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Purpose: We determined nadir prostate specific antigen (PSA) after salvage cryotherapy to distinguish patients who are potentially cured from those at risk for subsequent biochemical and biopsy proved failure., Materials and Methods: A total of 146 patients who underwent salvage cryotherapy were followed a median of 21 months (range 3 to 47) with regular serum PSA analysis and digital rectal examination. Sextant biopsies were performed at 6 months or earlier when PSA increased greater than 2 ng./ml. from the nadir value (biochemical failure) or there was a palpable local recurrence. We compared the incidence of biochemical failure and biopsy specimens positive for cancer to pretreatment PSA and posttreatment nadir PSA., Results: In 59 of the 146 patients (40%) PSA decreased to an undetectable level within a median of 3 months. In 85 of the 109 patients (78%) who underwent biopsy the specimens were negative for cancer. Low serum PSA nadir values were associated with low pretreatment PSA and a low incidence of biochemical failure. In 6 of 60 patients (10%) in whom PSA nadir was 0.5 ng./ml. or less and in 18 of 49 (37%) with a higher PSA nadir biopsy was positive for cancer., Conclusions: A PSA nadir of 0.5 ng./ml. or less should be achieved after salvage cryotherapy. Higher nadirs are more likely to be associated with increasing posttreatment PSA and positive biopsies. PSA nadir is a better prognostic indicator of biochemical and biopsy proved failure after salvage cryotherapy than pretreatment PSA.

Purpose: We review the results of 5 years of using the unmodified appendix for reconstruction of neobladders and native bladders, and describe the mechanism of continence., Materials and Methods: Between 1993 and 1997, 24 patients have undergone continent urinary diversion using the unaltered appendix. Median patient age at the time of surgery was 62 years. Patients were followed at the urological outpatient clinic for a mean of 18 months (range 7 to 47). Video urodynamic studies were performed once in the first 6 months postoperatively and repeated if there was any history of incontinence or bladder problems., Results: Of the patients with an appendicovesicostomy onto the native bladder 80% were dry during the day and night. This figure was improved to 94% when 2 patients with incontinence catheterized more frequently. Patients with a neobladder were more likely to be continent and had a longer interval between catheterizations, which reflects the larger reservoir volume rather than better continence mechanism in these patients. The level of continence is at the appendiceal bladder junction in the native bladder and the appendicocecal junction in the neobladder, which is able to withstand reservoir pressures of 30 to 40 cm. water. Stress incontinence driven by abdominal pressure did not occur. Instead incontinence occurred when the bladder became over full and the pressure increased, or during an unstable contraction., Conclusions: The appendix does not need to be tunneled through the bladder wall to achieve satisfactory continence. In a low pressure reservoir continence may be achieved simply by anastomosing the appendix directly onto the bladder or leaving it in situ when creating a neobladder.

Purpose: We evaluated the presentation, methods of diagnosis and treatment of pelvic recurrence following radical cystectomy for transitional cell carcinoma of the bladder., Materials and Methods: We reviewed the records of 33 patients who underwent radical cystectomy for transitional cell carcinoma between May 1960 and August 1995 at our cancer center and who later had pelvic recurrence., Results: The majority of patients underwent cystectomy for clinically advanced transitional cell carcinoma. Median time from cystectomy to recurrence was 10 months. Of the patients 25 were symptomatic (76%) at the time recurrence was diagnosed. Recurrence was discovered by digital rectal examination in 4 asymptomatic patients (12%) and by routine pelvic imaging in 2. Treatment included chemotherapy, surgery or radiation (alone or in combination). Of the 33 patients 29 died of progressive disease with a median survival of 7 months from the time of recurrence, and 4 remained free of disease at 7, 14, 26 and 95 months after local recurrence. Despite the poor survival rate following treatment 11 of 14 patients had complete resolution of symptoms following chemotherapy., Conclusions: The prognosis of patients with local recurrence is poor regardless of therapy. These recurrences are often symptomatic but careful post-cystectomy tumor surveillance, including digital rectal examination and pelvic imaging, provides an opportunity to diagnose local recurrences when they may be amenable to therapy. Systemic chemotherapy offers excellent palliation for symptomatic patients.

Objectives: To report out experience with performing nephrectomy and vena caval thombectomy in patients with metastatic renal cell carcinoma., Methods: A retrospective review was performed of 15 patients who underwent surgical excision of the primary tumor and a caval thrombus and treatment of concurrent metastases between 1989 and 1995. The sites of metastases included lungs (n = 8), bone (n = 3), bulky retroperitoneal or mediastinal lymph nodes (n = 2), liver (n = 1), and contralateral adrenal (n = 1). The level of caval involvement was suprahepatic in 3 cases, retrohepatic in 2 cases, and infrahepatic in 10 cases. Three patients had an Eastern Cooperative Oncology Group performance score of 0, 11 had a score of 1, and 1 had a score of 2. Median follow-up was 17 months., Results: Median operative time was 6.5 hours and median hospitalization was 10 days. Two patients required re-exploration for postoperative hemorrhage. There were no perioperative deaths. Four patients underwent surgery for resection of solitary metastases (1 lung, 2 spine, and 1 humerus); 2 of the 4 received adjuvant radiotherapy. Two patients received biologic therapy preoperatively, 3 received it both preoperatively and postoperatively, and 6 received it only postoperatively. The median time to initiation of postoperative biologic therapy was 48 days (range 25 to 110). Eleven patients are currently alive, 7 with no evidence of disease at a median follow-up of 17 months (range 6 to 66) and 4 with stable metastases at 14 months (range 4 to 22). Ten of the 13 symptomatic patients had improved performance scores after surgery. Four patients have died from metastatic disease: 2 from rapid progression at 2 and 5 months after surgery and the other 2 at 17 and 42 months., Conclusions: Nephrectomy and vena caval thrombectomy can be safely performed in selected patients with metastatic disease. Furthermore, in patients receiving biologic therapy, nephrectomy may enable a better quality of life and prolonged survival.

Purpose: Hepatocyte growth factor/scatter factor (HGF/SF) is a potent mitogen to renal epithelial cells in vitro and in vivo. HGF/SF signals through its receptor which is coded by the c-met proto-oncogene. We hypothesized that altered expression of the HGF/SF receptor, c-met, may be involved in the pathogenesis of certain renal cell carcinomas. Our objectives were to 1) assess the presence and localization of c-met protein in benign and malignant human renal tissues, and 2) correlate the presence of c-met protein with renal carcinoma histological subtype, tumor stage and tumor grade., Materials and Methods: Immunohistochemical analysis of c-met protein was performed in 41 normal and malignant human renal samples., Results: c-met Immunostaining was detected in the normal kidney tissue in all 41 samples. In the normal kidney c-met immunostaining was limited to the cell membrane and/or cytoplasm of epithelial cells in specific tubular segments, including the proximal convoluted tubule, thin and thick limbs of the loop of Henle, and the collecting duct. The glomeruli, distal convoluted tubule and stroma were consistently negative for c-met staining. c-met Immunostaining was detected in 68% of renal cell carcinomas and was more common in higher nuclear grade cancers (p < 0.034)., Conclusions: The c-met receptor is present in specific tubular segments in the normal kidney and is frequently expressed in higher nuclear grade renal cancers, suggesting a role in renal carcinoma progression. Future studies should evaluate the biological significance of the HGF/ SF-c-met pathway in normal renal physiology, and renal cancer growth and progression.

Purpose: Orthotopic bladder reconstruction in women is the focus of considerable interest. To define suitable candidates for orthotopic reconstruction among women with bladder cancer, we reviewed the risk of secondary urethral, vaginal and cervical involvement by transitional cell carcinoma in patients who underwent radical cystectomy at our institution., Materials and Methods: We retrospectively reviewed the charts of women who underwent radical cystectomy for primary transitional cell carcinoma of the bladder between 1985 and 1995. These cases also were reviewed pathologically., Results: Of 115 patients who underwent radical cystectomy for transitional cell carcinoma of the bladder 9 (8%) also had secondary transitional cell carcinoma of the urethra, including 2 with concomitant involvement of the vagina or cervix. In 4 patients (3%) the vagina or cervix was involved but not the urethra. Vaginal and cervical invasion correlated with stages T3b and T4 disease (p = 0.04). By logistic regression analysis the sole significant risk factor for urethral involvement was bladder neck involvement (p = 0.0005). Unlike previous studies 2 of 9 patients with secondary urethral transitional cell carcinoma did not have apparent cancer at the bladder neck., Conclusions: We report secondary urethral involvement without apparent bladder neck involvement in women with transitional cell carcinoma. Women who are candidates for orthotopic reconstruction should undergo biopsies of the bladder neck and urethra as part of the preoperative evaluation. In patients with palpable masses (stage T3b) on bimanual examination, transvaginal biopsies should also be considered. Intraoperative frozen sections of the urethral and vaginal margins should be obtained.

Background: The optimal management of patients with renal cell carcinoma with inferior vena cava tumor thrombus remains unresolved. Traditional approaches have included resection with or without the use of cardiopulmonary bypass. Chemotherapy has played a minor role except for biotherapeutic agents used for metastatic disease., Methods: From January 1989 to January 1996, 37 patients with renal cell carcinoma and inferior vena cava tumor thrombus underwent surgical resection. The 27 men and 10 women had a median age of 57 years (range, 29 to 78 years). Thirty-six patients presented with symptoms; 21 had hematuria. Distant metastases were present in 12 patients. Tumor thrombi extended to the infrahepatic inferior vena cava (n = 16), the intrahepatic inferior vena cava (n = 16), the suprahepatic inferior vena cava (n = 3), and into the right atrium (n = 2). All tumors were resected by inferior vena cava isolation and, when necessary, extended hepatic mobilization and Pringle maneuver, with primary or patch closure of the vena cavotomy. Cardiopulmonary bypass was necessary in only 2 patients with intraatrial thrombus., Results: Complications occurred in 11 patients, and 1 patient died 2 days postoperatively of a myocardial infarction (mortality, 2.7%). Twenty patients are alive; overall 2- and 5-year survival rates were 61.7% and 33.6%, respectively. For patients without lymph node or distant metastases (stage IIIa), 2- and 5-year survival rates were 74% and 45%, respectively. The presence of distant metastatic disease (stage IV) at the time of operation did not have a significant adverse effect on survival, as reflected by 2- and 5-year survival rates of 62.5% and 31.3%, respectively. Lymph node metastases (stage IIIc) adversely affected survival as there were no long-term survivors., Conclusions: Resection of an intracaval tumor thrombus arising from renal cell carcinoma can be performed safely and can result in prolonged survival even in the presence of metastatic disease. In our experience, extracorporeal circulatory support was required only when the tumor thrombus extended into the heart.

Purpose: A phase I/II study was done to evaluate the efficacy and complications of salvage cryotherapy as a treatment for locally recurrent prostate cancer following full dose radiation therapy and/or systemic therapy. The efficacy of single and double freeze-thaw cycles was compared using posttreatment prostate specific antigen (PSA) levels and prostate biopsies as end points., Materials and Methods: A total of 150 patients with locally recurrent prostate cancer following radiation, hormonal therapy and/or systemic chemotherapy underwent salvage cryotherapy using a single (71 men, mean followup 17.3 months) or double (79 men, mean followup 10.0 months) freeze-thaw cycle. PSA was measured approximately every 3 months postoperatively and sextant biopsies were repeated 6 months postoperatively. Complications were assessed by retrospective chart review and a mailed quality of life survey., Results: Overall, 45 patients (31%) had persistently undetectable PSA. Patients with a history of radiation therapy only who underwent a double freeze-thaw cycle had a higher negative biopsy rate (93 versus 71%, p < 0.02) and lower biochemical failure rate (defined as an increase in serum PSA of 0.2 ng./ml. above the nadir value, 44 versus 65%, p < 0.03) than those who underwent a single freeze-thaw cycle. The main complications of salvage cryotherapy were urinary incontinence (73% of the patients), obstructive symptoms (67%), impotence (72%) and severe perineal pain (8%)., Conclusions: Salvage cryotherapy impacts local tumor control as evident by the high frequency of negative posttreatment biopsies. A double freeze-thaw cycle appears more effective than a single cycle. Like salvage prostatectomy, salvage cryotherapy causes significant morbidity.

Purpose: We correlated the expression of bcl-2 with accumulation of p53 protein in bone marrow metastases from patients with androgen independent prostate cancer and a history of hormonal ablation therapy. These results were correlated with clinical parameters, including the extent of bone marrow metastases and patient survival., Materials and Methods: All 43 patients studied had evidence of prostate cancer progression following androgen deprivation therapy and histologically confirmed bone marrow metastases. Decalcified tissue sections were used for immunohistochemical evaluation of bcl-2 protein and p53 protein accumulation., Results: We previously established that p53 protein accumulation as detected by immunohistochemistry is a reliable indicator of p53 gene mutation in prostate cancer. Immunoreactivity was demonstrated for p53 protein in 22 of 43 cases and for bcl-2 protein in 14. A total of 28 cases (65%) exhibited immunohistochemical evidence of p53 and/or bcl-2 expression, and 15 (35%) were negative for p53 and bcl-2. The expression of bcl-2 and accumulation of p53 were independent events (p < 0.01). The expression of bcl-2 or accumulation of p53 protein in prostate cancer metastases did not significantly influence patient survival or the extent of metastatic disease., Conclusions: The presence or absence of p53 protein accumulation and/or bcl-2 expression did not correlate with tumor burden or patient survival in stage D androgen independent prostate cancer bone marrow metastases. The expression of bcl-2 protein occurs independently of and is inversely correlated with p53 mutations in advanced prostate cancer.

Purpose: We report long-term followup of patients with incontinence and obstruction after salvage cryosurgical ablation of the prostate., Materials and Methods: We reviewed the records of 143 patients who underwent cryosurgical ablation of the prostate for treatment failure after radiation therapy. Data were collected by telephone interview with each patient and chart review. Median followup was 27 months (range 12 to 42)., Results: Of 107 patients who underwent cryosurgical ablation of the prostate using a commercially available urethral warmer 15 (14%) had significant obstruction or retention that required transurethral resection of the prostate in 10, of whom 6 became incontinent. Urinary incontinence occurred in 45 patients (42%) and resolved in 21 (47%), for an overall 28% long-term incontinence rate. Of 28 patients who underwent cryosurgical ablation of the prostate using an alternative urethral warmer 13 (46%) had incontinence and 15 (54%) had significant obstruction or retention. Resolution was rare and 89% of the patients are currently incontinent. Eight patients underwent 2 separate cryosurgical ablations with an 88% incontinence rate (43% overall). The double freezing technique did not increase postoperative obstruction or incontinence., Conclusions: Incontinence and urinary retention rates are increased in patients undergoing cryosurgical ablation of the prostate after failure of radiation therapy but spontaneous resolution occurs in half of the patients within 1 year if an effective urethral warmer is used. Incontinence treatments should be delayed until after this period. Postoperative incontinence and obstruction rates are significantly greater when an effective urethral warmer is not used and spontaneous resolution is rare.

Patients with radioresistant clinically localized prostate cancer may be treated by various means. Although androgen ablation is relatively noninvasive, it cannot be considered a curative option. We believe that a subset of patients with locally recurrent prostate cancer without subclinical metastatic disease exists and would benefit from maximally aggressive local therapy. Salvage surgery may offer long-term cancer control, particularly when the tumor is organ-confined, but is a technically challenging operation with a high incidence of postoperative incontinence. Cryoablation of the prostate for postirradiation recurrence may offer a less invasive alternative to radical surgery, but its long-term efficacy remains to be fully determined. Each therapeutic option has its characteristic attendant morbidity and the choice of therapy for local recurrence should be made with informed consent after frank discussion between physician and patient. We propose the treatment algorithm shown in Figure 1 for the management of patients with suspected recurrence after radiation therapy with the caveat that individual therapeutic strategies must be patterned around individual patient needs.

Local recurrence of invasive bladder cancer after radical cystectomy has an aggressive natural history with a poor prognosis. Most patients with this difficult clinical problem have either objective or subclinical metastatic disease. Accordingly, patients should be treated with a multimodality approach that includes systemic treatment (chemotherapy) as well as aggressive local treatments, such as surgery and radiation therapy. Although the prognosis is generally poor, long-term disease-free survival is achievable in a few patients with a multimodality treatment approach

Purpose: We evaluated the outcome of patients with locally recurrent renal cell carcinoma treated at our university., Materials and Methods: We retrospectively analyzed 16 cases of locally recurrent renal cell carcinoma in the renal fossa treated with surgical resection alone or in combination with biological therapy., Results: Complete resection was possible in 15 patients of whom 3 had positive surgical margins. Of the 12 patients with negative margins 6 are free of disease while the 3 with positive margins had involvement of a remaining ipsilateral adrenal gland and distant metastasis. Of all 16 patients 12 are alive a median of 23.5 months after the diagnosis of locally recurrent renal cell carcinoma. Of those treated with the combination of biological therapy and surgery 50% have no evidence of disease compared to 25% of those treated with surgery alone., Conclusions: Long-term survival can be achieved with an aggressive surgical approach. Incomplete resection or positive surgical margins are associated with a high risk of local or distant failure, and combined treatment with immunotherapy and surgery may offer a benefit compared to surgery alone.

Purpose: We determined the feasibility of renal cryotherapy in humans., Materials and Methods: Two patients with tumors in a solitary kidney were treated with renal cryotherapy., Results: Both patients tolerated renal cryotherapy well with no change in renal function and no postoperative complications., Conclusions: Cryoablation of select renal lesions can be performed safely with minimal loss of renal function.

Purpose: We determined whether an extended sentinel lymph node dissection is effective for staging penile squamous carcinoma associated with clinically negative inguinal lymph nodes., Materials and Methods: A retrospective review was done of 20 consecutive patients who underwent extended sentinel lymph node dissection between 1985 and 1994., Results: Of the patients 14 underwent bilateral extended sentinel lymph node dissection, and 6 underwent ipsilateral extended sentinel lymph node dissection plus contralateral inguinal or ilioinguinal lymphadenectomy. All lymph nodes included in the extended sentinel node dissection were negative for metastases. Five patients had inguinal metastases at a median of 10 months (range 3 to 21) after negative extended sentinel lymph node dissection., Conclusions: Although it is a more extensive procedure than sentinel lymph node biopsy, extended sentinel lymph node dissection is still associated with a significant false-negative rate (25%). Thus, its routine use can no longer be recommended.

Frequent loss of an allele at specific chromosomal regions implicates these regions as sites of tumor suppressor genes (TSG) that become inactivated during tumor progression. We have studied chromosome 8p allele losses in 32 primary human prostate carcinomas with 16 polymorphic microsatellite sequences. Overall, 22 of 32 (69%) informative specimens showed loss of allele in at least one locus. The most frequent losses of heterozygosity (LOH) occurred at the LPL locus (46%) on chromosome 8p22 and at the D8S360 (45%) and NEFL (43%) loci on chromosome 8p21. Homozygous deletions were detected at the LPL and NEFL loci at 8p22 and 8p21, respectively. The minimal region with frequent LOH and homozygous deletion, around the LPL locus, was restricted between the MSR locus and the D8S258 marker, separated by less than 9 cM. The second region was restricted between markers D8S1128 and D8S131 separated by 12 cM. The results suggest the existence of two chromosome 8p sites for candidate TSGs in prostate cancer.

Previously, we demonstrated that hepatocyte growth factor/scatter factor (HGF/SF) is expressed by human bone stromal cells and is a powerful mitogen to prostatic epithelial cells in culture. Based on these observations, we hypothesized that, if prostate cancer cells in the prostate or bone environment respond to HGF/SF as a mitogen, then they must express the HGF/SF receptor, which is coded by the c-met proto-oncogene. We used immunohistochemical techniques to: 1) assess the presence and localization of c-met protein in benign and malignant human prostate tissues and 2) correlate the presence of c-met protein with tumor stage, grade and androgen sensitivity. c-met protein immunostaining was consistently observed in the basal epithelial layer of normal prostate glands but was absent in luminal epithelial cells of the peripheral and transition zones. c-met protein immunostaining was detected in 10 of 11 foci (91%) of high grade prostatic intraepithelial neoplasia (PIN). Overall, c-met protein staining was noted in 36 of 43 (84%) primary prostate cancer samples versus 2 of 11 (18%) benign prostate hyperplasia samples (p < 0.0001) and in 4 of 4 (100%) lymph node metastases, 23 of 23 (100%) bone marrow metastases and 1 of 3 (33%) other metastatic sites. There was a clear relationship between c-met protein staining and higher grade adenocarcinomas (p < 0.001). c-met protein is frequently detected in PIN and higher grade prostate cancers; future studies should evaluate the biological significance of these findings.

Cell adhesion molecules have been suggested to function as tumor suppressor molecules. We have been studying one of the epithelial cell adhesion molecules (C-CAM), which belongs to the immunoglobulin gene superfamily. Transfection of a C-CAM cDNA expression vector into a highly tumorigenic human prostate cancer cell line (PC-3) suppresses tumor formation in nude mice. Alternatively, reducing C-CAM expression levels in the nontumorigenic rat prostate epithelial cell line NbE by the antisense expression vector markedly increases tumorigenicity of NbE cells in nude mice. These results suggest that C-CAM may be a tumor suppressor in prostate cancer. In this study, we examined the relationship between C-CAM expression during human prostate development and neoplastic progression by immunohistochemical staining of frozen sections. C-CAM predominantly localized on the plasma membrane of the basal cell layer in both the fetal and normal adult prostate gland. However, an overall decreased staining was seen in benign prostatic hyperplasia and high grade prostatic intraepithelial neoplasia. Furthermore, C-CAM was not detected in prostate carcinomas. Thus, a decrease in C-CAM expression may be an early event in hyperplastic/neoplastic transformation. These observations support the suggestion that C-CAM is a tumor suppressor in prostate cancer progression.

Mutations in microsatellite sequences, especially expansion in the number of di- and trinucleotide repeats, have been implicated as the cause of several heritable disorders, including fragile X syndrome and myotonic dystrophy. We examined the possibility that a similar mutation mechanism might be involved in human prostate cancer. Our findings indicate that mutations in microsatellite sequences are frequent in prostate cancer. Six of thirty patients (20%) had an allele gain in at least one microsatellite sequence; three patients (10%) had allele gains in multiple loci. The new alleles were present in the tumor DNA, but not in the normal DNA. Although we did not detect mutations in the androgen receptor microsatellite sequences, it is likely that this type of mutation affects other genes important in prostate cancer, thereby promoting tumor development and progression.

We used the fluorescence in situ hybridization (FISH) method to show that chromosome 7 trisomy is associated with the progression of human prostate cancer. Thirty-six specimens including 15 primary prostate carcinomas, 16 metastatic lesions, and 5 normal prostate tissues, as well as 2 prostate carcinoma cell lines of different tumorigenic potential, were examined for chromosome 7 aneuploidy. Our results showed that the androgen-unresponsive tumorigenic cell line PC-3 exhibited a significantly higher ratio of chromosome 7 to total chromosome number than the androgen-responsive nontumorigenic cell line LNCaP (P = 0.001). In prostate specimens, the frequency of trisomy 7 cells was significantly increased (P < 0.05) in the advanced stage tumors (C and DI) but not in the early (B) stage tumors or normal prostatic tissue. Furthermore, metastases showed a higher frequency of trisomy 7 cells than primary tumors (P = 0.005). In 2 patients with paired primary and metastatic tumors, trisomy 7 cells increased from 4-7% in the primary tumors to 42-45% in the metastatic tumor cells in the bone marrow. Therefore, our data suggest that trisomy 7 may be a common feature associated with local and metastatic progression and serve as a novel marker for human prostate cancer progression.

In search of biomarkers that predict of human prostate cancer progression, we hypothesized that these markers must be expressed in prostatic epithelial cells during multi-step prostate carcinogenesis. Since both genetic and epigenetic factors have been implicated in human prostate cancer development, two osseous-metastatic experimental models were developed in our laboratory, one based on gene transfection and the other on stromal-epithelial interaction studies. In the genetic model, PC-3 cells transfected with point-mutated c-erbB-2/neu oncogene subsequently acquired the potential to metastasize from the prostate to soft tissues and the skeleton. In the epigenetic model, sublines derived from the parental androgen-dependent LNCaP cell line metastasized from the primary tumor to the lymph node and bone. Cells with known lineage relationships were cloned from both the primary and the metastatic tumors and were characterized extensively using cellular, biochemical, immunohistochemical, and molecular techniques. Relevant stage-specific biomarkers associated with prostate cancer progression in these two models were defined and used to evaluate human prostate tissues obtained from the clinic. In this communication, we focused our discussion on the potential importance of c-erbB-2/neu oncogene, vimentin, hepatocyte growth factor/scatter factor and its receptor, c-met oncogene, tumor angiogenesis and neuroendocrine factors as biomarkers for human prostate cancer progression.

Background: Nuclear accumulation of p53 protein has been shown to be strongly associated with missense p53 mutations. Studies of nuclear accumulation of p53 protein in prostate carcinoma cells have to date been confined to material from primary tumors., Purpose: We studied the accumulation of p53 protein in specimens obtained from primary and metastatic sites of prostate carcinoma. By examining the accumulation of this protein as a function of stage, histologic grade, and androgen responsiveness of the tumor, we hoped to determine the role of p53 mutation in the progression of prostate carcinoma., Methods: The accumulation of the p53 protein in the cell nuclei was determined by immunohistochemical methods using polyclonal antibody to human p53 CM-1. The material studied consisted of formalin-fixed, paraffin-embedded tissue obtained from primary tumors and metastases of 92 patients with prostate carcinoma. Twelve samples from 11 patients were analyzed for the presence of mutations within exons 5-8 of the p53 gene (also known as TP53) by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) analysis. Sequence analysis was subsequently performed on DNA obtained by polymerase chain reaction amplification of PCR-SSCP reactions produced from six different specimens. The chi-square test, Fisher's exact test, and the Freeman Halton test were used for statistical analyses of the results., Results: All tumors with p53 accumulation were metastatic (stage D), poorly differentiated, and androgen independent. Nuclear accumulation of p53 protein was strongly associated with stage (D2 versus D1 versus A-C, P < .0001), grade (Gleason score 8-10 versus 5-7, P < .003), and androgen sensitivity (androgen independent versus dependent, P < .0001). Logistic regression analysis demonstrated that androgen sensitivity predicted p53 outcome better than did stage (P < .0001) or grade alone (P < .006). There was a perfect concordance between the results obtained by PCR-SSCP analysis and the p53 protein accumulation determined by immunohistochemistry in the 12 samples studied. Mutation of the p53 gene was confirmed by sequencing DNA obtained from six specimens positive in the PCR-SSCP assay., Conclusions: p53 gene mutation is a late event in the progression of prostate cancer and is associated with advanced (metastatic) stage, loss of differentiation, and the transition from androgen-dependent to androgen-independent growth., Implication: Testing of prostate cancer biopsy specimens from metastatic sites for p53 protein accumulation and gene mutation may provide useful prognostic information and could influence the recommended course of treatment.

We describe our experience with a simple inexpensive test with 2 practical uses: 1) to detect unrecognized intraoperative rectal injury and 2) to assess the adequacy of repair of rectal injuries.

A total of 20 patients received intravesical bacillus Calmette-Guerin (BCG) or mitomycin C for the treatment of carcinoma in situ following previous pelvic radiation therapy. Of the patients 14 (70%) responded completely after 1 or 2 courses of intravesical therapy. Mean followup from diagnosis of carcinoma in situ currently is 15.7 months. Complications of BCG and mitomycin C therapy were compared to the established complications of intravesical therapy with these agents. The incidences of fever greater than 103F, hematuria and bladder contracture were increased in patients receiving BCG following radiation therapy, although the cause of bladder contracture was probably multifactorial in our patient population. Our data suggest that BCG and mitomycin C are safe and biologically effective agents for the intravesical treatment of carcinoma in situ after pelvic radiation therapy.

Infusion of plasma containing zymosan-activated complement into sheep produces leukopenia, pulmonary leukostasis, pulmonary hypertension, hypoxia and increased plasma levels of thromboxane. We investigated the effects of the calcium channel blocking agent verapamil in this system using conscious sheep. Verapamil in 5 mg and 10 mg doses was administered by intravenous infusion prior to an infusion of autologous plasma containing zymosan-activated complement. Pretreatment with verapamil inhibited thromboxane synthesis, the rise in pulmonary artery pressure and the hypoxia without affecting the transient leukopenia. These effects are similar to those previously demonstrated with nonsteroidal antinflammatory drugs, suggesting that verapamil is acting at one or more early steps of the arachidonic acid cascade in addition to its influence on the calcium-sensitive protein interactions involved in smooth muscle function.