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Purpose: We present a 30-year experience with performing salvage surgery in patients with persistent prostate cancer (PCA) after definitive radiotherapy., Materials and Methods: Patients with biopsy proven PCA following definitive radiotherapy who underwent salvage surgery were identified retrospectively (1967 to 2000). Prostate specimens were evaluated by a single pathologist. Progression-free survival (PFS) and cancer specific survival (CSS) estimates were made with multivariate analysis of outcome predictors. Complications were reviewed., Results: Sufficient information was available on 199 patients, including 138 with retropubic prostatectomy (RP) and 61 with cystoprostatectomies (CP). Median followup was 7.0 years. Rectal injury rates (5% for RP and 10% for CP) remained stable, while transfused units of blood decreased. Urinary extravasation (15% of cases) and bladder neck contracture (22%) were the most common complications. Urinary continence (0 pads) improved from 43% to 56% of patients (p = 0.17) with an additional 20% requiring 1 or fewer pad daily. Overall 10-year CSS in all patients undergoing salvage surgery was 65%. Patients undergoing RP fared better than those needing CP (10-year CSS 77% vs 38%, p <0.001 and median PFS 8.7 vs. 4.4 years, p <0.001). Tumor ploidy, percent 4/5 Gleason grade and pathological stage were strong predictors of outcome, while margin status and preoperative prostate specific antigen had minimal predictive strength., Conclusions: Significant PFS and CSS can be expected following salvage surgery for radioresistant PCA. Several pathological features of the removed prostate are predictive of survival. The surgical risks of salvage surgery are now defined. Morbidity rates, including continence, have moderately improved with time.

An estimated 20-40% of men experience a biochemical recurrence within 10 years of definitive prostate cancer treatment. No single prostate-specific antigen (PSA) value is invariably associated with clinical metastasis or cancer-specific survival; PSA kinetics might prove to be a more important predictor of eventual progression-free survival and cancer-specific survival than absolute PSA level alone. With only one-third of patients progressing from biochemical recurrence to clinical disease, therapeutic morbidity should not outpace risk of disease progression. Salvage radiation therapy following radical prostatectomy has widely variable long-term biochemical control rates (from 18 to 64% depending on the follow-up period). Early hormonal therapy delivered as castration or complete androgen blockade might delay clinical metastasis in patients with high-risk pathologic disease; however, the adverse effects and morbidity of long-term therapy must not be underestimated. Non-steroidal antiandrogens as monotherapy for early biochemical recurrence, particularly for younger men who wish to preserve their libido and sexual potency, have received considerable attention, but there are conflicting data on long-term outcomes. Because of their favorable adverse-effect profiles, non-traditional therapies that exert localized hormonal or cellular effects are receiving considerable attention for treatment of early, PSA-only recurrence. Data from animal models provide a rationale for the use of these therapies, but there is a lack of evidence to support prolongation of progression-free survival or cancer-specific survival.

Purpose: Therapy for men with detectable prostate specific antigen (PSA) following radical prostatectomy (RP) for prostate cancer remains controversial. Salvage radiotherapy (SRT) is commonly used because of its relatively low morbidity. We present a single institution retrospective review of patients treated with SRT., Materials and Methods: A longitudinal cohort study (between April 1987 and April 2000) using the referral based Mayo Clinic Prostate Cancer Registry was conducted. A total of 211 patients were included in this study if detectable serum PSA was the sole indication for SRT and no hormonal therapy was administered., Results: Median followup from surgery to death or last followup was 7.2 years, from RP to SRT was 1.7 years and from SRT to last contact was 4.2 years. Median PSA and prostate specific antigen doubling time (PSADT) at SRT initiation was 0.60 ng/ml and 7.32 months; respectively. Of the patients 90% had nadir PSA less than 0.4 ng/ml within 3 years of SRT. Biochemical disease-free rates at 5 years for PSADT less than 12 or 12 months or greater was 48% and 66%; respectively (p = 0.080). By 10 years there was no significant difference in biochemical disease-free rate (34% vs 35%). Clinical metastasis (10% and 29%) developed in patients with a PSADT less than 12 months at a significantly higher rate than in patients with a PSADT of 12 months or more (0% and 17%, p = 0.045) at 5 and 10 years, respectively. Multivariate analysis revealed pre-SRT PSADT (less than 12 months, H.R. 3.88, p = 0.032), seminal vesicle invasion (H.R. 3.22, p = 0.008), pathological grade (H.R. 1.58, p = 0.023) and PSA at SRT (H.R. 1.29 for a 2-fold increase, p = 0.044) to be significant independent predictors of clinical recurrence. The interval from RP to SRT did not add to the model (p = 0.22)., Conclusions: A biochemical response can be expected in the majority of patients within 3 years of receiving SRT. Patients with a pre-SRT PSADT of 1 year or less have a less sustained biochemical response to SRT than patients with a PSADT greater than 1, yet the majority of patients appear to receive long-term benefit from this adjunctive therapy. PSADT is an independent predictor of biochemical and clinical disease recurrence following SRT.

Purpose: Surgical margin (SM) status is widely reported as a significant risk factor for prostate cancer recurrence following radical prostatectomy (RP). It has been presupposed that preserving the neurovascular bundle may compromise cancer control due to the limited surgical margin obtained with a resultant increase in treatment failure. We examined whether neurovascular bundle preservation during RP is a risk factor for positive SMs and progression-free survival after adjusting for disease severity., Materials and Methods: Outcomes following RP in 7,268 men between 1990 and 2000 were examined retrospectively. Median followup in those last known to be alive is 6.4 years. RP was performed by a total of 21 surgeons in the same basic fashion with strict attention to anatomical detail., Results: Overall a positive SM was identified in 38% of patients. The positive SM rate was higher for wide excision than for nerve sparing (NS) (42% vs 34%) (p

We have used the single electron oxidizing agent (SCN)(2)(*)(-) (generated by gamma-irradiation of aqueous thiocyanate) to produce guanyl radicals in plasmid DNA. The stable product(s) formed from these radicals can be detected after conversion with a base excision repair endonuclease to single strand breaks. The yield of enzyme-induced breaks is decreased by the presence during irradiation of indole compounds. Rate constants for the reduction of DNA guanyl radicals by these indoles can be calculated from the concentration dependence of the attenuation in the yield of enzyme sensitive sites. Indoles bearing electron-donating groups (methoxy or methyl) appear to react at the diffusion-controlled rate, but those bearing electron-withdrawing groups (cyano or nitro) are significantly less reactive. At physiological pH values, the reduction of a DNA guanyl radical involves the transfer of a proton as well as an electron. Comparison of the kinetic results with literature thermodynamic data suggests that the source of this proton is the complementary base-paired cytosine.

Guanyl radical species are produced in DNA by electron removal caused by ionizing radiation, photoionization, oxidation, or photosensitization. DNA guanyl radicals can be reduced by electron donation from mild reducing agents. Important biologically relevant examples are the redox active amino acids cysteine, cystine, methionine, tryptophan, and tyrosine. We have quantified the reactivity of derivatives of these amino acids with guanyl radicals located in plasmid DNA. The radicals were produced by electron removal using the single electron oxidizing agent (SCN)(2)(*)(-). Disulfides (cystine) are unreactive. Thioethers (methionine), thiols (cysteine), and phenols (tyrosine) react with rate constants in the range 10(4)-10(6), 10(5)-10(6), and 10(5)-10(6) dm(3) mol(-1) s(-1), respectively. Indoles (tryptophan) are the most reactive with rate constants of 10(7)-10(8) dm(3) mol(-1) s(-1). Selenium analogues of amino acids are over an order of magnitude more reactive than their sulfur equivalents. Increasing positive charge is associated with a ca. 10-fold increase in reactivity. The results suggest that amino acid residues located close to DNA (for example, in DNA binding proteins such as histones) might participate in the repair of oxidative DNA damage.

It has been strongly suggested that androgens and the cognate receptor (AR) may play important roles in the development and progression of prostate cancer. The AR is a transcription factor consisting of three major domains, i.e., N-terminal transactivation, middle DNA binding, and C-terminal steroid binding domains. Molecular events of androgen induced activation of the AR include conformation change, phosphorylation, acetylation, genomic DNA binding, and co-regulator recruiting. Many of these events can be manipulated in certain prostate cancer cells in favor of their progression. Dietary compounds and certain herbs have recently drawn a great deal of attention because of their relevance to development of several cancers including prostate cancer. We discuss in depth the findings from our and other laboratories of effects of dietary factors or herbs on the function of the AR and potential mechanisms on expression of the AR and AR regulated genes. We further discuss the potential implication of these dietary chemicals on prevention of development and progression of prostate cancer.

By using gamma-irradiation in the presence of thiocyanate ions, we have generated guanyl radicals in plasmid DNA. These can be detected by using an Escherichia coli base excision repair endonuclease to convert their stable end products to strand breaks. The yield of enzyme-sensitive sites is strongly attenuated by the presence of micromolar concentrations of one of a series of singly substituted phenols, and it is possible to derive bimolecular rate constants for the reduction of DNA guanyl radicals by these phenols. More strongly reducing phenols were found to react more rapidly. This electron-transfer reaction also involves a proton transfer. By comparing the expected energetics of the reaction with the observed rate constants, the electron transfer is found to be mechanistically coupled with the proton transfer.

Cystoprostatectomy specimens removed for bladder malignancy (1988-2000) at two referral centers (Mayo Clinic, Rochester, MN, The University Hospital of Innsbruck, Innsbruck, Austria) were examined for the coincidental finding of prostate cancer (PCA). Centralized examination of the prostate by a single uropathologist was performed if at the time of surgery the patient's serum PSA was < or =2.0 ng/mL and there were no suspicious lesions by digital prostate examination. Pathologic grade, stage, morphometric volume, number of tumor foci and association with areas of high grade prostatic intraepithelial neoplasia (HGPIN) were assessed by light microscopy. DNA ploidy and cellular proliferative index were assessed through digital image analysis. Clinically significant cancers were defined as tumors with > or =0.5 cc volume, Gleason 4 or 5 architecture, pT3, positive surgical margin, multifocality >3, nondiploid DNA content or proliferation index >5%. From nearly 1600 cystoprostatectomy specimens, 129 met the enrollment criteria. Thirty-patients (23%) within this group had PCA identified. Sixty percent of these tumors met the criteria for a clinically significant cancer. Nondiploid nuclear content was present in 17%. HGPIN was present in 70% and directly abutting carcinoma in 86% of prostates. The biologic activity of PCA appears to be independent of serum PSA. Any future definition of a clinically significant PCA should not be solely based upon histologic criteria, but needs to encompass clinical parameters (age, co-morbidities) and a noninvasive assessment of tumor volume and biologic doubling time.

Purpose: Information regarding the clinical impact of delayed (5 years or greater) biochemical failure (BF) after radical prostatectomy (RP) is lacking. We undertook an investigation to differentiate the innocuous recurrence of serum prostate specific antigen (PSA) from that which heralds an eventual clinical failure (CF), and to determine if there is a period following RP when a patient is cured of clinical disease., Materials and Methods: Men with clinically localized prostate cancer (PCA) undergoing RP (1987 to 1995) were identified from our longitudinal PCA registry. Outcome measurements were based on the detection of post-RP serum PSA 0.4 ng/ml or greater, clinical identification of cancer recurrence and disease related death., Results: Following RP in 3,903 eligible men, 33% had a detectable PSA (median followup 8.8 years). Of these BFs 27% occurred after 5 or more disease-free years. Currently, 29% of all men with BF have clinical evidence of PCA, with 8% dying of PCA (median actuarial survival time from CF to death 9.8 years). Progression from BF to CF was not significantly altered by the disease-free interval (p = 0.544). A PSA doubling time less than 12 months significantly increased the risk of CF regardless of the interval from surgery. Risk factors for BF were significant throughout the duration of followup., Conclusions: Patients are at prolonged risk for BF and CF following RP. Regardless of the timing of the initial PSA recurrence the PSA doubling time is the most powerful predictor of progression, stratifying patients with BF into high and low risk groups for CF.

When claims for the long-term survival of viable organisms are made, either within terrestrial minerals or on Mars, considerations should be made of the limitations imposed by the naturally occurring radiation dose to which they have been exposed. We investigated the effect of ionizing radiation on different bacterial spores by measuring the inactivation constants for B. subtilis and S. marismortui spores in solution as well as for dry spores of B. subtilis and B. thuringiensis. S. marismortui is a halophilic spore that is genetically similar to the recently discovered 2-9-3 bacterium from a halite fluid inclusion, claimed to be 250 million years old (Vreeland et al., Nature 407, 897-900, 2000). B. thuringiensis is a soil bacterium that is genetically similar to the human pathogens B. anthracis and B. cereus (Helgason et al., Appl. Environ. Microbiol. 66, 2627-2630, 2000). To relate the inactivation constant to some realistic environments, we calculated the radiation regimen in a halite fluid inclusion and in the Martian subsurface over time. Our conclusion is that the ionizing dose of radiation in those environments limits the survival of viable bacterial spores over long periods. In the absence of an active repair mechanism in the dormant state, the long-term survival of spores is limited to less than 109 million years in halite fluid inclusions, to 100 to 160 million years in the Martian subsurface below 3 m, and to less than 600,000 years in the uppermost meter of Mars.

The proper management of patients with locally advanced adenocarcinoma of the prostate has been contentious and too frequently based on antiquated misconceptions. Non-extirpative treatments, even when combined with neoadjuvant hormonal therapy, are inferior to the surgical removal of the prostate for controlling local progression and distant dissemination of the cancer. Radical prostatectomy combined with early adjunctive hormonal therapy for patients with nodal metastasis is superior to all other forms of therapy and should be considered the standard of care. This approach provides survival rates comparable with patients with clinically organ-confined prostate cancer.

Dietary factors and other naturally occurring substances may emerge as potent therapeutic or preventative agents in the battle against prostate cancer. Much of the current support for these agents is epidemiologically based, but new prospective studies are now underway which may support their use in conventional medical practice.

Purpose: The ideal imaging study for evaluation of the upper urinary tract in patients with microhematuria has been debated. We prospectively compared the diagnostic yield of computerized tomography (CT) to excretory urography (IVP) in the initial evaluation of asymptomatic microhematuria., Materials and Methods: Between December 1998 and June 2001, 115 patients presenting with asymptomatic microhematuria underwent CT and IVP before cystoscopy. Helical CT images with 5 mm. adrenal and kidney slices with and without contrast material were followed by delayed 5 mm. ureteral contrast images through the bladder base. Each CT and IVP was examined by a radiologist who was blinded to the result of the other imaging study. Diagnostic yields of the imaging techniques were compared using the test of 2 proportions and chi-square analysis., Results: Radiographic abnormalities were noted on CT or IVP in 38 patients. Sensitivity was 100% for CT and 60.5% for IVP, and specificity 97.4% for CT and 90.9% for IVP. CT accuracy was 98.3% compared to IVP accuracy which was 80.9% (p <0.001). A total of 40 nonurological diagnoses were made by CT, including 3 abdominal aortic aneurysms and 1 iliac artery aneurysm. No additional diagnoses were made by IVP. Fewer additional radiographic studies were recommended after CT than after IVP., Conclusions: The use of CT in the initial evaluation of asymptomatic microhematuria results in better diagnostic yield. In addition, more nonurological diagnoses can be made and less additional radiography is needed to confirm a diagnosis.

Purpose: Lymphadenectomy, especially extended lymphadenectomy, is not commonly performed in patients undergoing a radical nephrectomy for clear cell renal cell carcinoma. Surgeons may sample suspicious regional lymph nodes, but the lymph node status of many patients with renal cell carcinoma remains unknown, termed stage pNx. Outcome models based on large institutional reviews have been criticized for grouping stages pNx and pN0 cases because of concern that the pNx category may include unrecognized stages pN1/pN2 disease. We evaluated cancer specific survival differences in patients with clear cell renal cell carcinoma and a lymph node stage of pNx, pN0 or pN1/pN2., Materials and Methods: We searched the registry at our institution for patients who underwent radical nephrectomy for clear cell histology renal cell carcinoma between 1970 and 1998. Those with distant metastases at surgery were excluded from study. Clinical features obtained from the medical record included age at surgery, history of tobacco use, hypertension and symptomatic disease at presentation. A single urological pathologist reviewed all tumor specimens for nuclear grade, tumor necrosis, surgical margin status, 1997 tumor stage and lymph node status. These features were compared in patients with stages pNx and pN0 tumors. Cox proportional hazards models were used to compare cancer specific survival in univariate fashion, and after adjusting for tumor stage and grade., Results: The study cohort consisted of 1,535 patients with sporadic, unilateral clear cell renal cell carcinoma who underwent radical nephrectomy. There were 600 patients (39%) with stage pNx, 870 (57%) with stage pN0 and 65 (4%) with stages pN1/pN2 tumors. At an average of 4.2 years after surgery 414 patients died of renal cell carcinoma. On univariate analysis patients with stage pN0 tumors were significantly more likely to die of renal cell carcinoma than those with stage pNx tumors (risk ratio 1.40, 95% confidence interval 1.12 to 1.75, p = 0.003). However, after adjusting for tumor stage and nuclear grade the difference in outcome for stages pNx and pN0 tumors was not statistically significant (risk ratio 1.07 95% confidence interval 0.85 to 1.34, p = 0.583). Patients with stage pNx disease were significantly less likely to be symptomatic at presentation (p = 0.002), have tumors that were less than 5 cm. (p <0.001) and of lower stage (p <0.001) and grade (p = 0.005), and to have tumors with necrosis (p = 0.024) than patients with stage pN0 disease., Conclusions: Combining stages pNx and pN0 cases to create outcome prediction models after radical nephrectomy for clear cell renal cell carcinoma is appropriate in a multivariate setting that includes tumor stage and grade. Clinical features available preoperatively and during surgery can help guide the decision to perform limited lymph node sampling. When the tumor is 5 cm. or greater, shows pathological necrosis or is advanced grade 3 or 4, lymph node sampling adds little prognostic information.

Purpose: Buccal mucosa has been advocated as an ideal graft material for urethral reconstruction. We report our multicenter experience with buccal mucosa ventral onlay urethroplasty for complex bulbar urethral reconstruction in adults., Materials and Methods: A retrospective analysis of patients who had undergone buccal onlay urethroplasty at 4 military medical treatment facilities participating in the Uniformed Services Urology Research Group was performed. The database generated included demographic data, genitourinary history, preoperative symptoms (American Urological Association symptom score), preoperative urinary flow rate, stricture length and operative statistics. Postoperative followup data included symptom score, flow rate, retrograde urethrogram results, and complications., Results: A total of 53 patients (average age 32 years, range 17 to 64) underwent buccal mucosa graft urethroplasty between January, 1996 and March, 1998 for refractory strictures. Sixteen patients had undergone an average of 2.2 prior endoscopic procedures (range 1 to 7). Average stricture length was 3.6 plus or minus standard deviation 1.8 cm. (range 2 to 7.5) as measured on preoperative retrograde urethrogram. Followup averaged 25 months (range 11 to 40 months). Average symptom scores decreased from 21.2 (range 14 to 33) preoperatively to 5.4 (range 3 to 8) postoperatively (p <0.001). Average peak urinary flow rates increased from 7.9 preoperatively to 30.1 ml. per second postoperatively (p <0.001). Postoperative retrograde urethrograms were available for 34 patients and were normal in 24. The overall complication rate was 5.4%. Three patients required endoscopic incisions. One patient has a recurrent narrowing and treatment is considered a failure. There were 4 sacculations (7.5%) and 6 narrowings, 3 of which required further treatment. Of the patients 50 required no additional procedures (94.3%)., Conclusions: Buccal mucosa grafts used as a ventral onlay for bulbar urethral reconstruction yield reproducibly excellent results with minimal morbidity and low complication rates. Longer followup will be required to confirm the durability of our results.

The ionizing radiation induced bystander effect is initiated by damage to a cellular molecule which then gives rise to a signal exported to other cells. The nature of this damage is considered with the understanding that it may not be the same as that responsible for the traditional cellular effects of radiation. Consideration is give to amounts of endogenous damage and to radiation yields of the various candidate lesions.