Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer.

OBJECTIVES: No standard noninvasive diagnostic test reliably differentiates patients with organ-confined prostate cancer from those with lymph node metastases. The ability of a radiolabeled monoclonal antibody, indium-111 (111ln)-capromab pendetide, to identify sites of metastatic disease in patients at moderate to high risk of nodal involvement was investigated. METHODS: The study prospectively evaluated 160 patients with prostate cancer scheduled to undergo pelvic lymph node dissection (PLND) before or during definitive treatment. All were at relatively high risk of nodal involvement by virtue of significantly elevated baseline prostate-specific antigen (PSA) values, Gleason scores, and/or locally advanced clinical stages of disease. The histologic findings of the PLNDs were compared with the results of immunoscintigraphy, computed tomography, and magnetic resonance imaging. RESULTS: Among the 152 evaluable patientS studied with 111In-capromab pendetide before PLND, the sensitivity of immunoscintigraphy for lymph node detection was 62% and the specificity was 72%; the positive predictive value was 62% and the negative predictive value was 72%. In comparison, the sensitivity of computed tomography and magnetic resonance imaging was 4% and 15%, respectively, and the specificity was 100% for both procedures on the basis of a large number of negative interpretations. Logistic regression analysis revealed that immunoscintigraphy with 111In-capromab pendetide provided strong, independent evidence of the presence of lymph node metastases. Furthermore, the analysis indicated that certain combinations of PSA, Gleason score, and 111In-capromab pendetide were particularly effective at predicting the risk of nodal involvement. CONCLUSIONS: Immunoscintigraphy with 111In-capromab pendetide outperformed standard diagnostic imaging techniques in the detection of prostate cancer lymph node metastases and provided independent prognostic information that complemented PSA, Gleason score, and clinical stage.

Multicenter radioimmunoscintigraphic evaluation of patients with prostate carcinoma using indium-111 capromab pendetide.

BACKGROUND: Optimum therapy for prostate carcinoma patients requires accurate staging, but computed tomography (CT) and magnetic resonance imaging (MRI) have limitations as methods for detecting soft tissue metastases. In this study, radioimmunoscintigraphy (RIS) was evaluated for its ability to identify sites of metastatic disease in lymph nodes. METHODS: RIS was evaluated in 51 prostate carcinoma patients at high risk for metastatic disease. An intravenous infusion of indium-111 capromab pendetide was given, followed by nuclear medicine imaging on two separate dates. Bilateral, open pelvic lymph node dissection was performed with additional exploration and biopsy of scan positive extraprostatic regions. Histologic evaluation of removed tissue confirmed the accuracy of RIS. In addition, results were compared with other standard methods for diagnosing patients prior to surgery. RESULTS: Nineteen patients (37%) had evidence of lymph node involvement with RIS. Fifteen of the 19 positive patients had pathologic evidence of cancer in the biopsied lymph nodes. Sensitivity, specificity, accuracy, and the positive predictive value for detection of extraprostatic disease were 75%, 86%, 81%, and 79%, respectively. CT, MRI, and ultrasound of the pelvis demonstrated a combined accuracy of only 48% in detecting lymph node disease. Twenty-five previously undetected sites were deemed positive with RIS. Fourteen of these were biopsy-proven tumor sites, seven were probable tumor sites, and four were assumed to be false-positive. CONCLUSIONS: RIS had an impact on patient management through its detection of occult disease in more than 50% of prostate carcinoma patients studied, and it provided information concerning the likelihood that lymph node metastases would be found during surgery.

Prostate cancer abdominal metastases detected with indium-111 capromab pendetide.

To provide appropriate therapy for prostate cancer, accurate staging of the patient's disease is essential. Determination of tumor size, location, periprostatic extension and metastatic disease in the skeleton and soft tissue are needed to stage properly. Current diagnostic modalities may lead to understaging in 40%-70% of prostate cancer. Detection of metastatic disease, both at the time of initial diagnosis and in patients with suspected local recurrence, can significantly alter the type of therapy given. Clinical studies using the (111)In radiolabeled immunoconjugate, MAb 7E11-C5.3-GYK-DTPA (capromab pendetide), have shown the superiority of radioimmunoscintigraphy over other diagnostic modalities in the detection of both primary and metastatic prostate cancer. Radioimmunoscintigraphy with capromab pendetide depends on expression of tumor-associated antigen rather than lesion size. Earlier detection of extraprostatic invasion and metastases by means of radioimmunoscintigraphy provides valuable information for treatment decisions. A case of metastatic prostate cancer in the abdomen of a patient without local disease, in which the extent of disease was confirmed at autopsy after sudden cardiac arrest, is presented.

Monoclonal antibody imaging of recurrent and metastatic prostate cancer.

In summary, this agent is safe for administration and more accurate than any currently available imaging modality for the detection of extraprostatic metastases. This agent is still under investigation and some day may aid urologists in the evaluation of prostate cancer by improving preoperative staging and demonstration of advanced disease and postoperative localization of recurrent disease. Improved staging and localization will reduce unnecessary tests and treatment that will lead to reduced morbidity, better management, earlier detection, and intervention in advanced disease and improved cost-effectiveness.

Histocultures of human prostate tissues for pharmacologic evaluation.

This study evaluated the growth of human prostate tumors in histoculture, an in vitro culture technique that maintains three-dimensional tissue structure and organization. Eighty-six percent of 50 tumor specimens from 50 patients were successfully cultured. The histocultures showed proliferation of epithelial tumor cells and stromal cells. Prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) were detectable by immunohistochemistry for at least 8 weeks. Synthesis of PSA was further confirmed by its presence in medium. The mean thymidine labeling index (LI) of the neoplastic cells was 62%. There was no correlation between thymidine LI and tumor grade. The explants maintained their characteristics for at least 8 weeks as indicated by unchanged thymidine LI, PSA and PAP immunohistochemistry after 2 and 8 weeks in culture. A 24 to 48 hour delay in processing the tissues for culture did not reduce the thymidine LI. The thymidine LI and PSA and PAP staining in tumors cultured in a Minimal Essential Medium (MEM)-based or a PFMR-4-based culture medium were similar, suggesting an insignificant effect of the medium on cell proliferation. Migration of neoplastic cells from the tissue fragments into the collagen gel matrix was noted in 1 of 10 samples cultured in MEM-based medium versus 8 of 10 samples cultured in PFMR-4 medium (p < 0.01). Exposure of 13 patient tumors to suramin, doxorubicin and 5-fluorouracil at clinically relevant concentrations and duration showed tumor sensitivity in 23%, 31% and 15% of the specimens. These values approximate the historical clinical response rates. These data suggest that the histoculture system holds promise for short-term culture of human patient prostate tumor specimens for biologic and pharmacologic studies.

Pharmacokinetics of intravesical doxorubicin in superficial bladder cancer patients.

The urine and plasma pharmacokinetics of intravesical doxorubicin were studied in 8 patients with a history of superficial bladder cancer. Patients received 6 weekly treatments of 40 mg. doxorubicin in 20 ml. physiological saline. Doxorubicin was detectable (0.2 ng./ml. or more) in plasma from 6 of 8 patients during the initial treatment. The maximal concentrations ranged from 0.5 to 4.5 ng./ml. (mean 1.4). Doxorubicin was not detected in plasma from 7 of 8 patients during treatment 2 and not detected in any patient during treatment 4. The doxorubicin concentrations in urine decreased to approximately 50% at 5 minutes after dosing due to dilution by post-catheterization residual urine, and decreased by a further 6-fold by the end of the 2-hour treatment due to urine production. The recovery of doxorubicin at the end of treatment averaged 88.3%, with an additional recovery of 3.7% during the subsequent 4 hours. Urinary pH (range 5.5 to 8.5) did not affect the stability nor the systemic absorption of doxorubicin. In conclusion, we found that for intravesical doxorubicin therapy there was insignificant systemic exposure to doxorubicin, the highest systemic absorption from the bladder occurred shortly after surgery, there was high target site (bladder tissue) specificity, insignificant metabolism and/or degradation of doxorubicin, and dilution of urinary doxorubicin concentrations and, therefore, decreased tumor exposure to the drug due to residual urine and urine production.

Radioimmunoguided radical prostatectomy and lymphadenectomy.

BACKGROUND: The feasibility of using radioimmunoguided surgery (RIGS) (Neoprobe Corp., Columbus, OH) for intraoperative detection of prostate cancer was examined in a pre-Phase I clinical study involving 10 patients having radical prostatectomy and lymphadenectomy. METHODS: Patients were injected with iodine 125-radiolabeled B72.3 monoclonal antibody, which has been shown previously to bind to TAG-72, a pancarcinoma and oncofetal antigen. At a mean of 26 days after injection, RIGS was performed with a specially designed intraoperative gamma-detecting probe. RESULTS: By comparing probe counts with counts of appropriate background tissues, the RIGS system successfully localized tumor to the prostate of all 10 patients. Clinically occult and histologically confirmed bilateral intraprostatic tumor was identified in three patients. One additional patient had bilateral positive intraprostatic probe count ratios with the RIGS technique; on histologic examination, tumor was identified unilaterally, and extensive high-grade prostatic intraepithelial neoplasia was found on the contralateral side. Probe count ratios were positive in the lymph nodes of three patients; two had tumor confirmed histologically. CONCLUSIONS: The current investigation supports the feasibility of the RIGS technique and the need for additional studies.

The Cantwell-Ransley technique for repair of epispadias.

A total of 26 boys with bladder exstrophy (20) and epispadias (6) underwent initial urethral reconstruction between 1988 and 1991 using the Cantwell-Ransley technique. Penile reconstruction included wide mobilization of the urethral plate from the underlying corpora based on a mesentery from the ventral penoscrotal skin, corporeal lengthening by dividing the suspensory ligaments and attachments to the undersurface of the pubis, urethral and glandular tubularization, chordee correction by medial incision of the corpora with anastomosis dorsal to the urethra and penile skin coverage. All exstrophy patients had adequate phallic length, with 13 having an intact urethral plate and 13 having had prior paraexstrophy skin flap interposition. Postoperatively, repairs were intubated with silicone stents for 10 days. Two urethrocutaneous fistulas developed, 1 of which closed spontaneously. One patient had a small degree of penile skin loss that did not affect the neourethra. All patients currently have a cosmetically acceptable penis and all but 1 (previously diverted) are voiding per urethram. The neourethra in such patients allows for easier access for endoscopy and the ventral position aids in maintaining correction of the dorsal chordee. The low complication rate of this procedure coupled with the better anatomical configuration of the neourethra makes it useful for urethral and penile reconstruction in the exstrophy and epispadias patient.

Recurrent or aggressive bladder cancer. Indications for adjuvant intravesical therapy.

Advances in understanding of the variables that adversely affect the prognosis of patients with superficial bladder cancer allow more accurate predictions of the aggressive biologic potential of tumors. Intravesical therapy appears to be an effective and essential adjuvant in those patients with high-risk tumor variables. Multiple risk factors related to the tumor, individual patient characteristics, and treatment modality must be evaluated. Assignment of the relative importance of these risk factors will differ from patient to patient. Factors useful for predicting tumor aggressiveness in order to decide the appropriateness of adjuvant intravesical therapy include tumor size, configuration, and grade; ploidy status; Tis and T1 categories; multifocality; postoperative cytologic analysis; the failure of prior intravesical therapy; and prostatic urethral involvement. The integration of this information with formulation of a treatment plan represents both the art and the science of urologic oncologic practice. Research efforts need to be directed at the development of better tumor markers for superficial bladder cancer.

Penile cancer. Clinical presentation, diagnosis, and staging.

A high index of suspicion for penile cancer and a low threshold for biopsy of all penile lesions that do not respond to a short trial of conservative therapy are the primary requirements for early diagnosis and treatment of patients with penile cancer. Survival is related to stage; however, there is a considerable difference between clinical and pathologic stage. This discrepancy is attributable to the difficulty in determining corpora cavernosal invasion and inguinal lymph node metastases because of concomitant inflammatory changes and inaccuracies in diagnostic imaging modalities. Aggressive clinical staging may identify otherwise occult tumor and improve locoregional control and survival.

Anatomic radical cystoprostatectomy.

Radical cystoprostatectomy is considered one of the most difficult urologic operations. The nerve-sparing modifications that have allowed preservation of potency have resulted from an improved understanding of pelvic anatomy. This knowledge is not only important for preservation of potency; it also allows the entire operation to be done more precisely with increased exposure and decreased perioperative morbidity. Although many of the steps described above may seem routine to the urologist who does this operation frequently, we hope that this step-by-step guide proves useful to the practicing urologist who does only a few each year and to the resident who is learning the procedure.

Nerve growth factor, nerve grafts and amniotic membrane grafts restore erectile function in rats.

In an effort to reduce complications arising from radical pelvic surgery, an improved technique for restoration of autonomic innervation has been developed. The ability of nerve growth factor (NGF) alone or in combination with interposition nerve grafts, as well as the use of fetal amniotic membrane as an alternative growth matrix to enhance regeneration of ablated cavernous nerves were investigated in rats. Rats with ablated cavernous nerve displayed little or no penile erection, either in response to direct electrical stimulation or to an estrous female rat. A step wise improvement in electrically induced erections was observed by NGF alone, nerve graft alone, and the combination of NGF and nerve graft. Restoration of sexual behavior followed the same pattern obtained with electrical stimulation. Furthermore, the use of neonatal amniotic membrane as an alternative nerve growth matrix enhanced both electrically stimulated erection and mating behavior. These results suggest that the use of NGF and appropriate grafting materials can facilitate autonomic nerve regrowth and potentially reduce the morbidity of surgically induced nerve injuries.

Improved technique for creation of ileal conduit stoma.

Creation of a circumferentially protruding urinary intestinal stoma is an important aspect to prevent stomal regression, stenosis and parastomal herniation. Furthermore, an improperly fashioned stoma may make fitting of an ostomy appliance difficult, resulting in urinary leakage with secondary dermatitis and incrustation. The major difficulty in fashioning the stoma is everting the mucosa over the intestinal mesentery. We describe our method of stoma formation that creates a circumferentially symmetrical protruding stoma free of tension that has been used successfully even in obese patients. This technique has made the use of a Turnbull stoma unnecessary in our recent experience.

Advanced small cell carcinoma of the bladder. Successful treatment with combined radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy.

Undifferentiated small cell carcinoma of the bladder is a rare tumor with pathologic features similar to those of oat cell carcinoma of the lung. This neuroendocrine neoplasm of the bladder has a highly malignant biological behavior; most patients present with either locally advanced or distant metastatic disease and die despite aggressive therapy. Here the histologic, immunocytochemical, and ultrastructural features of small cell carcinoma of the bladder are reviewed in detail. In addition, two patients with advanced small cell carcinoma of the bladder who were treated successfully with radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy (M-VAC) are presented. Both men had regional lymph node involvement and are disease free at follow-up of 1 year and 2.5 years, respectively. This is the first report of combined surgical and M-VAC chemotherapy in the treatment of undifferentiated small cell carcinoma of the bladder.

Enhanced anti-tumor effects of recombinant human tumor necrosis factor plus VP-16 on metastatic renal cell carcinoma in a xenograft model.

A nude mouse renal subcapsular and subcutaneous implantation xenograft model utilizing the SN12C human renal carcinoma cell line was investigated. In the absence of treatment, renal subcapsular implantation of SN12C resulted in metastatic spread (lung, liver and lymph nodes) and death of all animals. Radical nephrectomy of the tumor-bearing kidney after various periods of tumor implantation demonstrated that surgery alone after 18 days of tumor growth resulted in no statistically significant increase in survival with 100% of the nephrectomized animals succumbing to local recurrence and distant metastases. Recombinant human tumor necrosis factor (rTNF) and VP16 (etoposide), both well known cytotoxic and cytostatic anticancer agents, were tested singly and in combination against this metastatic model of human renal adenocarcinoma. Single agent rTNF or VP16 therapy after radical nephrectomy demonstrated only minimal efficacy with no significant decrease in local recurrence and distant metastases as compared to nephrectomy only control animals. In contrast, the combination of rTNF plus VP16 when given after nephrectomy resulted in a significant decrease in local recurrence and no gross evidence of metastasis in any animal. Subcutaneously growing SN12C tumor nodules were also treated with the same rTNF, VP16 and combination regimens. Regression in tumor size was noted only in the combination treatment group. rTNF or VP16, as single agents, demonstrated only slight growth inhibition that was not statistically significant. These results suggest that by combining TNF plus VP16, a synergistic enhancement of antineoplastic activity against local as well as metastatic human renal cell carcinoma can be produced.

Abdominal polyorchidism: an unusual variant.

We describe an 18-month-old boy with polyorchidism in whom both ipsilateral testes were located intra-abdominally. To our knowledge no prior reports have documented a similar case in the literature to date. This case has important implications pertaining to the treatment of intra-abdominal cryptorchid testes. Intra-abdominal polyorchidism and its management are discussed briefly.