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hypogastric and pelvic nerves by both the SNS (innervates stromal smooth muscle cells), which causes discharge of prostatic secretions, and the PNS (innervates epithelial secretory cells), which is responsible for secretions. The role of neural innervation of the prostate gland in its growth and maintenance is well known, but the function of this innervation in PCa initiation and dissemination was poorly understood until recently. A few studies have reported on evidence linking the involvement of nerves to cancer growth and progression. Perineural invasion—the process by which tumor cells invade around nerves—and its correlation with poor prognosis and increased density in prostatic preneoplastic and neoplastic lesions are well known [1]. In analogy to neoangiogenesis, which is vascularization of tumors due to release of angiogenic factors and recently postulated lymphangiogenesis, cancer-related axonogenesis and neoneurogenesis were proposed [2]. The role of nerves in PCa is further reinforced by studies demonstrating that patients with spinal cord injury rarely develop PCa [3]. These new findings raise the possibility of new pharmaceuticals targeting neoneurogenic processes as useful therapies for PCa. This idea is further substantiated by evidence provided by epidemiologic studies demonstrating that PCa patients on b-blockers have low mortality [4]. Designing new drugs to specifically target these b-receptors will not be trivial, however, as these receptors are involved in a wide array of vital processes. These insights, along with a much more clear understanding of how neurostimulation leads to different stages of PCa, may help us in determining the appropriate timing for drugbased therapies to disrupt the neoneurogenic mechanisms involved in the development and progression of PCa.
Re: Punctuated Evolution of Prostate Cancer Genomes Baca SC, Prandi D, Lawrence MS, et al. Cell 2013;153:666–77 Experts’ summary: The authors profiled 57 prostate cancer (PCa) samples using next-generation whole-genome sequencing (WGS) and highthroughput single-nucleotide polymorphism microarray technologies to map somatic DNA alterations associated with PCa initiation and progression. They discovered characteristic distributions of DNA break points and translocations, resulting in a computational model of complex genomic restructuring. The restructuring event is characterized by a high frequency of interchromosomal deletions resulting in an interdependent and coordinated chain of translocations, termed chromoplexy by the authors. This phenomenon was found in 88% of tumors, affecting well-known oncogenes and tumor suppressors across the genome. The model illustrates a sequence of tumorigenic events during tumor initiation and progression in which few early, mostly clonal genomic lesions accumulate in a chain. Subsequently, this results in mostly subclonal genomic lesions. The punctuated evolution described before transforms cells into incipient
Conflicts of interest: Ashutosh Tewari is the principal investigator on research grants from Intuitive Surgical, Inc. (Sunnyvale, CA, USA), th Prostate Cancer Foundation, and Boston Scientific Corporation. He is a noncompensated director of the Prostate Cancer Institute (Pune, India) and the Global Prostate Cancer Research Foundation. He has received research funding from the Prostate Cancer Foundation, The LeFrak Family Foundation, Mr. and Mrs. Paul Kanavos, Craig Effron & Company, Charles Evans Foundation, and Christian and Heidi Lange Family Foundation.
References [1] DeLancey JO, Wood Jr DP, He C, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology 2013;81:354–7. [2] Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol 2007;25:4298–307. [3] Patel N, Ngo K, Hastings J, Ketchum N, Sepahpanah F. Prevalence of prostate cancer in patients with chronic spinal cord injury. PM R 2011;3:633–6. [4] Grytli HH, Fagerland MW, Fossa˚ SD, Taske´n KA, Ha˚heim LL. Use of b-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 2013;73:250–60.
Adnan Ali, Sailaja Pisipati, Ashutosh Tewari* Center for Prostate Cancer, Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA *Corresponding author. Weill Cornell Medical College, New York Presbyterian Hospital, 525 East 68th Street, Starr 900, New York, NY 10021, USA. E-mail address: [email protected] (A. Tewari). http://dx.doi.org/10.1016/j.eururo.2013.11.021
cancer cells and provides them with survival advantages. Therefore, the authors introduced a model for PCa evolution that can be applied to other tumors. This clonal–subclonal hierarchy of coordinated, interdependent rearrangements and deletions occurring in multiple rounds of chromoplexy during tumor development represents an approach to mapping the accumulation of gene alterations.
Experts’ comments: Understanding the molecular basis of PCa is key to providing effective health care to patients. This knowledge has been facilitated by the rise of novel high-throughput genomeprofiling technologies in combination with chromoplexy. We believe that these tools might enable the subclassification of PCas based on their genomic profiles, thus tackling the problem of clinical and molecular PCa heterogeneity head on. This study further opens the door to subdividing PCa into relevant homogenous diseases based on molecular signatures. Such a classification may promote a concept of subgrouping and thus a group-specific treatment. The classification is likely to make it more feasible to identify genes representing ‘‘driver events’’ in a homogenous subgroup than in a large, heterogeneous disease. Such a
667
EUROPEAN UROLOGY 65 (2014) 665–670
classification enables the identification of distinct molecular alterations that may provide a subset of tumors with selective advantage. Additionally, the classification sheds light into early events that may render patients more susceptible to developing PCa and into the likelihood of aggressiveness. Together, WGS and the punctuated evolution model have the potential to be integrated into clinical practice. This development may support the clinician’s ability to identify patients at high risk of developing an aggressive disease and to diagnose, manage, and treat patients based on specific gene alterations.
Conflicts of interest: The authors have nothing to disclose.
Re: Pazopanib Versus Sunitinib in Metastatic Renal-cell Carcinoma Motzer RJ, Hutson TE, Cella D, et al.
as the upper bound of the 95% CI of the HR. In this trial, noninferiority was assumed if the upper bound of the 95% CI of the HR was
EUROPEAN UROLOGY 65 (2014) 665–670
hypogastric and pelvic nerves by both the SNS (innervates stromal smooth muscle cells), which causes discharge of prostatic secretions, and the PNS (innervates epithelial secretory cells), which is responsible for secretions. The role of neural innervation of the prostate gland in its growth and maintenance is well known, but the function of this innervation in PCa initiation and dissemination was poorly understood until recently. A few studies have reported on evidence linking the involvement of nerves to cancer growth and progression. Perineural invasion—the process by which tumor cells invade around nerves—and its correlation with poor prognosis and increased density in prostatic preneoplastic and neoplastic lesions are well known [1]. In analogy to neoangiogenesis, which is vascularization of tumors due to release of angiogenic factors and recently postulated lymphangiogenesis, cancer-related axonogenesis and neoneurogenesis were proposed [2]. The role of nerves in PCa is further reinforced by studies demonstrating that patients with spinal cord injury rarely develop PCa [3]. These new findings raise the possibility of new pharmaceuticals targeting neoneurogenic processes as useful therapies for PCa. This idea is further substantiated by evidence provided by epidemiologic studies demonstrating that PCa patients on b-blockers have low mortality [4]. Designing new drugs to specifically target these b-receptors will not be trivial, however, as these receptors are involved in a wide array of vital processes. These insights, along with a much more clear understanding of how neurostimulation leads to different stages of PCa, may help us in determining the appropriate timing for drugbased therapies to disrupt the neoneurogenic mechanisms involved in the development and progression of PCa.
Re: Punctuated Evolution of Prostate Cancer Genomes Baca SC, Prandi D, Lawrence MS, et al. Cell 2013;153:666–77 Experts’ summary: The authors profiled 57 prostate cancer (PCa) samples using next-generation whole-genome sequencing (WGS) and highthroughput single-nucleotide polymorphism microarray technologies to map somatic DNA alterations associated with PCa initiation and progression. They discovered characteristic distributions of DNA break points and translocations, resulting in a computational model of complex genomic restructuring. The restructuring event is characterized by a high frequency of interchromosomal deletions resulting in an interdependent and coordinated chain of translocations, termed chromoplexy by the authors. This phenomenon was found in 88% of tumors, affecting well-known oncogenes and tumor suppressors across the genome. The model illustrates a sequence of tumorigenic events during tumor initiation and progression in which few early, mostly clonal genomic lesions accumulate in a chain. Subsequently, this results in mostly subclonal genomic lesions. The punctuated evolution described before transforms cells into incipient
Conflicts of interest: Ashutosh Tewari is the principal investigator on research grants from Intuitive Surgical, Inc. (Sunnyvale, CA, USA), th Prostate Cancer Foundation, and Boston Scientific Corporation. He is a noncompensated director of the Prostate Cancer Institute (Pune, India) and the Global Prostate Cancer Research Foundation. He has received research funding from the Prostate Cancer Foundation, The LeFrak Family Foundation, Mr. and Mrs. Paul Kanavos, Craig Effron & Company, Charles Evans Foundation, and Christian and Heidi Lange Family Foundation.
References [1] DeLancey JO, Wood Jr DP, He C, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology 2013;81:354–7. [2] Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol 2007;25:4298–307. [3] Patel N, Ngo K, Hastings J, Ketchum N, Sepahpanah F. Prevalence of prostate cancer in patients with chronic spinal cord injury. PM R 2011;3:633–6. [4] Grytli HH, Fagerland MW, Fossa˚ SD, Taske´n KA, Ha˚heim LL. Use of b-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 2013;73:250–60.
Adnan Ali, Sailaja Pisipati, Ashutosh Tewari* Center for Prostate Cancer, Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA *Corresponding author. Weill Cornell Medical College, New York Presbyterian Hospital, 525 East 68th Street, Starr 900, New York, NY 10021, USA. E-mail address: [email protected] (A. Tewari). http://dx.doi.org/10.1016/j.eururo.2013.11.021
cancer cells and provides them with survival advantages. Therefore, the authors introduced a model for PCa evolution that can be applied to other tumors. This clonal–subclonal hierarchy of coordinated, interdependent rearrangements and deletions occurring in multiple rounds of chromoplexy during tumor development represents an approach to mapping the accumulation of gene alterations.
Experts’ comments: Understanding the molecular basis of PCa is key to providing effective health care to patients. This knowledge has been facilitated by the rise of novel high-throughput genomeprofiling technologies in combination with chromoplexy. We believe that these tools might enable the subclassification of PCas based on their genomic profiles, thus tackling the problem of clinical and molecular PCa heterogeneity head on. This study further opens the door to subdividing PCa into relevant homogenous diseases based on molecular signatures. Such a classification may promote a concept of subgrouping and thus a group-specific treatment. The classification is likely to make it more feasible to identify genes representing ‘‘driver events’’ in a homogenous subgroup than in a large, heterogeneous disease. Such a
667
EUROPEAN UROLOGY 65 (2014) 665–670
classification enables the identification of distinct molecular alterations that may provide a subset of tumors with selective advantage. Additionally, the classification sheds light into early events that may render patients more susceptible to developing PCa and into the likelihood of aggressiveness. Together, WGS and the punctuated evolution model have the potential to be integrated into clinical practice. This development may support the clinician’s ability to identify patients at high risk of developing an aggressive disease and to diagnose, manage, and treat patients based on specific gene alterations.
Conflicts of interest: The authors have nothing to disclose.
Re: Pazopanib Versus Sunitinib in Metastatic Renal-cell Carcinoma Motzer RJ, Hutson TE, Cella D, et al.
as the upper bound of the 95% CI of the HR. In this trial, noninferiority was assumed if the upper bound of the 95% CI of the HR was
