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Urological Oncology: Testis Cancer
1994
TESTIS CANCER
Cost-Effectiveness of Fracture Prevention in Men Who Receive Androgen Deprivation Therapy for Localized Prostate Cancer K. Ito, E. B. Elkin, M. Girotra and M. J. Morris Memorial Sloan-Kettering Cancer Center, New York, New York Ann Intern Med 2010; 152: 621– 629.
Background: Androgen deprivation therapy (ADT) increases the risk for fractures in patients with prostate cancer. Objective: To assess the cost-effectiveness of measuring bone mineral density (BMD) before initiating ADT followed by alendronate therapy in men with localized prostate cancer. Design: Markov state-transition model simulating the progression of prostate cancer and the incidence of hip fracture. Data Sources: Published literature. Target Population: A hypothetical cohort of men aged 70 years with locally advanced or high-risk localized prostate cancer starting a 2-year course of ADT after radiation therapy. Time Horizon: Lifetime. Perspective: Societal. Intervention: No BMD test or alendronate therapy, a BMD test followed by selective alendronate therapy for patients with osteoporosis, or universal alendronate therapy without a BMD test. Outcome Measures: Incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained. Results of Base-case Analysis: The ICERs for the strategy of a BMD test and selective alendronate therapy for patients with osteoporosis and universal alendronate therapy without a BMD test were $66,800 per QALY gained and $178,700 per QALY gained, respectively. Results of Sensitivity Analyses: The ICER for universal alendronate therapy without a BMD test decreased to $100,000 per QALY gained, assuming older age, a history of fractures, lower mean BMD before ADT, or a lower cost of alendronate. Limitations: No evidence shows that alendronate reduces actual fracture rates in patients with prostate cancer who receive ADT. The model predicted fracture rates by using data on the surrogate BMD end point. Conclusion: In patients starting adjuvant ADT for locally advanced or high-risk localized prostate cancer, a BMD test followed by selective alendronate for those with osteoporosis is a cost-effective use of resources. Routine use of alendronate without a BMD test is justifiable in patients at higher risk for hip fractures. Editorial Comment: This well-done cost-effectiveness analysis underscores the need for urologists to become more cognizant of bone health in their patients with prostate cancer. Most urologists do not prescribe bisphosphonates in their patients with prostate cancer, nor do they routinely assess bone mineral density. This study clearly documents that a strategy of BMD testing and alendronate treatment in men with osteoporosis is costeffective. More importantly the base case is not an individual with metastatic disease, but rather one receiving 2 years of adjuvant hormone ablation following radiotherapy. Urologists need to be aware of this study, and need to consider BMD testing and appropriate treatment in their patients with prostate cancer who will undergo androgen ablation, even if it will be for only 1 to 2 years. David F. Penson, MD., M.P.H.
Urological Oncology: Testis Cancer Genome-Wide DNA Methylation Profiling Reveals Novel Epigenetically Regulated Genes and Non-Coding RNAs in Human Testicular Cancer H. H. Cheung, T. L. Lee, A. J. Davis, D. H. Taft, O. M. Rennert and W. Y. Chan Laboratory of Clinical Genomics, Section on Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Br J Cancer 2010; 102: 419 – 427.
Background: Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males. Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited
BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY
number of genes are known to be epigenetically changed in TGCT. This report documents the genomewide analysis of differential methylation in an in vitro model culture system. Interesting genes were validated in TGCT patient samples. Methods: In this study, we used methylated DNA immunoprecipitation (MeDIP) and whole-genome tiling arrays to identify differentially methylated regions (DMRs). Results: We identified 35 208 DMRs. However, only a small number of DMRs mapped to promoters. A genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. We identified several candidate genes, including APOLD1, PCDH10 and RGAG1, which were dysregulated in TGCT patient samples. Surprisingly, APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. We also observed aberrant methylation in the loci of some non-coding RNAs (ncRNAs). One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples, and also in our in vitro model culture system. Conclusion: This report is the first application of MeDIP-chip for identifying epigenetically regulated genes and ncRNAs in TGCT. We also demonstrated the function of intergenic and intronic DMRs in the regulation of ncRNAs. Editorial Comment: Aberrant methylation of tumor suppressor genes provides information concerning the epigenetic role in tumor development. The initial genome wide studies of DNA methylation testicular tumors used restriction landmark genome scanning. Newer techniques such as global high resolution analysis of methylation changes have not been published in testicular germ cell tumors. Tiling array technology permits elucidation of differentially methylated regions of the whole genome. The authors applied a popular chip based method of methylated DNA immunoprecipitation with the use of antibodies hybridized to custom arrays. This method represents a powerful tool for identification of differentially methylated genes. Several candidate genes were identified, the most important of which was APOLD1. This gene has previously been mapped to the testicular germ cell tumor susceptibility locus at 12p13.1. Additional epigenetically regulated genes and noncoding RNAs were identified as well. This report represents the initial application of a new chip technology for identifying epigenetically regulated genes in testicular tumors. Jerome P. Richie, M.D.
Bladder, Penis and Urethral Cancer, and Basic Principles of Oncology The Impact of Improving Outcomes Guidance on the Management and Outcomes of Patients With Carcinoma of the Penis A. C. Bayles and K. K. Sethia Department of Urology, Norfolk and Norwich University NHS Trust, Norwich, United Kingdom Ann R Coll Surg Engl 2010; 92: 44 – 45.
Introduction: The Improving Outcomes Guidance (IOG) for patients with carcinoma of the penis states that treatment should be provided supraregionally to populations of 4 million or greater who treat over 25 cases of penis cancer each year. This study assesses the impact of this guidance on the management and outcomes of patients with the disease in our region. Patients and Methods: We retrospectively compared the records of 44 patients with carcinoma of the penis treated in our institution between 1969 and 1990 with 101 patients treated between 2002 and 2006, i.e. after supraregional centralisation of the service. Results: There was no significant change in the stage or grade of the tumours. However, the results show that, in modern times, there was a significant increase in the amount of penis-preserving and nodal surgery as well as a fall in mortality. The improved survival is greatest in patients with poorly-differen-
1995
TESTIS CANCER
Cost-Effectiveness of Fracture Prevention in Men Who Receive Androgen Deprivation Therapy for Localized Prostate Cancer K. Ito, E. B. Elkin, M. Girotra and M. J. Morris Memorial Sloan-Kettering Cancer Center, New York, New York Ann Intern Med 2010; 152: 621– 629.
Background: Androgen deprivation therapy (ADT) increases the risk for fractures in patients with prostate cancer. Objective: To assess the cost-effectiveness of measuring bone mineral density (BMD) before initiating ADT followed by alendronate therapy in men with localized prostate cancer. Design: Markov state-transition model simulating the progression of prostate cancer and the incidence of hip fracture. Data Sources: Published literature. Target Population: A hypothetical cohort of men aged 70 years with locally advanced or high-risk localized prostate cancer starting a 2-year course of ADT after radiation therapy. Time Horizon: Lifetime. Perspective: Societal. Intervention: No BMD test or alendronate therapy, a BMD test followed by selective alendronate therapy for patients with osteoporosis, or universal alendronate therapy without a BMD test. Outcome Measures: Incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained. Results of Base-case Analysis: The ICERs for the strategy of a BMD test and selective alendronate therapy for patients with osteoporosis and universal alendronate therapy without a BMD test were $66,800 per QALY gained and $178,700 per QALY gained, respectively. Results of Sensitivity Analyses: The ICER for universal alendronate therapy without a BMD test decreased to $100,000 per QALY gained, assuming older age, a history of fractures, lower mean BMD before ADT, or a lower cost of alendronate. Limitations: No evidence shows that alendronate reduces actual fracture rates in patients with prostate cancer who receive ADT. The model predicted fracture rates by using data on the surrogate BMD end point. Conclusion: In patients starting adjuvant ADT for locally advanced or high-risk localized prostate cancer, a BMD test followed by selective alendronate for those with osteoporosis is a cost-effective use of resources. Routine use of alendronate without a BMD test is justifiable in patients at higher risk for hip fractures. Editorial Comment: This well-done cost-effectiveness analysis underscores the need for urologists to become more cognizant of bone health in their patients with prostate cancer. Most urologists do not prescribe bisphosphonates in their patients with prostate cancer, nor do they routinely assess bone mineral density. This study clearly documents that a strategy of BMD testing and alendronate treatment in men with osteoporosis is costeffective. More importantly the base case is not an individual with metastatic disease, but rather one receiving 2 years of adjuvant hormone ablation following radiotherapy. Urologists need to be aware of this study, and need to consider BMD testing and appropriate treatment in their patients with prostate cancer who will undergo androgen ablation, even if it will be for only 1 to 2 years. David F. Penson, MD., M.P.H.
Urological Oncology: Testis Cancer Genome-Wide DNA Methylation Profiling Reveals Novel Epigenetically Regulated Genes and Non-Coding RNAs in Human Testicular Cancer H. H. Cheung, T. L. Lee, A. J. Davis, D. H. Taft, O. M. Rennert and W. Y. Chan Laboratory of Clinical Genomics, Section on Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Br J Cancer 2010; 102: 419 – 427.
Background: Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males. Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited
BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY
number of genes are known to be epigenetically changed in TGCT. This report documents the genomewide analysis of differential methylation in an in vitro model culture system. Interesting genes were validated in TGCT patient samples. Methods: In this study, we used methylated DNA immunoprecipitation (MeDIP) and whole-genome tiling arrays to identify differentially methylated regions (DMRs). Results: We identified 35 208 DMRs. However, only a small number of DMRs mapped to promoters. A genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. We identified several candidate genes, including APOLD1, PCDH10 and RGAG1, which were dysregulated in TGCT patient samples. Surprisingly, APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. We also observed aberrant methylation in the loci of some non-coding RNAs (ncRNAs). One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples, and also in our in vitro model culture system. Conclusion: This report is the first application of MeDIP-chip for identifying epigenetically regulated genes and ncRNAs in TGCT. We also demonstrated the function of intergenic and intronic DMRs in the regulation of ncRNAs. Editorial Comment: Aberrant methylation of tumor suppressor genes provides information concerning the epigenetic role in tumor development. The initial genome wide studies of DNA methylation testicular tumors used restriction landmark genome scanning. Newer techniques such as global high resolution analysis of methylation changes have not been published in testicular germ cell tumors. Tiling array technology permits elucidation of differentially methylated regions of the whole genome. The authors applied a popular chip based method of methylated DNA immunoprecipitation with the use of antibodies hybridized to custom arrays. This method represents a powerful tool for identification of differentially methylated genes. Several candidate genes were identified, the most important of which was APOLD1. This gene has previously been mapped to the testicular germ cell tumor susceptibility locus at 12p13.1. Additional epigenetically regulated genes and noncoding RNAs were identified as well. This report represents the initial application of a new chip technology for identifying epigenetically regulated genes in testicular tumors. Jerome P. Richie, M.D.
Bladder, Penis and Urethral Cancer, and Basic Principles of Oncology The Impact of Improving Outcomes Guidance on the Management and Outcomes of Patients With Carcinoma of the Penis A. C. Bayles and K. K. Sethia Department of Urology, Norfolk and Norwich University NHS Trust, Norwich, United Kingdom Ann R Coll Surg Engl 2010; 92: 44 – 45.
Introduction: The Improving Outcomes Guidance (IOG) for patients with carcinoma of the penis states that treatment should be provided supraregionally to populations of 4 million or greater who treat over 25 cases of penis cancer each year. This study assesses the impact of this guidance on the management and outcomes of patients with the disease in our region. Patients and Methods: We retrospectively compared the records of 44 patients with carcinoma of the penis treated in our institution between 1969 and 1990 with 101 patients treated between 2002 and 2006, i.e. after supraregional centralisation of the service. Results: There was no significant change in the stage or grade of the tumours. However, the results show that, in modern times, there was a significant increase in the amount of penis-preserving and nodal surgery as well as a fall in mortality. The improved survival is greatest in patients with poorly-differen-
1995