Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success?

The success of targeted therapies, including inhibitors of the vascular endothelial growth factor pathway or the mammalian target of rapamycin, in the treatment of metastatic renal cell carcinoma led to interest in testing their efficacy in the adjuvant setting. Results from the first trials are now available, with other studies due to report imminently. This review provides an overview of adjuvant targeted therapy in renal cell carcinoma, including interpretation of currently available conflicting data and future direction of research. We discuss the key differences between the completed targeted therapy adjuvant trials, and highlight the importance of accurately identifying patients who are likely to benefit from adjuvant treatment. We also consider reasons why blinded independent radiology review and treatment dose may prove critical for adjuvant treatment success. The implications of using disease-free survival as a surrogate end point for overall survival from the patient perspective and measurement of health benefit have recently been brought into focus and are discussed. Finally, we discuss how the ongoing adjuvant trials with targeted therapies and checkpoint inhibitors may improve our understanding and ability to prevent tumor recurrence after nephrectomy in the future.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes.

Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

The effect of a live Neospora caninum tachyzoite vaccine in naturally infected pregnant dairy cows.

Neosporosis, caused by the intracellular protozoan Neospora caninum, is a major cause of abortion and reproductive failure in cattle worldwide. The principal route of transmission of neosporosis is via in utero infection of the offspring. There is no effective prophylactic treatment or vaccine available against bovine neosporosis. A N. caninum NcIs491 isolate was examined for its ability to immunize and reduce abortions in naturally infected dairy cows under field conditions. N. caninum-seropositive pregnant dams were inoculated with 10(8) live tachyzoites during mid-term pregnancy. A total of 520 N. caninum seropositive dams were included in this study, of these, 146 were immunized and 374 cows served as a non-vaccinated control group. A significantly lower incidence of abortion was observed in vaccinated compared to non-vaccinated cows, 16 and 26% respectively (P=0.01), with a vaccine efficacy of 39%. However, the number of seropositive offspring remained similar in both groups. Overall, this field trial suggests that vaccination with live N. caninum tachyzoites should be considered as an effective measure to reduce abortions caused by neosporosis in naturally infected cows.

Genetic polymorphism of Babesia bovis merozoite surface antigens-2 (MSA-2) isolates from bovine blood and Rhipicephalus annulatus ticks in Israel.

This study demonstrated the genetic diversity among MSA-2c, MSA-2a1 and MSA-2b proteins of Babesia bovis isolates obtained from bovine blood and Rhipicephalus annulatus tick samples. The least identities that were observed among the deduced amino acid sequences of MSA-2c, MSA-2a1 and MSA-2b were 55, 63, and 71%, respectively. During the study four B. bovis calves, aged about 1 month, were found to be infected with virulent field strains and developed babesiosis. Probably, the calves had received insufficient antibodies, or the antibodies raised against the vaccine strain did not cross-protect against virulent field isolates. The complete msa-2 locus from the Israeli B. bovis vaccine strain and two field isolates were characterized. Similarly to the Australian strains and isolates, the msa-2 loci of the examined Israeli strain and isolates had only two msa-2 genes - msa-2c and msa-2a/b - located between msa-2c and orfB. Several of the examined samples, contained different MSA-2 genotypes concurrently. No obvious geographical relationships among isolates from various regions of Israel were established. Moreover, in the phylogenetic analyses, the Israeli deduced MSA-2 amino acid sequences of the three examined genes were clustered together with sequences derived from other countries, proving that the msa-2 gene sequences of B. bovis shared the same genetic characters worldwide. The present study clearly showed that the MSA-2 proteins of B. bovis isolates from Israel were genetically distinct from the vaccine strains. Thus, further research will be needed in order to understand the genetic diversity mechanisms of B. bovis, and the immunological responses of the infected animals.

Comparative analysis of mitochondrial markers from four species of Rhipicephalus (Acari: Ixodidae).

Mitochondrial sequences of four mitochondrial markers: 12S rRNA, 16S rRNA, cytochrome c oxidase subunit I (COX1) and cytochrome b (CytB) from four Rhipicephalus species were analyzed to establish genetic relationships and enable molecular identification. Field-collected samples from the species Rhipicephalus annulatus, Rhipicephalus bursa, Rhipicephalus sanguineus and Rhipicephalus turanicus were amplified by PCR and compared with GenBank™ annotated sequences. PCR products were obtained using primers that were designed to amplify orthologous sequences from different tick species and genera. The average intra-species sequence identity was 98.5-99.5%, while the average inter-species identity was 86.5-89.6%, reflecting a ≈ 10% decrease in the identity, when different species are compared. The "closest" two species, in terms of sequence identity, were R. sanguineus and R. turanicus, while the "least close" ones were R. annulatus and R. sanguineus. Molecular identification of each species was accomplished by a combined restriction analysis of 12S, COX1 and CytB markers, obviating the need for field sample sequencing. The restriction mapping data suggest that by using several markers, each with a unique digestion pattern, the identity of a given sample could be determined at the species level. It is anticipated that with the accumulation of more information on additional species and markers, molecular identification will become a standard approach for tick classification, complementing morphological taxonomy.

Cross-protection between geographically distinct Anaplasma marginale isolates appears to be constrained by limited antibody responses.

The rickettsia Anaplasma marginale causes the haemolytic disease bovine anaplasmosis, an economic problem in tropical and subtropical areas worldwide. The closely related but less pathogenic Anaplasma centrale is commonly used as a live vaccine to prevent anaplasmosis, but it can only be produced from infected blood. UFMG1 is a low pathogenic Brazilian strain of A. marginale, which has been shown to protect cattle against a high pathogenic Brazilian isolate. As UFMG1 can be grown in tick cells, the strain was proposed as a possible cell culture-derived vaccine. We have evaluated whether UFMG1 could protect cattle against a geographically distant heterologous strain, using A. centrale vaccination as a standard for comparison. Trial calves were infected with UFMG1, A. centrale or PBS. UFMG1-infected animals were more symptomatic than those infected with A. centrale, but none required treatment. All calves were then challenged with the Israeli A. marginale Gonen strain (one of the most prevalent strain in Israel). The A. centrale group had the mildest symptoms, while UFMG1 and control groups both had a more severe response. Nevertheless, the challenge did not cause life-threatening disease in any group. Animals infected with A. centrale had a significantly higher IgG response than UFMG1, when measured in an ELISA against initial bodies from their homologous strain or Gonen. The level of cross-reactivity of the response to initial infection correlated significantly with reduced symptoms after challenge. In conclusion, UFMG1 had limited effect in preventing disease by the geographically distant heterologous Gonen strain. While the low pathogenicity of the Gonen strain in this trial makes it impossible to conclusively state that UFMG1 would have given no protective effect against more serious disease, the comparatively low IgG response to UFMG1 suggests it would not have been as effective as A. centrale.

High sacrectomy for locally recurrent rectal cancer: Can long-term survival be achieved?

BACKGROUND: Locally recurrent rectal cancer involving the upper sacrum is generally considered a contra-indication to curative surgery. The aim of this study was to determine if a survival benefit was seen in patients undergoing high sacrectomy. METHODS: All patients with locally recurrent rectal cancer involving the sacrum above the 3rd sacral body between 1999 and 2007 were retrospectively reviewed. Kaplan-Meier survival analysis was performed. RESULTS: Nine patients were identified with a median age of 63 years. The proximal extent of sacral resection was through S2 (n = 6), S1 (n = 2), and L5-S1 (n = 1). All patients had R0 negative-margin resection. Median operative time was 13.7 hr, and median operative blood transfusion was 3.7 L. Thirty-day mortality was nil. Postoperative complications requiring surgical intervention occurred in three patients. Local re-recurrence in the pelvis occurred in one patient. The overall median survival was 31 months (range, 2-39 months). Three patients still alive are free of disease after 40, 76, and 101 months, respectively. Ultimately, all deaths were due to metastatic disease. CONCLUSIONS: High sacrectomy that achieves clear margins in patients with recurrent rectal cancer is safe and feasible. A majority will die of metastatic disease, but long-term survival may be possible in some patients.

Identification of Anaplasma centrale major surface protein-2 pseudogenes.

The present study was aimed to identify msp2 pseudogenes and MSP2 variants in the vaccine Anaplama centrale strain. Five msp2 pseudogenes were identified in the A. centrale genome, and multiple MSP2 variants that emerged during both acute and persistent infection were detected. The pseudogene copies of msp2 were truncated; they contained a central hypervariable region flanked by short portions of the 5' and 3' conserved regions. Alignment of the hypervariable region sequence of the expression site of MSP2 variants with msp2 pseudogenes showed that MSP2 variants are generated by two mechanisms, previously described in Anaplasma marginale: (i) recombination of the whole pseudogene into the single msp2 expression site, and (ii) recombination of small segments of pseudogenes into the expression site by segmental gene conversion. The present study showed that the A. centrale MSP2 variants and the msp2 pseudogene repertoire were different from those reported for A. marginale. Unique MSP2 variants and pseudogenes identified in the vaccine strain allow the A. centrale-vaccinated cattle to be superinfected with the field strains of A. marginale. The knowledge gained in the present study on the mechanisms of antigenic variations in the vaccine strain of A. centrale is a further step in the development of a new generation vaccine against anaplasmosis.

Experimental transmission of field Anaplasma marginale and the A. centrale vaccine strain by Hyalomma excavatum, Rhipicephalus sanguineus and Rhipicephalus (Boophilus) annulatus ticks.

The cattle rickettsia Anaplasma marginale is distributed worldwide and is transmitted by about 20 tick species, but only Rhipicephalus simus, a strictly African tick species, has been shown to transmit the vaccine strain of A. centrale. The aim of the present study was to examine transmission of field strains of A. marginale and of the vaccine strain of A. centrale by three tick species -Hyalomma excavatum, Rhipicephalus sanguineus and Rhipicephalus (Boophilus) annulatus - to susceptible calves. Two genetically distinct Israeli field strains of A. marginale, tailed and non-tailed (AmIsT and AmIsNT, respectively), were efficiently transmitted by R. sanguineus, whereas H. excavatum transmitted only the tailed isolate, and R. (Boophilus) annulatus did not transmit A. marginale. None of the three tick species transmitted A. centrale. By means of msp1a primers in PCR assays, amplicons of similar sizes were obtained from either A. marginale-infected calves that were used for acquisition feeding, from R. sanguineus fed on the infected calves, or from calves to which anaplasmosis had been successfully transmitted by these ticks. Although an A. centrale-specific fragment was amplified from salivary glands of R. sanguineus, no transmission to susceptible cattle occurred during 3 months of observation, and anaplasmosis was not induced in splenectomized calves that were subinoculated with blood from calves on which R. sanguineus had fed.

[Chromatin structure, heterochromatin, and transposable genetic elements--are they from one team?]. / Struktura khromatina, geterokhromatin i podvizhnye geneticheskie élementy--igroki odnoi komandy?

Gene content proved to be less than expected in completely sequenced eukaryotic genomes. Moreover, gene number differs only three times between such distant organisms as human and Drosophila. Hence it is likely that the essential functional and structural differences between the two species mostly depend on the regulation of gene activity than on the set and quality of genes themselves. New data demonstrate that changes in chromatin structure play a greater role in the fine gene activity regulation than considered before. R.B. Khesin had foresaw many chromatin functions that only recently came to be recognized. Khesin was interested in genome inconstancy over his last years. A higher content of several important chromosomal proteins was recently revealed in chromatin of transposable genetic elements (TGE). The possible role of TGE in chromatin organization in the nucleus is considered.

Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies.

PURPOSE: We hypothesized that markedly increasing the number of cores obtained during prostate needle biopsy may improve the cancer detection rate in men with persistent indications for repeat biopsy. MATERIALS AND METHODS: We performed saturation ultrasound guided transrectal prostate needle biopsy in 224 men under anesthesia in an outpatient surgical setting in whom previous negative biopsies had been performed in the office. The mean number of previous sextant biopsy sessions plus or minus standard deviation before saturation biopsy was 1.8 (range 1 to 7). A mean of 23 saturation biopsy cores (range 14 to 45) were distributed throughout the whole prostate, including the peripheral, medial and anterior regions. Indications for repeat biopsy were persistent elevated serum prostate specific antigen (PSA) in 108 cases, persistent elevated PSA and abnormal rectal examination in 27, persistent abnormal rectal examination in 4, high grade prostatic intraepithelial neoplasia in the previous biopsy in 64 and atypia in the previous biopsy in 21. RESULTS: Cancer was detected in 77 of 224 patients (34%). The number of previous negative sextant biopsies was not predictive of subsequent cancer detection by saturation biopsy. Median PSA was 8.7 ng./ml. and median PSA velocity was 0.63 ng./ml. yearly. Of the 77 patients in whom cancer was detected radical prostatectomy was performed in 52. Pathological stage was pT2 in 48 patients and pT3 in 4, while Gleason score was 4 to 5, 6 to 7 and 8 in 5, 46 and 1, respectively. At prostatectomy median cancer volume was 1.04 cc and 85.7% of removed tumors were clinically significant, assuming a 3-year doubling time. The overall complication rate for saturation needle biopsy was 12% and hematuria requiring hospital admission was the most common event. CONCLUSIONS: Saturation needle biopsy of the prostate is a useful diagnostic technique in men at risk for prostate cancer with previous negative office biopsies. This technique allows adequate sampling of the whole prostate gland and has a detection rate of 34% in this cohort of patients.

Proximity of prostate cancer to the urethra: implications for minimally invasive ablative therapies.

OBJECTIVES: The delivery of thermotherapy, cryotherapy, and interstitial radiation with minimal morbidity is dependent on the preservation of the prostatic urethra. Our aim was to determine the distribution of the distance between the urethra and the nearest prostate cancer. METHODS: We determined the location of cancer in 350 prostate cancers treated by radical prostatectomy between 1991 and 1993. Each pathologic specimen was totally embedded, serially sectioned, and whole mounted. For each prostate, the radial distance from the urethra to the nearest cancer was determined (urethral-cancer distance). The urethra-cancer distance was correlated with the clinical, pathologic, and laboratory factors. Univariate and multivariate associations with progression-free survival were determined. RESULTS: The mean follow-up was 6.1 years. Ninety-three patients had biochemical, local, or systemic cancer recurrence. The mean +/- SD distance from the urethra to the nearest cancer was 3 +/- 3 mm (range 0 to 18). In 58 patients (17%), the cancer touched the urethra. A decreasing urethra-cancer distance was associated with increasing rates of cancer recurrence (P = 0.009). The urethra-cancer distance correlated with each of the following preoperative factors: preoperative prostate-specific antigen (r = -0. 22, P <0.001), Gleason score in biopsy specimen (r = -0.13, P = 0.02), and percentage of Gleason score 4 or 5 in the biopsy specimen (r = -0.17, P = 0.008). CONCLUSIONS: The distance between the urethra and the nearest cancer was associated with prostate cancer outcome. Many patients have cancer close to the urethra. This finding may have implications for nonsurgical ablative therapies for prostate cancer.

Predicting the survival of bladder carcinoma patients treated with radical cystectomy.

BACKGROUND: Clinical outcomes vary for patients treated with radical cystectomy. The authors sought to identify factors associated with the survival of patients treated with radical cystectomy for urothelial carcinoma of the urinary bladder. METHODS: The authors studied 218 patients treated with radical cystectomy for urothelial carcinoma between 1980 to 1984. Patient ages ranged from 41 to 78 years (mean, 64 years). Using the 1997 TNM system, T classifications were Ta (17 patients), T1 (44), T2 (71), T3a (42), T3b (14), T4a (28), and T4b (2). Thirty-two patients had lymph node metastasis at the time of surgery. Histologic grade was determined according to the newly proposed World Health Organization and International Society of Urological Pathology grading system; tumor was low grade in 43 patients and high grade in 175. The male-to-female ratio was 4.9 to 1. The mean follow-up of patients still alive was 13.1 years (median, 13.8 years; range, 30 days to 18 years). Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on survival. RESULTS: Ten-year local recurrence free, distant metastasis free, cancer specific, and all-cause survival were 71%, 73%, 67%, and 41%, respectively. In univariate analysis, cancer size, T classification, and lymph node status were associated with distant metastasis free, cancer specific, and all-cause survival. Histologic grade and surgical margin status were significantly associated with worse cancer specific and all-cause survival, but not with distant metastasis free survival. In multivariate analysis, cancer size, margin status, T classification, and lymph node status were identified as significantly associated with cancer specific survival after adjustment for age and gender. CONCLUSIONS: Long term survival is achieved in a significant number of patients treated with radical cystectomy. In this study, patients with organ-confined (< or = pT2) and small size (< or = 3 cm) cancer had favorable 10-year distant metastasis free (93%) and cancer specific survival (88%) after cystectomy. Tumor size, margin status, extravesical involvement, and lymph node metastasis are important pathologic factors and should be considered as stratification variables in identifying patients for whom adjuvant chemotherapy should be evaluated in clinical trials.

The cell cycle inhibitors p21WAF1 and p27KIP1 are associated with survival in patients treated by salvage prostatectomy after radiation therapy.

We evaluated p27KIP1 and p21WAF1 expression in 52 patients treated by salvage radical prostatectomy and bilateral pelvic lymphadenectomy for biopsy-proven locally persistent or recurrent prostate cancer after external beam radiation therapy. We defined low and high expression based on the median value observed in our sample. Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p21 (< or =5%), compared with 94 and 100%, respectively, for those with high expression of p21 (>5%; P = 0.02 and 0.01, respectively). Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p27 (<50%), compared with 88 and 96%, respectively, for those with high expression of p27 (> or =50%; P = 0.06 and 0.01, respectively). These findings indicate that p21 and p27 expression levels are significant predictors of survival for patients selected for salvage prostatectomy for recurrent prostate cancer.

Outcome prediction with p53 immunostaining after radical prostatectomy in patients with locally advanced prostate cancer.

PURPOSE: Conventional pathological variables in prostate cancer may not provide optimal prediction of patient outcome. Pathological findings and p53 immunostaining were measured prospectively in radical prostatectomy specimens to determine the incremental improvement in prediction of patient outcome over clinical findings. MATERIALS AND METHODS: From a previous prospective study of 392 consecutive patients with prostate cancer who did not receive preoperative therapy and were treated with radical prostatectomy 25 had pathological stage pT3aN0M0, 24 had pT3bN0M0, 2 had pT2bN1M0, 7 had pT3aN1M0 and 14 had pT3bN1 prostate cancer. These locally advanced stage cases comprise the current study population and further analysis was done with p53 immunostaining. All prostate specimens were totally embedded, serially sectioned and whole mounted. We examined pathological, clinical and laboratory findings as well as p53 immunostaining. RESULTS: Median followup was 5.4 years (range 0.5 to 6.4). Univariate analysis revealed that pathological stage, 10% or greater immunostaining for p53, area and length of extraprostatic cancer extension, and cancer volume (all p

Squamous papilloma of the urinary tract is unrelated to condyloma acuminata.

BACKGROUND: To the authors' knowledge, there is no previous report of squamous papilloma of the urinary tract. It is uncertain whether there is a correlation between squamous papilloma, condyloma acuminatum, and verrucous carcinoma. METHODS: The authors evaluated the clinical and pathologic features of squamous papilloma (5 of the bladder, 2 of the urethra), condyloma acuminatum (3 cases), and verrucous carcinoma (3 cases) of the urinary bladder and performed human papillomavirus (HPV) DNA in situ hybridization studies to determine whether HPV was a common feature shared by these lesions. In addition, DNA ploidy evaluation by image cytometry and p53 immunohistochemical staining were performed. RESULTS: Squamous papilloma of the urinary tract occurred in elderly women and followed a benign clinical course with infrequent recurrence. All squamous papillomas were HPV DNA negative and DNA diploid with no or minimal p53 nuclear accumulation. Condyloma acuminata of the bladder contained HPV DNA, increased p53 protein expression, and aneuploid DNA content. All three cases of condyloma acuminata were associated with coexistent condylomata of the external genitalia, and two required pelvic exenteration for uncontrolled expansile growth. Verrucous carcinoma of the bladder occurred in elderly patients. All three cases of verrucous carcinoma were negative for HPV DNA and DNA aneuploid, and they exhibited consistent p53 expression. CONCLUSIONS: These data indicate that squamous papilloma is a distinct entity not related to condyloma or verrucous carcinoma. These lesions are benign, HPV DNA negative, DNA diploid, and they lack p53 overaccumulation.

Extranodal extension in lymph node-positive prostate cancer.

Evaluation of extranodal tumor extension may provide prognostic information for patients with epithelial malignancies. However, its importance for the patient who has prostate cancer with regional lymph node metastasis requires further investigation and clarification. This study was performed to evaluate the prognostic significance of extranodal extension (ENE) in a large series of node-positive patients. The study group included 212 node-positive patients who were treated by bilateral pelvic lymphadenectomy, radical retropubic prostatectomy, and androgen deprivation between 1987 and 1992 at the Mayo Clinic. ENE was defined as cancer perforating through the lymph node capsule into perinodal tissue. Nodal cancer volume was measured by the grid method. Univariate and multivariate risk ratios (RR) for distant metastasis-free and cancer-specific survival were estimated using the Cox proportional model. The mean follow-up was 6.3 years (median, 6.1 years). Distant metastasis-free and cancer-specific survival at 5 years for all patients was 91% and 95%, respectively. ENE was found in 126 of 212 patients (59%). The presence of ENE was not significantly associated with distant metastasis-free (RR = 1.6; 95% confidence interval [CI], 0.7 to 3.9) or cancer-specific survival (RR = 2.2; 95% CI, 0.7 to 6.8). Among 98 patients with a single positive node, there was no significant difference in distant metastasis or cancer-specific survival according to the presence of ENE (P = .88 and P = .36, respectively). After adjusting for Gleason score, DNA ploidy, and ENE, only nodal cancer volume was significantly associated with adverse distant metastasis-free (RR = 1.9; 95% CI, 1.5 to 2.8) and cancer-specific survival (RR = 1.4; 95% CI, 1.1 to 1.9). Our data indicate that the presence of ENE is not associated with unfavorable survival in patients with node-positive prostate cancer treated by radical retropubic prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation therapy. In contrast, nodal cancer volume was predictive of distant metastasis-free survival and cancer-specific survival.

Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin.

PURPOSE: Positive surgical margins are common after radical prostatectomy, and the role of adjuvant therapy in such cases is controversial. We determined the benefit of postoperative external beam radiation therapy in patients with margin positive prostate cancer with respect to biochemical progression or cancer recurrence. To decrease confounding factors that may affect the likelihood of biochemical progression our study was limited to men with organ confined cancer and a single positive margin. MATERIALS AND METHODS: We retrospectively evaluated the records of a nested matched cohort of 76 patients with pathological stage T2N0 prostate cancer and a single positive margin who underwent adjuvant radiation therapy within 3 months of radical prostatectomy. There was a positive margin at the prostatic apex in 35 cases, prostatic base in 18, posterior prostate in 11, urethra in 7, and prostatic apex and urethra in 5. These patients were matched 1:1 with 76 controls who did not receive adjuvant radiation therapy. Neither group received androgen deprivation therapy. Patients and controls were matched exactly for the margin positive site, age at surgery, preoperative serum prostate specific antigen, Gleason score and DNA ploidy. Biochemical relapse was defined as posttreatment PSA greater than 0.2 ng./ml. RESULTS: Overall there was significant estimated improvement plus or minus standard error in 5-year clinical and biochemical progression-free survival in 88%+/-5% versus 59%+/-11% of patients treated with adjuvant radiation therapy versus no radiation therapy (p = 0.005). No patient who received radiation therapy had local or distant recurrence, while 16% of controls had recurrence (p = 0.015). When stratified by site of margin positivity, the 5-year estimated clinical and biochemical progression-free rate in 18 cases and controls with a positive base margin was 95%+/-15% and 65%+/-13%, respectively (p = 0.02). The rate in 35 cases and cases with a positive apex margin was 95%+/-5% and 64%+/-15%, respectively (p = 0.07). Limited sample size precluded analysis of the other sites. CONCLUSIONS: Patients with localized prostate cancer and a singe positive surgical margin appear to have a lower rate of biochemical relapse at 5 years when adjuvant radiation therapy is administered. Definitive evidence of the beneficial effect of adjuvant radiation therapy for patients with involved surgical margins awaits conclusion of randomized clinical trials.

Paraganglioma of the urinary bladder: can biologic potential be predicted?

BACKGROUND: Paraganglioma of the urinary bladder is rarely encountered and its biologic behavior is uncertain. The authors sought to determine the prognostic factors that would predict patient outcome. METHODS: The Mayo Clinic experience over 53 years with paraganglioma of the bladder was reviewed. All histologic slides from 16 patients were reviewed by the authors. Eight cases were examined immunohistochemically with cytokeratin (AE1/3, cytokeratin 7, and cytokeratin 20), vimentin, S-100 protein, neuroendocrine markers (chromogranin, synaptophysin, and neuron specific enolase), p53 protein, and MIB-1. DNA ploidy was determined by digital image analysis in formalin fixed, paraffin embedded tissue. The mean follow-up was 6.3 years (range, 0.4-16.4 years). RESULTS: Paraganglioma usually occurred in young adult women (mean age, 45 years; range, 16-74 years). The male-to-female ratio was 1 to 3. The common symptoms and signs were hypertension and hematuria. The tumors were usually located intramurally in the lateral and posterior wall of the bladder and were multifocal in 3 cases (18%). Seven patients were treated by transurethral resection, eight by partial cystectomy, and one by radical cystectomy. T classification was T1 (1 patient), T2 (9 patients), T3 (2 patients), and T4b (4 patients). At the time of diagnosis, one patient had distant metastasis and one had regional lymph node metastasis. One patient developed metastasis 1 year after diagnosis and died of the disease 1.5 years later. None of the patients with T1 or T2 tumors had recurrence or tumor progression. All tumors were aneuploid. The mean MIB-1 labeling index was 1.5% (range, 0.03-7.0%). The tumor cells displayed immunoreactivity for S-100 protein and neuroendocrine markers and were negative for p53 (except 1 case) and cytokeratin. CONCLUSIONS: Paraganglioma of the urinary bladder occurs mostly in young adult women. Patients with tumor of advanced classification (>/=T3) are at risk of recurrence, metastasis, and dying of the disease, whereas patients in this study with T1 or T2 disease had favorable outcomes after complete tumor resection.