generate solutions for high quality and affordable diabetes care by convening community physicians in South Florida and querying them about solutions for delivering value-based care. METHODS: A physician-led task force of community physicians was convened to uncover unmet needs in the diabetes care continuum, identify areas of improvement for coordinating care across the continuum and effectively accessing specialty care. Focus groups were convened with 30 participants to capture qualitative data relative to unmet needs, utilizing the Rapid Ideation Technique. A survey instrument was designed and administered to the twenty-one community clinicians on the task force to augment the qualitative data with quantitative data. The first part of the survey captured characteristics of the participating clinicians, their practices, their diabetes services and management approaches. The second part of the survey captured individual ratings of the importance and merit of needs and/or potential solutions generated. RESULTS: The focus groups generated a wealth of information regarding challenges, issues, areas of opportunities, and potential solutions that could be organized within eight main themes: care coordination and integration; patient engagement, education and behavioral change; physician and practice support; EMR and data issues; telehealth solutions; health informatics and data analytics; and access to care. The surveys culminated in the formation of a Call-For-Action Agenda for immediate work. CONCLUSIONS: The ultimate goal of the taskforce was to catalyze innovation and generate solutions for high quality and affordable care. This article reports the findings and provides a roadmap for the future.

INTRODUCTION: There are currently no data, blueprints, best practices, or financial models available to guide the creation of a new medical school. Yet, the United States is experiencing unprecedented growth of new allopathic medical schools. FINDINGS: This article brings logic to the process. It converts the complexity of what is often regarded as an administrative exercise into the first published framework of management principles. Those principles were then translated into a process map and a financial optimization model. All three elements can be successfully implemented for establishing an accredited, value-driven medical education program that minimizes time from inception to implementation, and ensures sustainability over time. OUTCOMES: This case report provides a blueprint for planning and implementation of a new medical school. Outcomes include both process and optimization models, as well as valuable insights that have utility when considering a new medical school to mitigate the projected nationwide shortage of physicians.

Purpose: We identified structural abnormalities in the spermatic cord nerves that may explain how microsurgical denervation of the spermatic cord provides pain relief in patients with chronic orchialgia.Materials and Methods: We retrospectively reviewed a prospective database to compare spermatic cord biopsy specimens from 56 men treated with a total of 57 procedures for microsurgical denervation of the spermatic cord for chronic orchialgia vs a control group of men without pain treated with cord surgery, including varicocelectomy in 4 and radical orchiectomy in 6. Tissue biopsies were obtained from mapped regions of the spermatic cord in all cases. Biopsies stained with hematoxylin and eosin were examined by an independent pathologist. Three human cadaveric spermatic cords were dissected to confirm localization of the nerve distribution identified on pathological mapping.Results: We identified a median of 25 small diameter (less than 1 mm) nerve fibers in the spermatic cord. Of the 57 procedures for orch...

Purpose: Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. Experimental Design: We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function. Results: We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b+CCR8+ cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b+CCR8+ cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. Conclusions: This study provides the first evidence that CCR8+ myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8+ myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers. Clin Cancer Res; 19(7); 1670–80. ©2013 AACR.

Cancer stem cells (CSC) represent a malignant subpopulation of cells in hierarchically organized tumors. They constitute a sub-population of malignant cells within a tumor mass and possess the ability to self-renew giving rise to heterogeneous tumor cell populations with a complex set of differentiated tumor cells. CSC may be the cause of metastasis and therapeutic refractory disease. Because few markers exist to identify and isolate pure CSC, we used cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX) to create DNA aptamers that can identify novel molecular targets on the surfaces of live CSC. Out of 22 putative DNA sequences, 3 bound to ~90% and 5 bound to ~15% of DU145 prostate cancer cells. The 15% of cells that were positive for the second panel of aptamers expressed high levels of E-cadherin and CD44, had high aldehyde dehydrogenase 1 activity, grew as spheroids under non-adherent culture conditions, and initiated tumors in immune-compromised mice. The discovery of the molecular targets of these aptamers could reveal novel CSC biomarkers.

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly. Electronic supplementary material The online version of this article (doi:10.1186/s40425-016-0198-x) contains supplementary material, which is available to authorized users.

Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumor-associated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAM-mediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2–dependent and 15-LOX2–independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC. Cancer Res; 71(20); 6400–9. ©2011 AACR.

Bladder cancer is associated with enhanced inflammation and characterized by deregulated prostanoid metabolism. Here we examined prostaglandin E₂ (PGE₂) metabolism and myeloid cell subsets that infiltrate tumor tissue using two xenograft models of human bladder cancer. Human bladder tumor xenografts implanted into athymic nude mice become highly infiltrated with host CD11b myeloid cells of bone marrow origin. Fast growing SW780 bladder tumor xenografts were infiltrated with heterogeneous CD11b myeloid cell subsets including tumor-associated macrophages and myeloid-derived suppressor cells. In contrast, majority of myeloid cells in tumor tissue from slow growing bladder cancer Urothel 11 displayed more immature, homogenous phenotype and comprised mostly MHC II class-negative myeloid-derived suppressor cells. We demonstrate that human bladder tumors secrete substantial amounts of PGE₂. Normal bone marrow myeloid cell progenitors cultured in the presence of a bladder tumor-conditioned medium, which is enriched for PGE₂, failed to differentiate into mature APCs and acquired phenotype of the myeloid-derived suppressor cells or inflammatory macrophages with up-regulated chemokine receptor CXCR4. Collectively our data demonstrate that enhanced cancer-related inflammation and deregulated PGE₂ metabolism in tumor microenvironment promote immunosuppressive pro-tumoral phenotype of myeloid cells in bladder cancer. These data also suggest that not only local tumor microenvironment but other factors such as stage of cancer disease and pace of tumor growth could markedly influence the phenotype, differentiation and immune function of myeloid cells in tumor tissue.

Both cancer-related inflammation and tumor-induced immune suppression are associated with expansion of myeloid cell subsets including myeloid-derived suppressor cells. However, little known regarding characteristics of myeloid cells in patients with bladder cancer. In this study, we analyzed myeloid cells from peripheral blood (PBMC) and tumor tissue that were collected from patients with superficial noninvasive and invasive urothelial carcinomas. Our results demonstrate that PBMC from bladder cancer patients contain two major CD11b myeloid cell subsets: granulocyte-type CD15(high) CD33(low) cells and monocyte-type CD15(low) CD33(high) cells. The number of circulating granulocytic but not monocytic myeloid cells in cancer patients was markedly increased when compared to healthy individuals. Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. Granulocytic myeloid cells were able to inhibit in vitro T cell proliferation through induction of CD4(+) Foxp3(+) T regulatory cells. Analysis of bladder cancer tissues revealed that tumors were infiltrated with monocyte-macrophage CD11b(+) HLA-DR(+) and granulocytic CD11b(+) CD15(+) HLA-DR(-) myeloid cells. Collectively, this study identifies myeloid cell subsets in patients with bladder cancer. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.

Antiangiogenic therapy has shown promise in the treatment of patients with renal cell carcinoma (RCC). Two classes of antiangiogenic drugs, the anti-vascular endothelial growth factor antibody bevacizumab and the tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, have shown efficacy in patients with RCC and are approved by the US Food and Drug Administration for treatment of this cancer. In practice, the clinical benefit of antiangiogenic drugs in RCC has been heterogeneous, and in patients who do respond, benefits are modest and/or short-lived. To improve efficacy, combination targeted therapy has been attempted, but with either very limited additional efficacy or nontolerable toxicities. Recent advances in the molecular understanding of tumor angiogenesis and mechanism of resistance, along with the rapid development of targeted drug discovery, have made it possible to further explore novel combination therapy for RCC.

Tumors impair function of tumor-infiltrated antigen-presenting cells by altering intracellular PGE2 catabolism in the myeloid cells. Recent studies suggest that tumor-infiltrated myeloid cells frequently up-regulate COX-2 expression and have enhanced PGE2 metabolism. This may affect the maturation and immune function of tumor-infiltrated antigen-presenting cells. In vitro studies demonstrate that tumor-derived factors can skew GM-CSF-driven differentiation of Th1-oriented myeloid APCs into M2-oriented Ly6C+F4/80+ MDSCs or Ly6C–F4/80+ arginase-expressing macrophages. These changes enable myeloid cells to produce substantial amounts of IL-10, VEGF, and MIP-2. The tumor-mediated inhibition of APC differentiation was associated with the up-regulated expression of PGE2-forming enzymes COX-2, mPGES1 in myeloid cells, and the simultaneous repression of PGE2-catabolizing enzyme 15-PGDH. The presence of tumor-derived factors also led to a reduced expression of PGT but promoted the up-regulation of MRP4, which works as a PGE2 efflux receptor. Addition of COX-2 inhibitor to the BM cell cultures could prevent the tumor-induced skewing of myeloid cell differentiation, partially restoring cell phenotype and down-regulating the arginase expression in the myeloid APCs. Our study suggests that tumors impair the intracellular PGE2 catabolism in myeloid cells through simultaneous stimulation of PGE2-forming enzymes and inhibition of PGE2-degrading systems. This tumor-induced dichotomy drives the development of M2-oriented, arginase-expressing macrophages or the MDSC, which can be seen frequently among tumor-infiltrated myeloid cells.

Tumor-recruited CD11b myeloid cells, including myeloid-derived suppressor cells, play a significant role in tumor progression, as these cells are involved in tumor-induced immune suppression and tumor neovasculogenesis. On the other hand, the tumor-infiltrated CD11b myeloid cells could potentially be a source of immunostimulatory antigen-presenting cells (APCs), since most of these cells represent common precursors of both dendritic cells and macrophages. Here, we investigated the possibility of generating mature APCs from tumor-infiltrated CD11b myeloid cells. We demonstrate that in vitro exposure of freshly excised mouse tumors to DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine, AZA) results in selective elimination of tumor cells, but, surprisingly it also enriches CD45(+) tumor-infiltrated cells. The majority of "post-AZA" surviving CD45(+) tumor-infiltrated cells were represented by CD11b myeloid cells. A culture of isolated tumor-infiltrated CD11b cells in the presence of AZA and GM-CSF promoted their differentiation into mature F4/80/CD11c/MHC class II-positive APCs. These tumor-derived myeloid APCs produced substantially reduced amounts of immunosuppressive (IL-13, IL-10, PGE(2)), pro-angiogenic (VEGF, MMP-9) and pro-inflammatory (IL-1beta, IL-6, MIP-2) mediators than their precursors, freshly isolated tumor-infiltrated CD11b cells. Vaccinating naïve mice with ex vivo generated tumor-derived APCs resulted in the protection of 70% mice from tumor outgrowth. Importantly, no loading of tumor-derived APC with exogenous antigen was needed to stimulate T cell response and induce the anti-tumor effect. Collectively, our results for the first time demonstrate that tumor-infiltrated CD11b myeloid cells can be enriched and differentiated in the presence of DNA demethylating agent 5-aza-2'-deoxycytidine into mature tumor-derived APCs, which could be used for cancer immunotherapy.

Many cancers are known to produce high amounts of PGE2, which is involved in both tumor progression and tumor-induced immune dysfunction. The key enzyme responsible for the biological inactivation of PGE2 in tissue is NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). It is well established that cancer cells frequently show down-regulated expression of 15-PGDH, which plays a major role in catabolism of the PGE2. Here we demonstrate that tumor-infiltrated CD11b cells are also deficient for the 15-PGDH gene. Targeted adenovirus-mediated delivery of 15-PGDH gene resulted in substantial inhibition of tumor growth in mice with implanted CT-26 colon carcinomas. PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE2, IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80+ tumor-associated macrophages (TAM) into M1-oriented CD11c+ MHC class II-positive myeloid APCs. Notably, the administration of the 15-PGDH gene alone demonstrated a significant therapeutic effect promoting tumor eradication and long-term survival in 70% of mice with preestablished tumors. Surviving mice acquired antitumor T cell-mediated immune response. This study for the first time demonstrates an important role of the 15-PGDH in regulation of local antitumor immune response and highlights the potential to be implemented to enhance the efficacy of cancer therapy and immunotherapy.

OBJECTIVE To develop and apply a standardized evaluation form for assessing the methodological and reporting quality of observational studies of surgical interventions in urology. METHODS An evaluation standard was developed using the Consolidated Standards for Reporting Trials statement and previously reported surgical reporting quality instruments. Consensus scoring among three reviewers was developed using two distinct sets of studies. All comparative observational trials involving therapeutic surgical procedures published in four major urological journals in 1995 and 2005 were randomly assigned to each reviewer. Categories of reporting adequacy included background, intervention, statistical analysis, results and discussion. RESULTS Twenty-seven articles in 1995 and 62 in 2005 met the inclusion criteria; 90% of studies were retrospective. From 1995 to 2005, the overall reporting quality score increased by 3.9 points (95% confidence interval, CI, 2.7–5.9; P = 0.001), from a mean (sd) of 19.1 (3.9) to 23.0 (4.2) on a scale of 0–42. There were significant improvements in the reporting categories of study background (+0.7 points, 95% CI 0.1–1.3, P = 0.043, 0–8-point scale), intervention (+1.6 points, 0.8–2.3, P = 0.001, 0–9-point scale), and statistical analysis (+0.8 points, 0.2–1.4, P = 0.006, 0–9-point scale). There were smaller and statistically insignificant improvements for results (+0.5 points, −0.3 to 1.2, P = 0.217, 0–10-point scale) and discussion reporting (+0.4 points, −0.1 to 0.8, P = 0.106, 0–6-point scale). CONCLUSIONS There have been minor improvements in the reporting of observational studies of surgical intervention between 1995 and 2005. However, reporting quality remains suboptimal. Clinical investigators, reviewers and journal editors should continue to strive for transparent reporting of the observational studies representing the bulk of the clinical evidence for urological procedures.

Randomized controlled trials potentially provide the highest level of evidence to inform clinical decision making. Appropriate use of statistical methods is a critical aspect of all clinical research, including randomized controlled trials. We report the first formal evaluation to our knowledge of the statistical methods of randomized controlled trials published in the urological literature in 1996 and 2004.All human subjects randomized controlled trials published in 4 leading urology journals in 1996 and 2004 were identified for formal review. A standardized evaluation form was developed based on the Consolidated Standards of Reporting Trials statement. Each article was evaluated by 2 independent reviewers with formal training in research design and biostatistics who were blinded to study authors and institution. Discrepancies were settled by consensus.A total of 152 randomized controlled trials were reviewed (65 in 1996, 87 in 2004). The median sample size (IQR) per arm of parallel design randomized controlled trials published in 1996 and 2004 was 36 (11, 96) and 50 (26, 134) study subjects, respectively (p = 0.157). Sample size justifications were provided by 19% of studies in 1996 and 47% of studies in 2004 (p = 0.001). Of randomized controlled trials 16 (25%) vs 32 (37%) identified a single primary outcome variable (p = 0.110). Effect size estimates for primary or secondary outcome variables were provided by 5% vs 13% (p = 0.090) and the precision of the effect was detailed by 5% vs 10% of randomized controlled trials (p = 0.195).This formal review suggests that statistical analysis in urological randomized controlled trials has improved. However, considerable deficiencies remain. Ongoing education in applied statistics may further improve urological randomized controlled trial reporting.

The concept of levels of evidence is one of the guiding principles of evidence based clinical practice. It is based on the understanding that certain study designs are more likely to be affected by bias than others. We provide an assessment of the type and levels of evidence found in the urological literature.Three reviewers rated a random sample of 600 articles published in 4 major urology journals, including 300 each in 2000 and 2005. The level of evidence rating system was adapted from the Center of Evidence Based Medicine. Sample size was estimated to detect a relative increase in the proportion of studies that provided a high level of evidence (I and II combined) from 0.2 to 0.3 with 80% power.Of the 600 studies reviewed 60.3% addressed questions of therapy or prevention, 11.5% addressed etiology/harm, 11.3% addressed prognosis and 9.2% addressed diagnosis. The levels of evidence provided by these studies from I to IV were 5.3%, 10.3%, 9.8% and 74.5%, respectively. A high level of evidence was provided by 16.0% of studies in 2000 and by 15.3% in 2005 (p = 0.911).This study suggests that a majority of studies in the urological literature provide low levels of evidence that may not be well suited to guide clinical decision making. We propose that editors of leading urology journals should promote awareness for this guiding principle of evidence based clinical practice by providing a level of evidence designation with each published study.

We investigated the impact of nerve sparing technique on erectile function, urinary continence and health related quality of life after radical perineal prostatectomy using a validated self-assessment questionnaire.The Expanded Prostate Cancer Index Composite questionnaire was administered preoperatively and at defined intervals after surgery to 265 patients who underwent radical perineal prostatectomy at 2 institutions between January 2001 and December 2004. Of these patients 153 (57.7%) and 112 (42.3%) underwent nonnerve sparing and nerve sparing approaches, respectively. Kaplan-Meier analysis was used to determine time to recovery of erectile function (erections firm enough for intercourse) and urinary continence (0 pads per day).Median patient age was 60.6 years. Median followup was 15 months. In multivariate analysis preoperative erectile function (p = 0.005) and preservation of the neurovascular bundle (p = 0.018) were independent predictors of earlier recovery of erectile function, with hazard ratios of 2.3 (95% CI 1.2-4.6) and 4.0 (95% CI 1.5-10.3), respectively. Median time to recovery of urinary continence was 4.8 months in the nerve sparing group and 6.1 months in the nonnerve sparing group (p = 0.001). In multivariate analysis nerve sparing technique (p = 0.001, HR 1.4, 95% CI 1.1-1.9) and age (p = 0.012, HR 1.7, 95% CI 1.3-2.2) were independent predictors of recovery of continence.This analysis suggests that nerve sparing radical perineal prostatectomy is associated with improved recovery of urinary continence and favorable health related quality of life scores and, therefore, should be considered a viable alternative to other nerve sparing approaches.

We determined the potential influence of an early adopter bias in patients undergoing robot assisted laparoscopic prostatectomy.We compared baseline demographic, clinical and health related quality of life characteristics of patients undergoing 3 different surgical procedures for clinically localized prostate cancer following the introduction of robot assisted laparoscopic prostatectomy at our institution. Patients included in this analysis were participating in a prospective health related quality of life study using the SF-12(R) and Expanded Prostate Cancer Index Composite validated questionnaires.Of 402 patients 159 (39%) underwent robot assisted laparoscopic, 144 (36%) underwent radical perineal and 99 (25%) underwent radical retropubic prostatectomy. There were no statistically significant associations between procedure type and patient age (p = 0.267), race (p = 0.725), number of medical comorbidities (p = 0.490), income (p = 0.056) and level of education (p = 0.495). Mean prostate specific antigen was 5.9 +/- 3.3, 7.3 +/- 5.5 and 5.7 +/- 5.0 ng/ml for robot assisted laparoscopic, radical perineal and radical retropubic prostatectomy, respectively (p = 0.030). The proportion of robot assisted laparoscopic, radical perineal and radical retropubic prostatectomy patients with a final Gleason score of 4-6 was 55%, 45% and 39%, respectively (p = 0.037). The proportion of robot assisted laparoscopic, radical perineal and radical retropubic prostatectomy patients with stage T2 disease was 91%, 68% and 80%, respectively (p = 0.001). Statistically significant associations of higher income and education with higher baseline health related quality of life scores were seen in the sexual and physical domains (each p0.01).We failed to find evidence of an early adopter bias for patients undergoing robot assisted laparoscopic prostatectomy. Nevertheless, observational studies comparing robot assisted laparoscopic prostatectomy to radical perineal and radical retropubic prostatectomy should account carefully for patient baseline characteristics to allow meaningful comparisons of surgical outcomes.

Many abstracts presented at scientific meetings never come to full text publication, which is a prerequisite for the critical appraisal of a given study for its validity, impact and generalizability. We determined factors associated with the publication of abstracts presented at the American Urological Association national meeting.All abstracts addressing clinical research accepted for presentation at the 2002 and 2003 meetings of the American Urological Association were reviewed. A comprehensive MEDLINE search was performed for evidence of publication in full manuscript form. Data abstraction and literature searches were done between June 15 and August 30, 2005. Univariate and multivariate analyses were performed to determine the association between abstract characteristics and time to publication.Of the 1,683 abstracts reviewed 740 (44.0%) were published within a median followup of 27.8 months (range 25.9 to 39.7). Time to publication was associated with abstract origin in the United States and the reporting of statistical testing (HR 1.2, 95% CI 1.0-1.4, p=0.040 and HR 1.2, 95% CI 1.1-1.4, p=0.010, respectively). Other variables, such as presentation type, study design, clinical question type and negative outcome, were not predictive.Nonpublication of research findings is a problematic issue that affects more than half of studies 2 years after presentation at the American Urological Association national meeting. Abstracts from the United States and those providing statistical testing were more likely to be published in full text form. Further efforts are warranted to identify and eliminate factors that hinder publication of research to bring it to the scrutiny of a broad audience of urologists.

In murine and human hyperoxaluric conditions macrophages can be seen surrounding renal calcium oxalate crystal deposits. We hypothesized that macrophages have a role in degrading and destroying these deposits. We investigated the inflammatory response and phagocytic mechanisms when macrophages were exposed to human kidney stones and inorganic crystals.Human monocytes were differentiated into resting, fully differentiated macrophages by treatment with recombinant human macrophage colony-stimulating factor (M-CSF) or GM-CSF (granulocyte M-CSF) for 6 days. After confirming phenotype by flow cytometry the macrophages were exposed for 20 hours to fragments of sterile human calcium oxalate stones or calcium oxalate crystals. Crystal uptake was determined, and supernatant cytokine and chemokine profiles were analyzed using antibody arrays. Quantitative reverse transcriptase-polymerase chain reaction was done to validate mRNA profile expression.Under direct vision fluorescence microscopy activated human macrophages were noted to surround stone fragments and synthesized crystals, and destroy them in a step-by-step process that involved clathrin mediated endocytosis and phagocytosis. An inflammatory cascade was released by macrophages, including the chemokines chemokine ligand (CCL)2, CCL3, interleukin (IL)-1 receptor antagonist (IL-1ra), complement component C5/C5a and IL-8. Response patterns to stone and crystal material depended on macrophage phenotype and activation status.In our in vitro study macrophages differentiated with M-CSF showed greater ability to phagocytize crystal deposits than those treated with GM-CSF. Following clathrin mediated endocytosis macrophages released a number of cytokines that are crucial for the inflammatory immune response. This suggests that tissue macrophages have an important role in preventing kidney stone disease by removing and digesting interstitial renal crystal deposits.

Objectives To compare the perioperative outcomes of severely obese and nonobese patients undergoing radical perineal prostatectomy (RPP). Methods A cohort of 71 severely obese patients, as defined by a body mass index of 35 kg/m 2 or more, who underwent RPP between 1992 and 2003 was retrospectively identified. These patients were matched by age, American Society of Anesthesiologists class, and year of surgery to a cohort of 71 nonobese patients (body mass index less than 25 kg/m 2 ). Statistical testing was performed to compare the estimated blood loss, transfusion requirements, and complication rates (primary endpoints), as well as the length of surgery, intraoperative anesthesia requirements, postoperative hematocrit level, length of stay, and surgical margin status (secondary endpoints). Results The mean body mass index ± standard deviation of patients in the obese and nonobese group was 38.9 ± 4.7 and 22.9 ± 1.6 kg/m 2 ( P = 0.001), respectively. Patients were similar with regard to baseline characteristics. Obese and nonobese patients did not demonstrate significant differences in mean estimated blood loss (571 ± 391 and 494 ± 317 mL, respectively; P = 0.06), transfusion rates (2.8% and 7.0%, respectively; P = 0.45), or positive surgical margin rates (14.1% and 9.9%, respectively; P = 0.22). The overall complication rates were significantly different at 16.9% and 7.0% ( P = 0.03). Conclusions Severely obese patients undergoing RPP had blood transfusion rates similar to those of the nonobese patients. Obese RPP patients were at increased risk of surgical and anesthesia-related perioperative complications, many of which might be avoidable. Specifically, efforts should be directed toward preventing the development of lower extremity neurapraxia by minimizing the operative time and optimizing patient positioning.

Telomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. A clinical trial was initiated in which hTERT mRNA-transfected dendritic cells (DC) were administered to 20 patients with metastatic prostate cancer. Nine of these subjects received DC transfected with mRNA encoding a chimeric lysosome-associated membrane protein-1 (LAMP) hTERT protein, allowing for concomitant induction of hTERT-specific CD8+ and CD4+ T cell responses. Treatment was well tolerated. Intense infiltrates of hTERT-specific T cells were noted at intradermal injection sites after repeated vaccination. In 19 of 20 subjects, expansion of hTERT-specific CD8+ T cells was measured in the peripheral blood of study subjects, with 0.9–1.8% of CD8+ T cells exhibiting Ag specificity. Patients immunized with the chimeric LAMP hTERT vaccine developed significantly higher frequencies of hTERT-specific CD4+ T cells than subjects receiving DC transfected with the unmodified hTERT template. Moreover, CTL-mediated killing of hTERT targets was enhanced in the LAMP hTERT group, suggesting that an improved CD4+ response could augment a CTL response. Vaccination was further associated with a reduction of prostate-specific Ag velocity and molecular clearance of circulating micrometastases. Our findings provide a rationale for further development of hTERT-transfected DC vaccines in the treatment of prostate and other cancers.

The lack of effective therapies for advanced prostate cancer mandates continued development of alternative treatment strategies. Insights into the regulation of immune responses and the malignant process have facilitated the emergence of new immune-based strategies, currently under investigation in clinical trials. Like other forms of targeted therapy, cancer vaccines hold the promise of achieving cancer control without inducing overt toxicity. Many prostate cancer vaccines at different phases of development have been tested in clinical trials. Vaccination strategies under consideration include: immunization with defined antigenic preparations such as synthetic peptides, proteins or plasmid DNA; antigen-loaded dendritic cells; manipulated tumor cells; or with viral vectors engineered to express immunogenic genes. Although the underlying mechanisms of immunization may vary, all strategies share the common goal of eliciting immune responses against prostate tumor-associated antigens or of enhancing an otherwise weak antitumor response in the cancer patient. Unlocking the therapeutic potential of cancer vaccines will require a thorough understanding of cellular and molecular mechanisms that modulate the immune response. In this review, we provide an overview of vaccine-based strategies for prostate cancer therapy, discuss their mechanisms of action, and provide relevant clinical trial data.

The discovery that dendritic cells (DC) play a key role in regulating antitumor immunity has prompted considerable efforts in developing DC-based cancer vaccines for use in clinical oncology. Early translational trials using antigen-loaded DC have established clear evidence of vaccine safety, and demonstrated bioactivity by stimulating immunological and even clinical responses in selected subjects. Despite these encouraging results, the vaccine-induced immune responses achieved to date are not yet sufficient to attain a robust and durable therapeutic effect in the cancer patient. Therefore, further improvements are required to enhance vaccine potency and optimize the potential for clinical success. This article presents a set of emerging concepts that, together, form a framework for a multi-pronged approach that will further enhance the efficacy of DC-based vaccination by either directly improving DC-mediated T cell activation or by inhibiting mechanisms that suppress the induction of an effective antitumor response. The clinical translation of these concepts will result in new opportunities to successfully modulate immune responses in clinical settings.

The appropriate management of elderly patients diagnosed with prostate cancer remains controversial. In order to provide guidelines as to when aggressive local treatment may be indicated, we provide estimates of the long-term probability of death from prostate cancer and other competing causes in patients of 70 years of age or older, who underwent radical surgery in the form of radical perineal prostatectomy for clinically non-metastatic disease. In this study, a total of 484 patients with an age of 70 or above who underwent radical perineal prostatectomy between 1970 and 2000 comprised a retrospective cohort of patients with clinically organ confined prostate cancer. Of these patients, 461 patients (95.3%) had a minimum follow-up of half a year and were included in the analysis. The median age was 73 years (range 70-81 years) and the median follow-up was 5.4 years. Overall 115 men died during the follow-up period with 49.6% of deaths attributable to prostate cancer. The median time to cancer-associated death was 17.5 years and the median time to death of any cause 11.6 years. When the likelihood of death from prostate cancer as a function of Gleason score was estimated, the 10-year cancer-associated death rates of patients with Gleason scores of 2-6, 7 and 8-10, were 15.2, 25.2 and 40.2%, respectively. In the subset of patient with margin positive disease the estimated likelihood of a cancer-associated death was 45.3% after 10 years. While the median time to cancer-associated death for margin positive patients with a Gleason score of 2-6 was not reached, patients with a Gleason score of 7 and 8-10 experienced median cancer-associated survival times of 9.6 and 7.6 years, respectively. In conclusion, Gleason score is a strong predictor of the likelihood of prostate cancer related death in elderly patients. Patients with a given Gleason score and a projected life expectancy of at least 10 years may be at similar risk of dying of prostate cancer as younger patients.

Objectives To perform a study to quantify the variables relating to postoperative pain, activity, and gastrointestinal function after radical perineal prostatectomy to allow comparisons with alternative treatments. Methods Ninety-eight consecutive radical perineal prostatectomy candidates between January 2001 and December 2001 with clinically localized prostate cancer were prospectively evaluated. The time to tolerate solid food, time to unassisted ambulation, postoperative pain levels (analog pain scale of 1 to 10), and perioperative analgesic requirements (in morphine equivalents) were selected as the analysis endpoints and correlated with preoperative (age, American Society of Anesthesiology class, body mass index, and serum prostate-specific antigen level), intraoperative (node dissection, operating room time, and estimated blood loss), and postoperative (Gleason score, tumor stage, and lower extremity neurapraxia) patient variables. Results The mean time to tolerate solid food and unassisted ambulation was 21.2 ± 1.4 and 22.4 ± 0.8 hours, respectively; 25.5% of patients experienced transient lower extremity neurapraxia, which was associated with longer operative times ( P = 0.001). In a multivariate regression analysis, lymph node dissection correlated with both a prolonged time to tolerate solid food ( P = 0.002) and unassisted ambulation ( P = 0.001) and neurapraxia with an extended time to unassisted ambulation ( P = 0.018). The narcotic requirements were greatest on postoperative day 1, totaling 31.7 ± 3.0 morphine equivalents, of which 90.5% ± 3.1% were met with oral analgesics. The average maximal pain scores were highest the first week after discharge (4.7 ± 0.3), yet approached baseline levels by 4 weeks (1.7 ± 0.2) after surgery at which time no patient required any pain medication. Conclusions Modern radical perineal prostatectomy offers a favorable outcome profile with early patient recovery and low narcotic requirements. A future prospective study should directly compare radical perineal, retropubic, and laparoscopic prostatectomy to document whether the latter offers any advantages with respect to these outcome parameters.

This study tested the hypothesis that combination of antiangiogenic therapy and tumor immunotherapy of cancer is synergistic. To inhibit angiogenesis, mice were immunized with dendritic cells (DCs) transfected with mRNA that encode products that are preferentially expressed during neoangiogenesis: vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie2 expressed in proliferating endothelial cells, and vascular endothelial growth factor (VEGF) expressed in the angiogenic stroma as well as the tumor cells used in this study. Immunization of mice against VEGF or VEGFR-2 stimulated cytotoxic T lymphocyte (CTL) responses and led to partial inhibition of angiogenesis. Antiangiogenic immunity was not associated with morbidity or mortality except for a transient impact on fertility seen in mice immunized against VEGFR-2, but not VEGF. Tumor growth was significantly inhibited in mice immunized against VEGF, VEGFR-2, and Tie2, either before tumor challenge or in the setting of pre-existing disease in murine B16/F10.9 melanoma and MBT-2 bladder tumor models. Coimmunization of mice against VEGFR-2 or Tie2 and total tumor RNA exhibited a synergistic antitumor effect. Synergism was also observed when mice were coimmunized with various combinations of defined tumor-expressed antigens, telomerase reverse transcriptase (TERT) or TRP-2, and VEGF or VEGFR-2. This study shows that coimmunizing mice against angiogenesis-associated and tumor-expressed antigens can deliver 2 compatible and synergistic cancer treatment modalities via a common treatment, namely immunization.

Gene-modified tumor cells have been employed in a vaccination setting to trigger therapeutic antitumor immunity against metastatic renal cell carcinoma. Recent studies suggest that dendritic cells may be even more potent, because these cells can efficiently present tumor antigens to effector T cells, thereby circumventing the poor antigen-presenting properties of tumor cells. Proof of concept studies using antigen-loaded dendritic cells have been performed, establishing clear evidence of vaccine safety and bioactivity by stimulating immunologic and even clinical responses in cancer patients. Nevertheless, key aspects of such vaccination remain undefined. The critical challenge remains to understand fully the mechanisms of action and to further optimize dendritic cell vaccines to produce effective, durable, and, ultimately, therapeutic antitumor responses.

Recent studies have suggested an increased incidence of fecal incontinence following radical perineal prostatectomy. We provide a prospective and longitudinal assessment of bowel related symptoms of patients undergoing radical perineal prostatectomy.A total of 78 patients who underwent radical perineal prostatectomy between January 1 and December 31, 2001 and had a minimal followup of 6 months were included in the analysis. Patient information was obtained from the chart and the bowel domain specific questions of a validated quality of life questionnaire, the Expanded Prostate Cancer Index Composite. The questionnaire was administered to the candidates preoperatively, at 4 weeks following surgery and subsequently at 3-months intervals. A mean bowel function, bother and summary health related quality of life score was calculated at each interval. The duration of new or worsened symptoms with respect to baseline was evaluated using Kaplan-Meier analysis.Symptoms of involuntary stool leakage and rectal urgency were reported by 11.5% (9 of 78) and 19.2% (15) of patients preoperatively. While all bowel related symptoms transiently increased following surgery, rectal urgency was the most persistent symptom, yet normalized in more than 90% of patients within 9 1/2 months. Compared to individual baseline 15.4%, 7.7%, 5.1% and 3.9% of patients reported worsened symptoms of fecal incontinence after 3, 6, 9 and 12 months, respectively. In the subset of 69 patients who denied preoperative fecal incontinence the incidence of involuntary stool leakage was 2.9% by 12 months following radical perineal prostatectomy. Of 10 patients 9 recovered individual health related quality of life score by 6 months after prostatectomy.Longitudinal assessment of self-reported questionnaire data suggests that fecal incontinence and bowel related symptoms are more prevalent following radical perineal prostatectomy compared to baseline, yet resolve in the majority of patients with time in the early postoperative period.

To establish a model for preoperative counseling and postoperative outcome in patients who choose radical perineal prostatectomy for the clinically localized prostatic malignancy, the following postulates have been identified: (1) the use of preoperative prostate specific antigen (PSA) and Gleason Sum at the time of biopsy can be used to segregate the outcome among patients with Gleason Sum 2 through 6, 7, and 8 through 10. (2) Postoperative PSA levels are excellent surrogate endpoints for defining disease control. (3) The biology of the primary malignancy defines the interval of death after recurrence. A total of 1242 men with the median age of 65.2 years who had Stage cT 1-2 NOMO disease underwent radical perineal prostatectomy. The final pathologic specimen was characterized with regard to disease extent and Gleason Sum. Patients were followed at 2 weeks, 2 months, and then at 6-month intervals for biochemical, physical, and radiographic evidence of disease recurrence. Outcome was evaluated by determining time to biochemical failure (PSA 0.5 ng/ml or greater) or cancer associated death (death with a detectable PSA independent of treatment). Median time to non-cancer death was 19.3 years. Median cancer-associated death endpoints were not reached by patients with organ confined disease. Results were 17.7 years for specimen confined disease and 12.7 years for margin positive disease. At 5 years, 8, 35, and 65% of patients with organ confined, specimen confined, or margin positive disease, respectively, had PSA failure. This served as an excellent surrogate endpoint, preceding cancer associated death by 5-12 years, depending on the biological aggressiveness predicted by Gleason Sum. When segregated by Gleason Sum 2 through 6, 7 or 8 through 10 at the time of biopsy, there was a distinct differentiation in survival among these Gleason Sum classifications according to the PSA at the time of biopsy. This study confirms our postulates and provides guidelines for preparing different therapies among institutions. It also emphasizes that enthusiasm for new treatments may be based on insufficient follow-up. PSA is an excellent surrogate endpoint and it is valuable in segregating patients prior to therapeutic selection and predicting outcome.

Autologous dendritic cells (DCs) transfected with mRNA encoding prostate-specific antigen (PSA) are able to stimulate potent, T cell-mediated antitumor immune responses in vitro. A phase I trial was performed to evaluate this strategy for safety, feasibility, and efficacy to induce T cell responses against the self-protein PSA in patients with metastatic prostate cancer. In 13 study subjects, escalating doses of PSA mRNA-transfected DCs were administered with no evidence of dose-limiting toxicity or adverse effects, including autoimmunity. Induction of PSA-specific T cell responses was consistently detected in all patients, suggesting in vivo bioactivity of the vaccine. Vaccination was further associated with a significant decrease in the log slope PSA in six of seven subjects; three patients that could be analyzed exhibited a transient molecular clearance of circulating tumor cells. The demonstration of vaccine safety, successful in vivo induction of PSA-specific immunity, and impact on surrogate clinical endpoints provides a scientific rationale for further clinical investigation of RNA-transfected DCs in the treatment of human cancer.