Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology.

Twenty-four patients with locally advanced prostate cancer (CaP) were enrolled in a phase I clinical trial using gene-based immunotherapy. A functional DNA-lipid complex encoding the interleukin 2 (IL-2) gene (Leuvectin; Vical, San Diego, CA) was administered intraprostatically into the hypoecogenic tumor lesion, using transrectal ultrasound guidance. Two groups of patients having locally advanced tumors were enrolled to receive a treatment regimen composed of two serial intraprostatic injections of the IL-2 gene agent administered 1 week apart. The first groups of patients included radical prostatectomy candidates who subsequently underwent surgery after the completion of the treatment regimen. The second group consisted of patients who had failed a prior therapy. Prostate specimens of the treated areas were attained after treatment and compared with the transrectal biopsies performed at baseline to assess for any responses. IL-2 gene therapy was well tolerated, with no grade 3 or 4 toxic reactions occurring. The most commonly reported symptoms were mild hematuria, transient rectal bleeding, and perineal discomfort that are likely attributable to the injection itself. During the entire course of treatment, there were no significant changes in American Urologic Association (AUA) symptom scores, in hematologic disturbances, electrolyte imbalances, or hepatic functions. Evidence of systemic immune activation was observed after IL-2 gene therapy, based on an increase in the intensity of T cell infiltration seen on immunohistochemical analysis of tissue samples from the injected tumor sites, and based on increased proliferation rates of peripheral blood lymphocytes that were cocultured with patient serum collected after treatment. Furthermore, transient decreases in serum prostate-specific antigen (PSA) (responders) were seen in 16 of 24 patients (67%) on day 1. Fourteen of the patients persisted in this decrease to day 8 (58%). In eight patients the PSA level rose (nonresponders). More patients (9 to 10) in the group that failed prior therapy responded to the IL-2 gene injections (chi-square test, p = 0.04), and 6 of the 9 also had lower than baseline PSA levels at week 10 after treatment. To the best of our knowledge, this is the first clinical study of its kind aimed at exploring the role of IL-2-based gene therapy in CaP patients. This phase I trial demonstrated the safety of intraprostatic Leuvectin injection, with transient PSA-based responses seen after therapy.

Clinical characteristics in black and white men with prostate cancer in an equal access medical center.

OBJECTIVES: To determine whether black men with newly diagnosed prostate cancer in an equal access health care center are more likely to present with metastatic disease, more poorly differentiated tumors, higher serum prostate-specific antigen (PSA) levels, and/or at younger ages compared with white men. METHODS: A retrospective survey was conducted that identified black and white men with newly diagnosed prostate cancer at the Los Angeles Regional Veterans Affairs Clinics between 1991 and 1997. Patient data were analyzed for racial differences in age at diagnosis, clinical stage, PSA level, and Gleason score of the prostate biopsy specimens. RESULTS: A total of 477 evaluable patients (230 black, 247 white) with newly diagnosed prostate cancer were identified. No significant differences in the average age (66.9 +/- 7.3 versus 67.9 +/- 7.5) or clinical stage at diagnosis were found between black and white men. Among black men, 87% presented with clinically localized disease (T1-2, Nx, M0) compared with 88% of white men. Only 6% of black men presented with distant disease (Tx, Nx, M1) compared with 4% of white men. Black men had higher median PSA levels than white men (14. 2 versus 9.4 ng/mL, P = 0.0001). Black men also had slightly higher average Gleason scores (6.2 versus 5.9, P = 0.025). CONCLUSIONS: This is the first study to show a low and equal percentage of black and white men presenting with metastatic prostate cancer. In this equal access center, no differences were found in patient age or clinical stage of prostate cancer between black and white men at the time of diagnosis. However, black men presented with higher serum PSA values and slightly higher Gleason scores.

Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer.

PURPOSE: We compare the detection of metastatic disease by helical computerized tomography (CT), positron emission tomography (PET) with F-18 fluorodeoxyglucose and monoclonal antibody scan with 111indium capromab pendetide in patients with an elevated prostate specific antigen (PSA) after treatment for localized prostate cancer. MATERIALS AND METHODS: A total of 45 patients with an elevated PSA (median 3.8 ng./ml.) were studied following definitive local therapy with radical prostatectomy in 33, radiation therapy in 9 and cryosurgery in 3. CT of the abdomen and pelvis, and whole body PET were performed in all patients, of whom 21 also underwent monoclonal antibody scan. Lymph nodes 1 cm. in diameter or greater on CT were considered abnormal and were sampled by fine needle aspiration in 12 patients. RESULTS: PET and CT were positive for distant disease in 50% of 22 patients with PSA greater than 4, and in 4 and 17%, respectively, of 23 with PSA less than 4 ng./ml. The detection rate for metastatic disease was similar for CT and PET, and higher overall than that for monoclonal antibody scan. Monoclonal antibody scan was true positive in only 1 of 6 patients, while PET was true positive in 6 of 9 with CT guided fine needle aspiration proved metastases. CONCLUSIONS: CT and PET each detected evidence of metastatic disease in 50% of all patients with a high PSA or PSA velocity (greater than 4 ng./ml. or greater than 0.2 ng./ml. per month, respectively). Both techniques are limited for detecting metastatic disease in patients with a low PSA or PSA velocity. Our data suggest that monoclonal antibody scan has a lower detection rate than CT or PET.

Intraoperative frozen section monitoring of nerve sparing radical retropubic prostatectomy.

PURPOSE: We describe the clinical and pathological outcomes of intraoperative frozen sections performed on the posterolateral prostate margins during nerve sparing radical prostatectomy. MATERIALS AND METHODS: We developed a technique of bilateral nerve sparing, inking the posterolateral prostate margins and obtaining frozen sections. When tumor was seen on frozen section, the fascia and neurovascular bundle were widely excised before completing the vesicourethral anastomosis. We reviewed 142 radical retropubic prostatectomies performed by a single surgeon between 1992 and 1997. Patients were divided into group 1--nerve sparing procedure using our technique (48 patients), 2--planned unilateral nerve sparing without frozen sections (46) and 3--planned bilateral nerve sparing without frozen sections (48). Potency was measured implicitly by physician assessment and explicitly with the UCLA Prostate Cancer Index. Group comparisons were made for positive margins, biochemical recurrence and potency. Mean followup was 24.5, 43.8 and 39.4 months for groups 1, 2 and 3, respectively. RESULTS: Of the 48 group 1 patients 9 (18%) had adenocarcinoma in the frozen section specimen, prompting wide excision of the bundles. None of these patients had biochemical recurrence during a mean followup of 20.5 months. Both bundles were spared in the remaining 39 patients (82%). There was no difference in survival or time to biochemical recurrence between groups 1 and 2. Potency was significantly different between groups 1 and 2 (36 versus 13%, p = 0.001), even after age adjustment (p = 0.05). In contrast, potency did not differ between groups 1 and 3 (38 versus 40%). Preoperative stage, grade and prostate specific antigen level were similar among the 3 groups. CONCLUSIONS: We found a significant difference in potency rates adjusted for age between patients with and without frozen sections. Our results indicate that this technique can enhance the ability of the surgeon to monitor the nerve sparing procedure without compromising cancer control.

Metastatic renal cell carcinoma with concurrent inferior vena caval invasion: long-term survival after combination therapy with radical nephrectomy, vena caval thrombectomy and postoperative immunotherapy.

PURPOSE: We report our experience using aggressive multimodal therapy in a high risk group of patients with metastatic renal cell carcinoma and concurrent inferior vena caval extension. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients in our kidney cancer database who had metastatic renal cell carcinoma and tumor thrombus extension into the inferior vena cava at the initial diagnosis. Patients were included in the study if they underwent radical nephrectomy and inferior venal caval thombectomy, and immunotherapy was planned for the postoperative period. Tumor size and grade, metastatic sites, level of vena caval extension, surgical complications and overall survival were obtained from the medical records. The primary end point analyzed was overall survival. RESULTS: We identified 31 cases of metastatic renal cell cancer with extensive disease and vena caval extension. Of the patients 23% had an isolated lung metastasis, and 53% had metastasis in the lung and at other sites. The remaining patients had involvement primarily at nonpulmonary metastatic sites, including lymph node in 38%, soft tissue in 13%, liver in 29% and bone in 10%. Average blood loss during nephrectomy was 3,200 cc (median 2,100) and the rate of major complications was 12%. Of the patients 80% underwent the full course of surgery and postoperative immunotherapy. At a mean followup of 18 months (34 for survivors) 26% of the patients are alive. Actuarial overall 5-year survival of the group was 17%. Tumor thrombus level did not correlate with overall survival, while immunotherapy, tumor grade and metastatic site provided significant prognostic information. In patients with an isolated pulmonary metastasis the 5-year survival rate was 43%, while in those with low grade tumors it was 52%. CONCLUSIONS: In contrast to the poor results of surgery only in patients with renal cell carcinoma and concurrent inferior venal caval invasion, reasonable 5-year survival may be achieved after combined aggressive surgery and immunotherapy. Patients in whom metastasis was limited to the lungs and those with grade 1 to 2 tumors had a better prognosis. With careful planning and experienced immunotherapists therapy may be completed in the majority of this high risk group of patients.

Gene therapy for prostate cancer. New perspectives on an old problem.

Recent advances in molecular biology have made the prospect of gene therapy for prostate cancer a reality. A wide variety of genetic strategies, vector designs, and delivery modalities are currently in use. This article examines the state of the art prostate cancer gene therapy and details the various options available to clinicians.

Sarcomatoid renal cell carcinoma: biologic behavior, prognosis, and response to combined surgical resection and immunotherapy.

PURPOSE: Sarcomatoid variants of renal cell carcinoma (RCC) are aggressive tumors that respond poorly to immunotherapy. We report the outcomes of 31 patients with sarcomatoid RCC treated with a combination of surgical resection and immunotherapy. PATIENTS AND METHODS: Patients were identified from the database of the University of California Los Angeles Kidney Cancer Program. We retrospectively reviewed the cases of 31 consecutive patients in whom sarcomatoid RCC was diagnosed between 1990 and 1997. Clinical stage, sites of metastasis, pathologic stage, and type of immunotherapy were abstracted from the medical records. The primary end point analyzed was overall survival, and a multivariate analysis was performed to distinguish any factors conferring an improved survivorship. RESULTS: Twenty-six percent of patients were male and 74% were female, and the median age was 59 years (range, 34 to 73 years). Length of follow-up ranged from 2 to 77 months (mean, 21.4 months). Twenty-eight patients (84%) had known metastases at the time of radical nephrectomy (67% had lung metastases and 40% had bone, 21% had liver, 33% had lymphatic, and 15% had brain metastases). Twenty-five patients (81%) received immunotherapy, including low-dose interleukin (IL)-2-based therapy (five patients), tumor-infiltrating lymphocyte-based therapy plus IL-2 (nine patients), high-dose IL-2-based therapy (nine patients), dendritic cell vaccine-based therapy (one patient), and interferon alpha-based therapy alone (one patient). Two patients (6%) achieved complete responses (median duration, 46+ months) and five patients (15%) achieved partial responses (median duration, 36 months). One- and 2-year overall survival rates were 48% and 37%, respectively. Using a multivariate analysis, age, sex, and percentage of sarcomatoid tumor (< or >50%) did not significantly correlate with survival. Improved survival was found in patients receiving high-dose IL-2 therapy compared with patients treated with surgery alone or any other form of immunotherapy (P = .025). Adjusting for age, sex, and percentage of sarcomatoid tumor, the relative risk of death was 10.4 times higher in patients not receiving high-dose IL-2 therapy. Final pathologic T stage did not correlate significantly with outcome, but node-positive patients had a higher death rate per year of follow-up than did the rest of the population (1.26 v 0.76, Cox regression analysis). CONCLUSION: Surgical resection and high-dose IL-2-based immunotherapy may play a role in the treatment of sarcomatoid RCCs in select patients.

Isolation of human intestinal defensins from ileal neobladder urine.

We describe the isolation of naturally occurring human intestinal defensins HD-5 and HD-6 from ileal neobladder urine and ileal mucosa. Using an antibody-based detection assay, we found multiple N-terminally processed forms of HD-5. The predominant HD-5 forms in tissue were longer than those in neobladder urine (amino acid (aa) 23-94 and 29-94 versus aa 36-94, 56-94 and 63-94) suggesting that Paneth cells store prodefensin that is processed to mature defensin during or after degranulation. Search for mature HD-6 yielded aa 69-100 as the predominant form in both sources. The ileal neobladder is a promising model to study human Paneth cell secretion.

The University of California, Los Angeles/Jennifer Jones Simon Foundation symposium on prostate cancer and epithelial cell biology: bringing together basic scientists and clinicians in the fight against advanced prostate cancer.

Prostate cancer is the most common solid tumor in American men and is the second most common cause of cancer deaths. Although surgery and radiation therapy are effective for the treatment of organ-confined cancer, there is no effective treatment that is currently available for patients who have metastatic disease. Antiandrogen therapy is only palliative, and chemotherapy has largely been ineffective. However, recent advances in the understanding of the molecular biology of prostate cancer have lead to the development of new treatment strategies for metastatic cancer, including gene-based therapies, immunotherapies, and antiangiogenesis-based therapy. In association with the Jonsson Comprehensive Cancer Center and the University of California, Los Angeles Department of Urology, the Jennifer Jones Simon Foundation assembled 30 of the world's experts in prostate cancer research to review the most recent advances in the study of prostate cancer, with the hope that the resulting discussions would facilitate the rapid translation of new discoveries from the laboratory bench to the clinic.

Diagnosis and treatment of prostate cancer.

In the United States, prostate cancer is the most common solid tumor malignancy in men and second to lung cancer as the leading cause of cancer deaths in this group. Even though prostate cancer is responsible for 40,000 deaths per year, screening programs are a matter of controversy because scientific evidence is lacking that early detection decreases morbidity and mortality. Furthermore, treatment decisions are difficult to make because of the generally indolent nature of prostate cancer and because it tends to occur in older men who often have multiple, competing medical illnesses. Depending on the specific situation, radical prostatectomy, radiotherapy or watchful waiting (observation) will be the most appropriate management option. In general, localized cancer is best treated with surgical removal of the prostate gland or radiotherapy. Hormone deprivation therapy is the primary method of controlling metastatic prostate cancer. At present, chemotherapy cannot cure disseminated prostate cancer. Watchful waiting is a reasonable management alternative for prostate cancer in an older patient or a patient with other serious illnesses.

Low p27 expression predicts poor disease-free survival in patients with prostate cancer.

PURPOSE: p27 is an inhibitor of the cell cycle with potential tumor suppressor function. Decreased levels of p27 protein expression have been correlated with poor prognosis in patients with breast and colorectal carcinomas. Although as many as a third of patients with clinically localized prostate cancer will have relapse after radical prostatectomy, predicting who will have recurrence remains enigmatic. We examined the ability of p27 protein levels to predict outcome in patients with clinically localized disease who underwent radical prostatectomy. MATERIALS AND METHODS: p27 protein expression was evaluated in 86 patients with clinical stage T1-2 prostate cancer who were treated with radical prostatectomy. Archived paraffin embedded specimens were sectioned and immunostained with p27 antibody, and scored by 2 independent observers in a blinded fashion. The absence or presence of p27 protein was then correlated with biochemical relapse in univariate and multivariate analyses. RESULTS: In a multivariate analysis that included age, preoperative prostate specific antigen, Gleason score and pathological stage p27 was a strong independent predictor of disease-free survival (p = 0.0184, risk ratio 3.04), second only to pathological stage (p = 0.0001, risk ratio 6.73). Even more strikingly, multivariate analysis demonstrated that p27 was the strongest predictor of biochemical recurrence (p = 0.0081, risk ratio 4.99) among factors studied in patients with pathological T2a-T3b disease. CONCLUSIONS: Absent or low levels of p27 protein expression appear to be an adverse prognostic factor in patients with clinically organ confined disease treated by radical prostatectomy. This marker appears to be especially useful in those patients in whom surgery is believed to be potentially curative, that is patients with pathological T2-T3b disease. Patients with low or absent p27 protein expression may be candidates for novel adjuvant therapies.

Gene therapy for prostate cancer.

The treatment options for the patient with advanced prostate cancer are limited. Due to the recent advances in the understanding of the molecular biology of prostate cancer, the easy accessibility of the gland for injection, and the availability of gene promoters that can provide tissue specific expression of therapeutic gene sequences, gene therapy for prostate cancer is rapidly advancing. Many potential approaches for prostate cancer gene therapy have been identified, with a few of these already entering Phase I clinical trials. This review will discuss the basis of prostate cancer gene therapy, look at the potential approaches, and will compare the different vectors that can be used to deliver the therapeutic genes to the prostate tumor.

Severe hypotension, bronchospasm, and urticaria from intravenous indigo carmine.

Indigo carmine is generally believed to be a safe, biologically inert substance. Adverse reactions to the intravenous administration of this dye have been seen only rarely. We report a life-threatening anaphylactoid reaction to indigo carmine that may have been due to either a drug allergy or to its intrinsic serotonergic properties.

[TNM classification system in cancer of the submandibular gland--a comprehensive retrospective study of 271 primary cases].

UNLABELLED: A total of 271 patients with submandibular gland cancer, treated in 149 hospitals in Japan in the period from 1958 to 1991, were retrospectively studied with regard to age, sex, TNM classification (UICC 1987, Geneva), histological diagnosis, therapeutic method and prognosis. The results were the following: 1. 157 males and 114 females 2. Stage I: 52 cases (19%); stage II: 64 cases (24%); stage III: 52 cases (19%) and stage IV: 103 cases (38%). 3. T1: 29 cases (11%); T2:116 cases (43%); T3: 93 cases (30%) and T4: 43 cases (16%). 4. Cervical lymph node involvement: 40%, ranging 25% in adenoid cystic carcinoma and acinic cell tumor, to 62% in undifferentiated carcinoma. 5. Distant metastasis: 11% 6. HISTOLOGY: adenoid cystic carcinoma 37%, adenocarcinoma 20%, mucoepidermoid tumor 16%, carcinoma in pleomorphic adenoma 10%, epidermoid carcinoma 10%, undifferentiated carcinoma 3%, acinic cell tumor 3%. 7. Treatment method: Surgical procedure alone; 51%, Combination of surgery and postoperative radiation; 18%. 8. 5-year and 10-year survival rates were 36% and 11%, respectively. 9. 5-year and 10-year survival rates varied according to the stages, being 76% and 38%, respectively, for stage I, 68% and 20%, respectively, for stage II, 15% and 10%, respectively, for stage III, and 14% and 4%, respectively for stage IV.