UROLOGICAL ONCOLOGY: PROSTATE CANCER

0022-5347/01/1664-1574/0 THE JOURNAL OF UROLOGY® Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 166, 1574 –1600, October 2001 Printed in U.S.A.

ABSTRACTS UROLOGICAL ONCOLOGY: PROSTATE CANCER A Candidate Prostate Cancer Susceptibility Gene at Chromosome 17p S. V. TAVTIGIAN, J. SIMARD, D. H. F. TENG, V. ABTIN, M. BAUMGARD, A. BECK, N. J. CAMP, A. R. CARILLO, Y. CHEN, P. DAYANANTH, M. DESROCHERS, M. DUMONT, J. M. FARNHAM, D. FRANK, C. FRYE, S. GHAFFARI, J. S. GUPTE, R. HU, D. ILIEV, T. JANECKI, E. N. KORT, K. E. LAITY, A. LEAVITT, G. LEBLANC, J. MCARTHURMORRISON, A. PEDERSON, B. PENN, K. T. PETERSON, J. E. REID, S. RICHARDS, M. SCHROEDER, R. SMITH, S. C. SNYDER, B. SWEDLUND, J. SWENSEN, A. THOMAS, M. TRANCHANT, A.-M. WOODLAND, F. LABRIE, M. H. SKOLNICK, S. NEUHAUSEN, J. ROMMENS AND L. A. CANNON-ALBRIGHT, Myriad Genetics, Inc., Genetic Epidemiology Group, Department of Medical Informatics, University of Utah School of Medicine and Genetic Research, Intermountain Health Care, LDS Hospital, Salt Lake City, Utah, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center and Laval University, Quebec City, Quebec, and Program in Genetics and Genomic Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada Nat Genet, 27: 172–180, 2001 It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3⬘ end cleavage and polyadenylation specificity factor (CPSF73).

Association of HPC2/ELAC2 Genotypes and Prostate Cancer T. R. REBBECK, A. H. WALKER, C. ZEIGLER-JOHNSON, S. WEISBURG, A.-M. MARTIN, K. L. NATHANSON, A. J. WEIN AND S. B. MALKOWICZ, Departments of Biostatistics and Epidemiology, Urology, and Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Am J Hum Genet, 67: 1014 –1019, 2000 HPC2/ELAC2 has been identified as a prostate cancer (CaP) susceptibility gene. Two common missense variants in HPC2/ELAC2 have been identified: a Ser3 Leu change at amino acid 217, and an Ala3 Thr change at amino acid 541. Tavtigian et al. reported that these variants were associated with CaP in a sample of men drawn from families with hereditary CaP. To confirm this report in a sample unselected for family history, we studied 359 incident CaP case subjects and 266 male control subjects that were frequency matched for age and race and were identified from a large health-system population. Among control subjects, the Thr541 frequency was 2.9%, and the Leu217 frequency was 31.6%, with no significant differences in frequency across racial groups. Thr541 was only observed in men who also carried Leu217. The probability of having CaP was increased in men who carried the Leu217/Thr541 variants (odds ratio ⫽ 2.37; 95% CI 1.06 –5.29). This risk did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of CaP in the general population of inference. These results suggest that common variants at HPC2/ELAC2 are associated with CaP risk in a sample unselected for family history or other factors associated with CaP risk.

Evaluation of Linkage and Association of HPC2/ELAC2 in Patients With Familial or Sporadic Prostate Cancer J. XU, S. L. ZHENG, J. D. CARPTEN, N. N. NUPPONEN, C. M. ROBBINS, J. MESTRE, T. Y. MOSES, D. A. FAITH, B. D. KELLY, S. D. ISAACS, K. E. WILEY, C. M. EWING, P. BUJNOVSZKY, B. CHANG, J. BAILEY-WILSON, E. R. BLEECKER, 1574

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P. C. WALSH, J. M. TRENT, D. A. MEYERS AND W. B. ISAACS, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, University of Maryland School of Medicine and Department of Urology, Johns Hopkins Medical Institutions, Baltimore and National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland Am J Hum Genet, 68: 901–911 To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us to reject the three alternative hypotheses of (1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11, (2) the allelic variants Leu217 or Thr541 of HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. Considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in our study sample, our results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees. Nor can we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk. Editorial Comment: Hereditary prostate cancer has been linked to loci on 3 chromosomes (the short and long arms of chromosome 1, the X chromosome and chromosome 20). However, the susceptibility genes at these sites have not been cloned. Thus, there was great excitement when Tavtigian et al described a candidate gene on the short arm of chromosome 17. This represented the first susceptibility gene for prostate cancer that had been cloned and the investigators called it HPC2. Subsequently, Rebbeck et al investigated a group of men with sporadic prostate cancer and reported that carriers of mutations in this gene had more than a 2-fold increased probability of developing prostate cancer. However, these findings have recently been challenged by Xu et al. They failed to demonstrate any association between this gene and familial transmission of the disease in families with hereditary prostate cancer. Furthermore, they were unable to show that this gene increased the risk of sporadic development of prostate cancer. Thus, these findings are not consistent with a major role for HPC2 as a prostate cancer susceptibility gene. Patrick C. Walsh, M.D.

New Clinical Trial Strategies for Prostate Cancer Prevention R. LIEBERMAN

AND

W. G. NELSON, National Cancer Institute, Rockville, Maryland

Urology, suppl., 57: 1, 2001 No Abstract Editorial Comment: This supplement summarizes a National Cancer Institute Workshop that was held in the summer of 1999. Anyone who has a serious interest in prostate cancer should read this supplement from cover to cover, as I did. Subjects include molecular targets and new agent development, intermediate end point biomarkers for prostate cancer prevention trials, identification and recruitment of high risk study populations, prevention, clinical trial designs and regulatory issues. It is one of the best recent symposia I have read on prostate cancer. Patrick C. Walsh, M.D.

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Men who Consume Vegetable Oils Rich in Monounsaturated fat: Their Dietary Patterns and Risk of Prostate Cancer (New Zealand) A. E. NORRISH, R. T. JACKSON, S. J. SHARPE AND C. M. SKEAFF, Departments of Community Health and Medicine, University of Auckland, Auckland and Department of Human Nutrition, University of Otago, Dunedin, New Zealand Cancer Causes Control, 11: 609 – 615, 2000 Objectives: To investigate (i) dietary patterns associated with consumption of vegetable oils rich in monounsaturated fatty acids (MUFA), and (ii) the risk of prostate cancer associated with consumption of these oils. Methods: A population-based case-control study was conducted in Auckland, New Zealand, involving 317 prostate cancer cases and 480 controls. A food-frequency questionnaire was used to collect data concerning consumption of MUFA-rich vegetable oils (including olive oil, canola or peanut oil) and other dietary variables. Biomarkers for fatty acids were measured in erythrocytes. Results: The group of participants who reported regular consumption of greater than 5.5 ml of MUFA-rich vegetable oils per day had a diet relatively high in monounsaturated fat, vegetables, lycopene, vitamin E, selenium, and n-3 fish oils. Increasing levels of MUFA-rich vegetable oil intake were associated with a progressive reduction in prostate cancer risk (multivariate relative risk ⫽ 0.5; 95% confidence interval 0.3– 0.9; ⬎5.5 ml per day vs. non-consumption, p trend ⫽ 0.005), and similar trends were observed across all strata of socioeconomic status. Prostate cancer risk was not associated with intake of total MUFA or the major animal food sources of MUFA. Conclusion: This finding may be explained by the protective effect of an associated dietary pattern high in antioxidants and fish oils, an independent protective effect of MUFA-rich vegetable oils unrelated to the MUFA component, or a combination of these factors.

Cancer and Mediterranean Dietary Traditions A. TRICHOPOULOU, P. LAGIOU, H. KUPER AND D. TRICHOPOULOS, Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece, and Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts Cancer Epidemiol Biomarkers Prev, 9: 869 – 873, 2000 The incidence of cancer overall in Mediterranean countries is lower than in Scandinavian countries, the United Kingdom, and the United States. This is mostly accounted for by the lower incidence among Mediterranean countries of cancer of the large bowel, breast, endometrium, and prostate. These forms of cancer have been linked to dietary factors, particularly low consumption of vegetables and fruit, and to a certain extent, high consumption of meat. The traditional Mediterranean diet is characterized by high consumption of foods of plant origin, relatively low consumption of red meat, and high consumption of olive oil, which in several studies has been reported to be more beneficial against cancer than other forms of added lipids. By taking into account the established or presumed nutritional causation of major forms of cancer and the composition of the traditional Mediterranean diet, estimates can be derived concerning the fraction of cancer occurrence in highly developed Western countries that could be attributed to their diets in comparison with the healthy traditional Mediterranean diet. Although estimates can only be crude, it can be calculated that up to 25% of the incidence of colorectal cancer, ⬃15% of the incidence of breast cancer, and ⬃10% of the incidence of prostate, pancreas, and endometrial cancer could be prevented if the populations of highly developed Western countries could shift to the traditional healthy Mediterranean diet. Editorial Comment: Epidemiological studies have shown relative low prostate cancer rates in southern European countries, such as Italy, Greece, Spain and Portugal. These countries have Mediterranean dietary patterns traditionally characterized by low intake of fat from animal sources, a high proportion of monounsaturated fatty acids in vegetable oil (olive, canola and peanut oils), and relatively high consumption of fruit and vegetables. Norrish et al showed that increased intake of monounsaturated rich vegetable oil was associated with a progressive reduction in prostate cancer risk in New Zealand. Trichopoulou et al estimate that the incidence of prostate cancer could be decreased by up to 10% if the population of highly developed Western countries shifted to the healthy Mediterranean diet. Because the effect of these dietary changes is not striking, Don Coffey has noted that there must be some other factor or factors responsible for the reduced risk of prostate cancer in southern Europe. Other possibilities include environmental factors that increase vitamin D levels (more sunlight and less calcium in the diet) or possibly the way meat is cooked (less charring). Patrick C. Walsh, M.D.

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Leptin and Prostate Cancer S. CHANG, S. D. HURSTING, J. H. CONTOIS, S. S. STROM, Y. YAMAMURA, R. J. BABAIAN, P. TRONCOSO, P. T. SCARDINO, T. M. WHEELER, C. I. AMOS AND M. R. SPITZ, Departments of Epidemiology, Urology and Pathology, University of Texas M.D. Anderson Cancer Center, and Department of Pathology, Baylor College of Medicine, Houston, Texas, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, Department of Diagnostic Oncology, Bayer Corporation, Tarrytown and Memorial Sloan-Kettering Cancer Center, New York, New York Prostate, 46: 62– 67, 2001 BACKGROUND. Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition). METHODS. In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors ⱕ0.5 cc measured after radical prostatectomy and 151 men with tumors ⬎0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases (“high-volume disease”), matched by age (⫾5 years) and year at diagnosis (⫾1 year). RESULTS. Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) ⫽ 2.35, 95% confidence interval (CI) ⫽ 1.01–5.44), as did men with high leptin and high testosterone (OR ⫽ 9.73, 95% CI ⫽ 2.05– 46.24) and men ⱖ5⬘8⬙ with high leptin (OR ⫽ 3.67, 95% CI ⫽ 1.40 –9.63). CONCLUSIONS. Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity.

Leptin is Associated With Increased Prostate Cancer Risk: A Nested Case-Referent Study ¨ , G. HALLMANS, A. BYLUND, R. KAAKS, U.-H. STENMAN, A. BERGH AND T. OLSSON, P. STATTIN, S. SODERBERG Departments of Urology and Andrology, Public Health and Clinical Medicine, Geriatric Medicine, and Pathology, Umea University Hospital, Umea, Sweden, International Agency for Research on Cancer, Lyon, France, and Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland J Clin Endocrinol Metab, 86: 1341–1345, 2001 A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1–3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1– 4.1), 2.6 (1.4 – 4.8), 1.4 (0.7–2.7), and 1.6 (0.8 –3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk. Editorial Comment: These articles suggest that increased levels of leptin are associated with increased risk for prostate cancer and in some cases advanced disease. Leptin is a hormone produced by fat cells that regulates appetite. There are rare cases of congenital leptin deficiency that are associated with gross obesity. However, leptin has also been associated with features of the insulin resistance syndrome and circulating levels of leptin are increased in obesity. It is unclear whether the association between prostate cancer and leptin is related to obesity or whether leptin may have some direct effects on the development of prostate cancer. Patrick C. Walsh, M.D.

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High-Grade Prostate Cancer is Associated With Low Serum Testosterone Levels ¨ , G. KRAMER, A. HAITEL G. SCHATZL, S. MADERSBACHER, T. THURRIDL, J. WALDMULLER Departments of Urology and Pathology, University of Vienna, Vienna, Austria

AND

M. MARBERGER,

Prostate, 47: 52–58, 2001 BACKGROUND. The aim of this study was to assess whether low serum testosterone levels in men with newly diagnosed prostate cancer have an association to the endocrine status, prostate-specific antigen (PSA) levels, Gleason score, and androgen receptor expression. METHODS. Besides a full clinical work-up, the following hormones were quantified in men with newly diagnosed prostate cancer by serum analysis: total testosterone, human luteinising hormone (hLH), human follicle stimulating hormone (hFSH), estradiol, and dehydroepiandrostendione (DHEA). In a subgroup of men, androgen receptor expression was determined immunohistochemically. RESULTS. One hundred and fifty six patients (65.7 ⫾ 8.5 yrs) with a mean PSA of 29.8 ng/ml (median: 7.4 ng/ml) were analysed. Fifty-two patients (33%) had a partial androgen deficiency (serum testosterone ⬍3.0 ng/ml). These men had lower hLH (3.3 vs. 5.9 mIU/ml), hFSH (6.2 vs. 8.4 mIU/ml), and estradiol (18.8 vs. 29.1 pg/ml) serum levels. Mean Gleason score was higher (7.4 vs. 6.2) in men with a low serum testosterone, PSA-levels were lower (25.3 vs. 31.9 ng/ml). Mean testosterone levels decreased from 4.1 ⫾ 1.7 ng/ml in patients with Gleason scores ⱕ5 to 2.8 ⫾ 2.7 ng/ml with Gleason scores ⱖ8. Androgen receptor expression was higher in patients with low serum testosterone. CONCLUSIONS. Patients with high Gleason score prostate cancer have lower testosterone and estradiol serum levels. The fact that gonadotropins were lower in parallel suggests a tumor-mediated suppression of the hypothalamic-pituitary-gonadal hormone axis particularly in men with high Gleason score tumours. Editorial Comment: It has been known for years that men with advanced prostate cancer have lower serum LH and testosterone than those with localized disease. Because this finding was often present in men with metastatic disease, it was assumed that it represented a manifestation of overall debility. However, this study suggests that testosterone is lower in men with high grade disease and is independent of other obvious factors, such as age or extent of disease as assessed by PSA. Why does this occur? We showed previously that serum LH and testosterone increased after radical prostatectomy.1 Based on this observation, we speculated that the prostate secreted a factor that produced negative feedback on the hypothalamic-pituitarygonadal axis. The observation in this article suggests that secretion of this factor may be higher in men with high grade tumors. Patrick C. Walsh, M.D. 1. Miller, L. R., Partin, A. W., Chan, D. W. et al: Influence of radical prostatectomy on serum hormone levels. J Urol, 160: 449, 1998

Intraoperative T Staging in Radical Retropubic Prostatectomy: Is it Reliable? A. VAIDYA, C. HAWKE, R. TIGUERT, F. CIVANTOS AND M. SOLOWAY, Departments of Urology and Pathology, University of Miami School of Medicine, Miami, Florida Urology, 57: 949 –954, 2001 Objectives. During radical prostatectomy, wide local excision of the lateral prostatic fascia and neurovascular bundle on the ipsilateral side of the tumor is advocated if nerve sparing is likely to result in a positive surgical margin. Our intent was to validate whether intraoperative T staging can predict the presence of positive surgical margins and aid in the decision of whether to perform nerve-sparing prostatectomy. Methods. One surgeon performed 100 consecutive radical prostatectomies, and one pathologist interpreted the pathologic findings. Topographic distribution of tumor within the specimen was assessed intraoperatively by palpation. The margin status was similarly assessed. This tactile clinical impression was compared with the final pathologic findings. Results. The surgical margins were positive in 39 (39%) of 100 cases. The intraoperative assessment of the margin status had a high false-negative rate and a sensitivity of only 7%. However, the specificity was 96%, because few margins were falsely positive. The overall accuracy was 62%, with a negative predictive value of 62%. The sensitivity of the intraoperative assessment of tumor location was 73%, and the positive predictive value was 65%. Conclusions. The results of our study indicate that the intraoperative assessment of the margin status is not accurate and thus cannot help determine which patients require excision of the neurovascular bundle. We believe the decision to preserve the neurovascular bundle should be based on the preoperative prognostic factors and the presence of an intact capsule covering the region of the gland adjacent to this structure. Editorial Comment: The conclusion in the abstract of this article does not correlate with the results or the discussion in the text. From reading this abstract, one would assume that intraoperative findings cannot be used to determine whether the neurovascular bundle should be

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preserved. However, when one looks at the text it is reported that of 39 positive surgical margins (I consider 39% a high rate of positive margins for any contemporary radical prostatectomy series) only 8 margins were positive posterolaterally at the neurovascular bundle! The authors also do not report the percentage of patients who had organ confined cancer, and so it is impossible to determine whether the high frequency of positive surgical margins in this series was caused by capsular incision or extensive extraprostatic tumor. They report that the highest frequency of positive surgical margins (72%) was at the apex. I believe that positive margins at the apex are not caused by nerve sparing (if it is performed correctly) but during division of the dorsal vein complex, striated urethral sphincter and urethra.1 During this maneuver it is often difficult to identify the precise separation between the anterior apical tissue and the striated sphincter dorsal vein complex or to determine whether there is tumor penetration at this site. If one hopes to perform radical prostatectomy with low morbidity, it is important to focus on the apical dissection to avoid positive surgical margins and to release the neurovascular bundles without separating the prostatic capsule from the specimen. As I will discuss, if one understands these principles, the need for wide excision of the neurovascular bundle can be reduced markedly without compromising cancer control. Patrick C. Walsh, M.D. 1. Shah, O., Melamed, S. and Lepor, H.: Analysis of apical soft tissue margins during radical retropubic prostatectomy. J Urol, 165: 1943, 2001

Interposition Sural Nerve Grafting During Radical Retropubic Prostatectomy E. D. KIM, P. T. SCARDINO, D. KADMON, K. SLAWIN AND R. K. NATH, Department of Surgery, Division of Urology, University of Tennessee Medical Center, Knoxville, Tennessee, Department of Urology, Sloan-Kettering Cancer Center, New York, New York, and Scott Department of Urology, Department of Neurosurgery, and Department of Surgery, Division of Plastic Surgery, Baylor College of Medicine, Houston, Texas Urology, 57: 211–216, 2001 No Abstract Editorial Comment: The authors report on 12 men with a minimum followup of 12 months who had bilateral nerve grafts placed after wide excision of both neurovascular bundles. These results are compared to those of 12 potent men who underwent bilateral nerve resection without nerve graft. At followup of more than a year 4 of the 12 men with nerve grafts had spontaneous medically unassisted erections sufficient for intercourse, and 3 with partial erections were able to have intercourse using sildenafil. These results are encouraging but in a subsequent article I suggested caution before everyone jumps on the nerve graft bandwagon.1 In that article I tried to make 4 points. 1) Patients who have invasion of the neurovascular bundle on both sides to the point where it is necessary to excise both neurovascular bundles are not curable with surgery and, thus, bilateral nerve grafts are rarely, if ever, necessary. In the study by Kim et al 58% of patients who underwent excision of both neurovascular bundles had organ confined disease. 2) Today most men with localized prostate cancer who undergo surgery can have preservation of both neurovascular bundles without compromising cancer control. 3) Patients who have extensive disease outside the prostate are less likely to recover sexual function, regardless of nerve status and, thus, are less likely to benefit from placement of a nerve graft. 4) A randomized properly controlled study of nerve grafts should be performed before nerve grafts are widely accepted in the management of localized prostate cancer. The most valuable thing one can do to ensure the recovery of sexual function in patients in whom it is necessary to excise 1 neurovascular bundle widely is not a nerve graft but precise preservation of the contralateral neurovascular bundle. Patrick C. Walsh, M.D. 1. Walsh, P. C.: Nerve grafts are rarely necessary and are unlikely to improve sexual function in men undergoing anatomic radical prostatectomy. Urology, 57: 1020, 2001

Efficacy Of First-Generation Cavermap to Verify Location and Function of Cavernous Nerves During Radical Prostatectomy: A Multi-Institutional Evaluation by Experienced Surgeons P. C. WALSH, P. MARSCHKE, W. J. CATALONA, H. LEPOR, S. MARTIN, R. P. MYERS AND M. S. STEINER, Johns Hopkins Medical Institutions, Baltimore, Maryland, Washington University School of Medicine, St. Louis, Missouri, New York University School of Medicine, New York, New York, Mayo Clinic, Rochester, Minnesota, and University of Tennessee School of Medicine, Nashville, Tennessee Urology, 57: 491– 494, 2001 Objectives. To evaluate, using five experienced surgeons, the efficacy of the first-generation Cavermap Surgical Aid to identify the cavernous nerves intraoperatively and to predict the recovery of sexual function.

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This study was not designed to determine whether this device improves the ability to preserve the nerves or improve outcome. Methods. Fifty men younger than 60 years old (mean age 52.5 years; range 43 to 59) with clinically localized prostate cancer (76% T1c, mean Gleason score 6, prostate-specific antigen level less than 10 ng/mL) underwent nerve-sparing radical prostatectomy (90% bilateral). Intraoperatively, the Cavermap device was used to test for the presence of the cavernous nerves once the neurovascular bundle was identified visually and to determine whether the nerves were intact after the prostate was removed. Erectile function was evaluated using the International Index of Erectile Function; men were considered potent if they were able to achieve unassisted intercourse in at least one half of their attempts. Results. Before the removal of the prostate, the tumescence response to stimulation of the neurovascular bundle was 87.8%; when tissue not containing the neurovascular bundle was stimulated, no tumescence response occurred in 54%. After prostatectomy, a bilateral response to stimulation occurred in 90%, a unilateral response in 5%, and no response in 5%. Postoperatively, 71% of the patients were potent at 12 months. In the patients who demonstrated bilateral stimulation after removal of the prostate, 78% were potent at 12 months. Conclusions. After radical prostatectomy performed by experienced surgeons, patient-reported potency rates in men younger than 60 years of age were high. Cavermap stimulation demonstrated an 87.8% sensitivity and 54% specificity in locating the neurovascular bundle as identified by experienced surgeons. The lack of specificity of this first-generation device limits its application for deciding which structures can be safely preserved or excised. Because virtually all patients demonstrated a positive response after removal of the prostate, the value of stimulation to predict the recovery of sexual function is yet to be determined. Editorial Comment: The ability of the Cavermap Surgical Aid (UroMed Corp., Norwood, Massachusetts) to identify the cavernous nerves intraoperatively and predict recovery of sexual function was investigated by 5 experienced surgeons from The Johns Hopkins Medical Institutions, Washington University, New York University, Mayo Clinic and the University of Tennessee. The patient reported potency rate at 12 months after radical prostatectomy was 71%, confirming the fact that in experienced hands most men younger than 60 years should be potent following this procedure. Unfortunately, this first generation machine did not function well in our hands, as its specificity in locating the neurovascular bundle was only 54%. Because the neurovascular bundle extends beyond the entire length of the prostate, it would be cumbersome to use this device to identify the neurovascular bundles bilaterally throughout their length and, because of the lack of specificity, one cannot depend on the findings. I believe that the use of magnification loupes provides a much more practical solution. Patrick C. Walsh, M.D.

Anastomotic Strictures Following Radical Prostatectomy: Insights Into Incidence, Effectiveness of Intervention, Effect on Continence, and Factors Predisposing to Occurrence R. PARK, S. MARTIN, J. D. GOLDBERG AND H. LEPOR, Departments of Urology and Environmental Medicine, Division of Biostatistics, New York University School of Medicine, New York, New York Urology, 57: 742–746, 2001 Objectives. To examine the incidence, effectiveness of intervention, effect on continence, and factors predisposing to the occurrence of anastomotic strictures following radical retropubic prostatectomy. Methods. Between January 1994 and June 1999, 753 radical retropubic prostatectomies were performed by a single surgeon. Anastomotic strictures were managed by dilatation followed by a self-catheterization regimen. Dilatations were repeated unless more than three dilatations were required over a 9-month interval. A control group representing a randomly selected group of men who did not develop anastomotic strictures was identified. The largest width of the midline vertical abdominal scar was measured. Results. Of the 753 radical retropubic prostatectomies, 36 (4.8%) developed an anastomotic stricture. The mean time interval between the surgical procedure and diagnosis of the stricture was 4.22 months. Of the 26 cases of anastomotic strictures with at least 1-year follow-up, 24 (92.3%) were managed successfully by dilatations alone. No baseline characteristics before surgery were associated with the development of a stricture. The maximal scar width was the only factor that was associated with the development of a stricture in this study. Men with a maximal scar of greater than 10 mm were eight times more likely to develop strictures than men with smaller scars. The percentage of men who required protective pads 1 year following radical retropubic prostatectomy in the control and stricture groups was 12.5% and 46.2%, respectively. Conclusions. Anastomotic strictures are relatively rare following radical prostatectomy and have a negative effect on the development of continence. Most men are successfully managed with dilatations alone. The development of anastomotic strictures in some men appears to be related to a generalized hypertrophic wound-healing mechanism. Editorial Comment: The authors make an interesting and unique observation. They found that men with maximal scars greater than 10 mm. wide were 8 times more likely to have develop

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anastomotic strictures than those with smaller scars. If keloids form in the abdominal incision, why should they not also form at the anastomosis? The authors suggest that we look at surgical scars in patients who have undergone other procedures. If they are hypertrophic, they suggest reconstructing the bladder neck to 28 to 30Fr instead of the usual 22 to 24Fr. Patrick C. Walsh, M.D.

The Role of External Beam Radiotherapy With I-125/Pd-103 Brachytherapy for Prostate Carcinoma J. C. BLASKO, P. D. GRIMM, J. E. SYLSVESTER AND W. CAVANAGH, Seattle Prostate Institute, Seattle, Washington Radiother Oncol, 57: 273–278, 2000 Background and purpose: To compare the biochemical outcomes of patients treated with Pd-103/I-125 brachytherapy alone vs. brachytherapy combined with external beam radiotherapy for early stage prostate carcinoma. Methods: Brachytherapy monotherapy was used in 403 patients. Brachytherapy was combined with 45 Gy of external beam radiotherapy in 231 patients. Median follow-up was 58 months. To compare the biochemical outcomes of these two treatment approaches, patients were stratified into three relative risk groups: low risk, T1–T2, Gleason 2– 6/10, PSA ⱕ10.0; intermediate risk, T3, Gleason 7–10/10, PSA ⬎10.0 (one factor); high risk, T3, Gleason 7–10/10, PSA ⬎10.0 (two factors). Results: The actuarial biochemical progression-free rate (bNED) for the entire 634 patients was 85% at 10 years. The bNED outcomes by risk group for monotherapy vs. combined therapy respectively were: low risk, 94 vs. 87%; intermediate risk, 84 vs. 85%; high risk, 54 vs. 62%. These differences did not reach statistical significance for any risk group. Rectal morbidity was slightly greater in the combined treatment patients. Conclusion: Although the addition of external beam irradiation to brachytherapy is conceptually appealing for patients with higher risk prostate carcinoma, we were unable to demonstrate a benefit. Whether this is because of patient selection biases within the risk groupings, an artefact of retrospective review, or because external radiotherapy does not offer additional benefit is uncertain. Editorial Comment: When I read this article I was taken by 2 of the observations: 1) the excellent cancer control following brachytherapy and 2) the lack of a difference in progression rates in patients who received monotherapy versus those who received brachytherapy combined with external beam irradiation. After rereading the article several times, I have some questions. At 10 years the actuarial biochemical progression-free survival averaged 85%. These results are based on the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria, in which treatment is not declared a failure until patients have had 3 consecutive increases in PSA. In those patients the time of treatment failure is backdated to the midpoint between the nadir and the first increase in PSA. The authors do not say what happened to patients who had only 1 or 2 increases in PSA or how they handled cases if hormonal therapy was initiated the first time PSA increased. However, these considerations are minor compared to the major issue of whether the ASTRO criteria can be used to calculate actuarial progression rates, and there are experts who think they should not.1 Why is this? Based on prior publications approximately half of patients who had PSA greater than 0.5 ng./ml. did so after 50 months.2 This event would be delayed by about 2 years using the ASTRO criteria. If 1 event occurred in this study at 8 years when there were only 50 patients, it would reduce the survival probability by 2%. However, using ASTRO criteria the event is backdated to the midpoint between the nadir and first increase when there were 300 or 400 patients. Thus, this failure would have little impact on the ultimate end point. A recent study from the Mayo Clinic showed that application of the ASTRO criteria to a radical prostatectomy series artificially increased the probability of being disease-free at 10 years by more than 20%.3 Thus, the 85% probability of being disease-free at 10 years cannot be used for comparison to surgical results. Unfortunately, these data are being used to convince patients that the results of surgery and brachytherapy are identical. Next, I tried to find out why the results of brachytherapy alone in this article were so much better than those reported by the same authors previously.2 In looking over the methods section it was impossible to tell how these patients were selected and where they came from. It was not until I read the conclusions that I understood. The authors admit that the results “. . .may be due to insufficient patient numbers and observations or the presence of the selected, nonrandomized nature of these patient cohorts.” Based on these observations they state, “. . .that prospective trials are necessary to answer this question.” I echo this sentiment and hope that everyone who uses data like these will understand some of the inherent difficulties in drawing conclusions. Patrick C. Walsh, M.D.

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Five-Year Retrospective, Multi-Institutional Pooled Analysis of Cancer-Related Outcomes After Cryosurgical Ablation of the Prostate J. P. LONG, D. BAHN, F. LEE, K. SHINOHARA, D. O. CHINN AND J. N. MACALUSO, JR., Department of Urology, Tufts-New England Medical Center, Boston, Massachusetts, Crittenton Hospital, Rochester, Michigan, Departments of Urology and Radiology, University of California, San Francisco, School of Medicine, San Francisco and Alhambra Hospital, Arcadia, California, and Urologic Institute of New Orleans, New Orleans, Louisiana Urology, 57: 518 –523, 2001 Objectives. To define the potential role of cryosurgical ablation of the prostate (CSAP) as a treatment option for patients with localized prostate carcinoma (PCA), we performed a retrospective outcomes analysis of a large database of patients undergoing CSAP constructed from five institutions and compared this with matching outcomes from contemporary reports of patient outcomes after radiotherapy. Methods. A total of 975 patients who underwent CSAP as primary therapy from January 1993 to January 1998 with sufficient outcomes data available were identified. Patients were stratified into three groups on the basis of their clinical features. Biochemical-free survival (BFS), post-CSAP biopsy results, and postCSAP morbidities were calculated and recorded. Results. The median follow-up for all patients was 24 months. The percentages of patients in the low, medium, and high-risk groups were 25%, 34%, and 41%, respectively. For prostate-specific antigen thresholds of less than 0.5 and less than 1.0 ng/mL, the 5-year actuarial BFS ranged from 36% to 61% and 45% to 76%, respectively, depending on the risk category. Overall, the positive biopsy rate was 18%. Morbidities included impotence in 93%, incontinence in 7.5%, rectourethral fistula in 0.5%, and transurethral resection of the prostate in 13% of patients (10% approved warming catheters versus 40% nonapproved). Conclusions. For each risk group, the 5-year BFS and positive biopsy rate after CSAP was comparable to matching outcomes reported after radiotherapy. Morbidities also seemed comparable, with impotence rates higher and rectal injury rates lower after CSAP than after radiotherapy. These data indicate that CSAP can be performed with low morbidity and can produce cancer-related results comparable to those reported for patients undergoing radiotherapy. Editorial Comment: The authors provide a sobering analysis of the 5-year results of cryotherapy. Of low risk patients (T1–T2a, PSA less than 10 ng./ml. and Gleason score less than 7) only 60% had PSA less than 0.5 ng./ml. In radical prostatectomy series that number is closer to 90% at 10 years. Of the patients 93% were impotent postoperatively, 7.5% had incontinence and 0.5% had a rectourethral fistula. Patrick C. Walsh, M.D.

Combined Androgen Blockade With Nonsteroidal Antiandrogens for Advanced Prostate Cancer: A Systematic Review B. SCHMITT, T. J. WILT, P. F. SCHELLHAMMER, V. DEMASI, O. SARTOR, E. D. CRAWFORD AND C. L. BENNETT, Veterans Administration Chicago Healthcare System/Lakeside Division, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Divisions of Hematology/Oncology and General Internal Medicine, and Institute of Health Services Research and Policy Studies, Northwestern University Chicago, Illinois, Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia, Atlantic Cancer Center, Salisbury, Maryland, Stanley Scott Cancer Center and Division of Hematology/Oncology, Louisiana State University, New Orleans, Louisiana, Division of Urology, University of Colorado, Denver, Colorado, Minneapolis Veterans Administration Center for Chronic Disease Outcomes Research and Veterans Administration Coordinating Center for the Cochrane Collaborative Review Group in Prostate Diseases and Urologic Malignancies, Minneapolis, Minnesota Urology, 57: 727–732, 2001 Objectives. Combined androgen blockade with medical or surgical castration plus a nonsteroidal antiandrogen for metastatic prostate cancer has been the subject of 20 randomized trials. The findings range from no expected increase in survival in 17 studies to an estimated 3.7 to 7 months’ survival improvement noted in 3 studies. Most recently, a 1999 evidence report from the Agency for Healthcare Research and Quality

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and a 2000 overview from the Prostate Cancer Trialists Collaborative Group indicated that combined androgen blockade was associated with an approximately 3% to 5% increase in 5-year survival. We report herein a systematic review on combined androgen blockade performed by the Cochrane Collaborative Review Group on Prostate Diseases. Methods. Controlled trials that included a randomization of immediate nonsteroidal antiandrogens with castration versus castration alone for metastatic prostate cancer and provided information on survival were reviewed. Information on overall survival, toxicity, progression-free survival, cancer-specific survival, and type of nonsteroidal antiandrogen and castration therapies was abstracted by two independent reviewers. Results. Twenty trials (n ⫽ 6320 patients) were included. The pooled odds ratio (OR) for overall survival with combined androgen blockade was 1.03 (95% confidence interval [CI] 0.85 to 1.25; n ⫽ 4970 from 13 trials), 1.16 (95% CI 1.00 to 1.33; n ⫽ 5286 from 14 trials), and 1.29 (95% CI 1.11 to 1.50; n ⫽ 3550 from 7 trials) at 1, 2, and 5 years, respectively. Progression-free survival was improved at 1 year (OR ⫽ 1.38; 95% CI 1.15 to 1.67; n ⫽ 2278 from 7 trials). Cancer-specific survival was improved at 5 years (OR ⫽ 1.58; 95% CI 1.05 to 2.37; n ⫽ 781 from 2 trials). When analysis was limited to studies identified as being of high quality, the pooled OR for overall survival progressively increased but was not significant at any follow-up interval. Conclusions. We find that there is a 5% improvement in the percentage of men surviving at 5 years (30% vs. 25%) with combined androgen blockade with nonsteroidal antiandrogens as well as improvements in progression-free survival at 1 year. Appropriate patients with metastatic prostate cancer should be informed of the potential benefits, toxicities, and out-of-pocket expenditures. Editorial Comment: Twenty years after Labrie claimed possible cures with combined androgen blockade, we are still arguing over whether there could be a 5% difference in survival at 5 years. This article, which has 3 authors who are on the Speaker’s Bureau for Schering-Plough, is a review of selected series evaluating total androgen blockade. Contrary to overview analyses that assess raw data gathered from multiple studies, this meta-analysis relies primarily on published reports. The conclusion of a 5% improvement at 5 years is troublesome because few studies have sufficient followup data to allow reliable 5-year survival data. The best studies are usually published once and have median followup times of 2 to 3 years. Indeed, according to the authors, only 7 of 20 (of a total of 27) trials had what they thought were evaluable 5-year data. This study confirms other large reports indicating no 2-year survival difference, a time point when most studies are reported. Patrick C. Walsh, M.D.

Low Doses of Oral Dexamethasone for Hormone-Refractory Prostate Carcinoma K. NISHIMURA, N. NONOMURA, Y. YASUNAGA, N. TAKAHA, H. INOUE, H. SUGAO, S. YAMAGUCHI, O. UKIMURA, T. MIKI AND A. OKUYAMA, Departments of Urology, Osaka University Medical School, Suita, Osaka Rosai Hospital, Sakai, Mino Municipal Hospital, Mino, Ikeda Municipal Hospital, Ikeda and Kyoto Prefectural University of Medicine, Kyoto, Japan Cancer, 89: 2570 –2576, 2000 BACKGROUND. Although glucocorticoids have been used to treat patients with hormone-refractory prostate carcinoma (HRPC), reports have varied regarding the types and doses of glucocorticoids used as well as their clinical benefits. In the current study, low doses of dexamethasone were investigated for their specific beneficial effects and the feasibility of long term treatment. METHODS. Thirty-seven patients diagnosed with HRPC were treated with oral dexamethasone (0.5–2 mg/day). The patients ranged in age from 53– 89 years (median, 74 years). Thirty-two patients, including 6 with lymph node metastases, had bone involvement whereas only 5 patients were found to have elevated serum prostate specific antigen (PSA) levels. RESULTS. Twenty-three patients (62%) who received no other concomitant therapy demonstrated a decline in their serum PSA level of ⱖ50%, which was confirmed by a second PSA value obtained ⱖ4 weeks later. The median time to PSA progression was 9 months. Among 18 patients with bone pain, 11 (61%) had improvement and in 5 patients (28%) the pain became stable. Among 21 patients with interpretable bone scans, 4 (19%) showed improvement and 8 (38%) achieved stable disease. Both symptomatic and objective responses of bone metastases were correlated with declines in the serum PSA level of ⱖ50%. Ten patients achieved an increase in their hemoglobin level of at least 2 g/dL. Patients whose PSA level declined by ⱖ50% with therapy had significantly prolonged survival (median, 22 months). As pretreatment markers, a longer interval before the initial evidence of disease progression appeared was found to correlate significantly with posttherapy PSA declines of ⱖ75%. All side effects of the glucocorticoids were reported to be mild. CONCLUSIONS. Low doses of dexamethasone were found to be beneficial in the treatment of HRPC, decreasing the severity of anemia and osseous disease as well as reducing serum PSA levels. A posttherapy serum PSA decline of ⱖ50% appears to be a reliable marker of improved survival with this therapy.

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Editorial Comment: All too often we encounter men who have hormone refractory prostate cancer and agonize over what to do. This study suggests that low dose dexamethasone provides an excellent alternative. This agent is inexpensive and has few side effects. Patrick C. Walsh, M.D.

IMAGING Spontaneous Perirenal Hematoma. A Case Report and Review of Literature N. P. GUPTA, S. C. KARAN, M. ARON, R. PAWAR of Medical Sciences, New Delhi, India

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M. S. ANSARI, Department of Urology, All India Institute

Urol Int, 64: 213–215, 2000 Permission to Publish Abstract Not Granted Editorial Comment: In this report the authors discuss a case of spontaneous perirenal hematoma and review the literature. Extensive imaging was performed and no underlying tumor was detected. However, renal cell carcinoma was detected on followup imaging 3 months later. This clinical point is important for urologists. The majority of spontaneous perirenal hematomas are due to tumors, which are mostly renal cell carcinomas with some benign angiomyolipomas. If the tumor is small and cortically based, and the hematoma is large, the resulting renal distortion due to the hematoma makes identification and characterization of the underlying tumor difficult or impossible. If a source for the underlying hematoma is not identified on the initial scan, we recommend that patients return after 3 months for dedicated renal imaging (either precontrast and post-contrast computerized tomography [CT] or magnetic resonance imaging [MRI]) to assess for a potentially small, cortically based tumor. These authors suggest that angiography is necessary when CT does not identify the cause of perirenal hematoma, specifically to diagnose polyarteritis nodosa or other vascular abnormalities. CT and MRI angiography can be considered as they have excellent resolution and can give an accurate assessment of the intrarenal branch vessels for diagnosis of polyarteritis nodosa. These noninvasive imaging studies should also be considered. Cary L. Siegel, M.D. Various Radiological Appearances of Angiomyolipomas in the Same Kidney F. OBUZ, N. KARABAY, M. SEC¸ IL, E. IGˇCI, A. KOVANLIKAYA AND K. YO¨RU¨KOG˘LU, Departments of Radiology and Pathology, Dokuz Eylu¨l University School of Medicine, Izmir, Turkey Eur Radiol, 10: 897– 899, 2000 A 21-year-old woman with tuberous sclerosis presented with abdominal distension and flank pain. Imaging studies, including CT and MR imaging, revealed bilateral renal mass lesions, containing fat and suggesting the diagnosis of tuberous sclerosis. However the imaging characteristics of one of these lesions differed from the others with no radiologically detectable fat tissue in this solid lesion suggesting renal cell carcinoma. Histopathological examination of this lesion in the left kidney revealed an angiomyolipoma within minimal fat tissue. The radiological diagnosis of angiomyolipomas with minimal fat tissue remains difficult and the differential diagnosis is discussed. Editorial Comment: The authors report on multiple angiomyolipomas in a 21-year-old female with tuberous sclerosis. Although a majority of angiomyolipomas have recognizable fat on CT or MRI, a small percentage of angiomyolipomas have no obvious radiographic fat content. These lesions are indistinguishable from renal cell carcinoma based on imaging characteristics. An isolated lesion without fat is presumed to be renal cell carcinoma and not atypical angiomyolipoma. These lesions are almost always surgically excised and at that time the radiologists are notified that it was, in fact angiomyolipoma. An option that these authors did not discuss is ultrasound or perhaps CT guided fine needle aspiration, or even core biopsy of the lesion. This procedure would be adequate to differentiate angiomyolipoma with little fat from renal cell carcinoma in most cases. Although we do not usually biopsy renal masses, there are specific situations, including this scenario, when the benefits of renal biopsy outweigh the risks. If a lesion becomes symptomatic options, such as surgical resection as well as embolization, may be considered. Cary L. Siegel, M.D.