Immunological effects of treatment with sequential administration of recombinant interferon gamma and alpha in patients with metastatic renal cell carcinoma during a phase I trial.

Many anticancer mechanisms of the interferons have been proposed but none have been associated with clinical response to date. The biological activities of the interferons in vivo have included effects upon the natural killer cell, T- and B-lymphocytes, and macrophages. This report details a prospective study of the immunological effects on peripheral blood mononuclear cells of sequentially administered recombinant (r) interferon (IFN) gamma and rIFN alpha in 28 patients with metastatic renal cell carcinoma. Natural killer cell activity, T-cell phenotype (CD4, CD8, CD56, CD16, CD4/HLA-DR, CD8/HLA-DR, CD56/HLA-DR) and 2',5'-oligoadenylate synthetase were measured prior to therapy, during therapy, and following completion of treatment. Statistical analysis of all parameters was performed for the entire group, by individual patient, by dosage, by time, and by clinical response. An overall significant depression in natural killer cell activity and in the percentage of circulating CD56, CD16, and CD8+ cells were noted. Significant increases in 2',5'-oligoadenylate synthetase and in the percentage of circulating CD4 cells were also noted. Although an association between the magnitude of change in percentage of CD16+ cells and 2',5'-oligoadenylate synthetase and dosage of rIFN gamma and rIFN alpha, respectively, was observed, optimal biological dose of this sequence of rIFNs could not be determined due to the limited number of patients. A decrease in the percentage of circulating CD8+ cells was observed among patients with objective clinical response (partial and complete). Sequentially administered rIFN gamma and rIFN alpha can modulate immunological parameters in vivo in patients with metastatic renal cell carcinoma. A fall in percentage of circulating CD8+ cell is associated with response and suggests that this sequence of rIFN alpha and rIFN gamma might influence T-cell mediated antitumor activity.

Bladder cancer-associated nuclear matrix proteins.

The early diagnosis of bladder cancer is central to the effective treatment of the disease. Presently, there are no methods available to easily and specifically identify the presence of bladder cancer cells. The prevailing method for the detection of bladder cancer is the identification of bladder cancer cells by morphological examination of exfoliated cells or biopsy material by a pathologist. A hallmark of the malignant or transformed phenotype is an abnormal nuclear shape, the presence of multiple nucleoli, and altered patterns of chromatin organization. Nuclear structural alterations are so prevalent in cancer cells that they are commonly used as markers of transformation for many types of cancer. Nuclear shape is determined by the nuclear matrix, the dynamic skeleton of the nucleus. The nuclear matrix is the structural component of the nucleus that determines nuclear morphology, organizes the DNA in a three-dimensional fashion that is tissue specific, and has a central role in the regulation of a number of nuclear processes, including the regulation of DNA replication and gene expression. Previous investigations into prostate and breast cancer have revealed that nuclear matrix protein (NMP) composition undergoes alterations with transformation and that the nuclear matrix can serve as a marker for the malignant phenotype. In this study, we have identified NMPs with which it is possible to differentiate human bladder tumors from normal bladder epithelial cells. We examined the NMP composition of 17 matched tumor and normal samples from patients undergoing surgery for bladder cancer. We have identified six proteins present in all tumor samples that are not present in the corresponding normal samples and three proteins that are unique to the normal bladder tissues in comparison with the tumor samples. Five of the six bladder cancer-associated proteins were also identified in three human bladder cancer cells lines examined (253j, UMUC-2, and T24). Therefore, we have demonstrated that nuclear matrix composition is able to differentiate bladder cancer from normal bladder tissue and may provide useful tools for early detection and recurrence of the disease. Importantly, these markers may provide valuable tools for cytopathological screening for bladder carcinoma.

A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma.

This study investigated the effects of sequentially administered recombinant interferon gamma (rIFN gamma) and recombinant interferon alfa (rIFN alpha) in 36 patients with metastatic renal cell carcinoma (RCC). rIFN alpha was subcutaneously administered daily for 70 days at dosages that varied (2.5, 5, 10, and 20 x 10(6) U/m2) across four cohorts of patients. Within each cohort of patients receiving a given dose of rIFN alpha, three subsets of patients received either 30, 300, or 1,000 micrograms/m2 rIFN gamma. rIFN gamma was administered intravenously for 5 days every third week, 6 hours prior to administration of rIFN alpha. Dose-limiting toxicity (DLT) included constitutional symptoms, leukopenia, nephrotic syndrome with acute renal failure, hypotension associated with death, and congestive heart failure. DLT was related more often to the rIFN alpha dose level than to rIFN gamma dose level. Maximum-tolerated dose (MTD) was 10 x 10(6) U/m2 rIFN alpha and 1,000 micrograms/m2 rIFN gamma. Six patients failed to complete a minimum of 21 days of therapy due to toxicity or rapid progression of disease. Clinical responses were seen in eight of 30 assessable patients. Two patients experienced complete remission and have remained in complete remission 20+ and 22+ months. An additional six patients have shown partial responses for 4 to 18+ months. One patient in partial remission continues to show slow regression of pulmonary and liver lesions off therapy with rIFNs. Clinical responses have remained durable for patients with complete remissions and patients with partial remissions. The results of this study suggest that toxicities associated with combination rIFN therapy can be reduced by administering these agents sequentially as opposed to simultaneously.

Pharmacological modulators of DNA-interactive antitumor drugs.

The poor therapeutic index and limited efficacy of current cancer chemotherapeutic agents represent an important pharmacological problem. Although there has been a significant increase in our understanding of the mechanisms by which anticancer drugs kill mammalian cells, identification of new, effective anticancer agents during the last decade has been exceeding slow. Thus, attention has focused on understanding the causes of drug resistance and on either sensitizing tumor cells to existing anticancer agents using what could be called 'chemoenhancers', or protecting non-malignant tissues against serious untoward effects using 'chemoprotectors'. John Lazo and Robert Bahnson review recent strategies attempting to modulate the activity of antineoplastic drugs.

Quantitative DNA analysis of small renal cortical neoplasms.

DNA aneuploidy is common in large renal cortical neoplasms (RCNs), but the incidence in small RCNs is not known. This study was undertaken to investigate whether the traditional 3.0-cm size distinction between small (benign) and large (malignant) tumors might have an objective correlate in the form of abnormal DNA content. Quantitative DNA analysis was performed retrospectively, by image analysis, on 59 RCNs measuring 5.0 cm or less from 30 nephrectomy specimens with solitary tumors and 17 with multiple tumors. DNA indices and the proportion of cells with DNA content greater than that of the G0/G1 population were evaluated with respect to tumor size, stage, and histologic parameters. There was a relationship between the presence of detectable nondiploid stem lines (NDSLs) and tumor size, stage, nuclear grade, and proportion of non-G0/G1 cells, but not histologic pattern. The relationship of NDSLs to tumor size was more apparent in the solitary tumor group, while the relationship of a high proportion of non-G0/G1 cells to tumor size was stronger in the multiple tumor group. Our results show that the incidence of NDSLs increases with tumor size and nuclear grade, and suggest that as RCNs enlarge, the emergence of NDSLs heralds potential biologic aggressiveness. Further, solitary tumors and multiple synchronous tumors may be biologically different in terms of etiologic factors and growth potential.

Carcinoma of prostate metastatic to parotid gland.

A rare case of prostate cancer with metastasis to the parotid salivary gland is reported. The prostatic origin of the mass was proven by incisional biopsy and immunohistochemical staining for prostate-specific antigen. Additional studies of the tumor included ultrastructural and quantitative deoxyribonucleic acid (DNA) analysis.

Epididymal metastasis from prostatic carcinoma.

A case of epididymal metastasis from carcinoma of the prostate with an unusual presentation is reported. A review of the literature disclosed only 10 reported cases of this rare finding. A mechanism for the method of metastasis in this patient is proposed.

Adjuvant radiation therapy in stages C and D1 prostatic adenocarcinoma: preliminary results.

Twenty patients with adenocarcinoma of the prostate underwent postradical prostatectomy adjuvant external beam megavoltage radiation therapy because of periprostatic disease in histologic evaluation of the resected specimen. Fourteen of these patients had pathologic Stage C and 6 pathologic Stage D1 disease. Treatment in most patients consisted of 5,000 rad delivered to the true pelvis. The five-year recurrence-free survival was 75 per cent for pathologic Stage C and 41 per cent for Stage D1 disease. The median time to first evidence of treatment failure was fifty months for D1 patients and has not been reached by the C group. Minor complications occurred in 85 per cent of patients and major complications in 5 per cent. In 1 patient with mild, postoperative stress incontinence total urinary incontinence developed after radiation therapy. These preliminary observations suggest a prolonged disease-free interval with an acceptable morbidity is obtained utilizing this regimen.

Ultrasonography and diagnosis of pediatric genitourinary rhabdomyosarcoma.

Rhabdomyosarcoma is the most common tumor of the lower genitourinary tract in children during their first two decades of life. Four patients with genitourinary rhabdomyosarcoma are presented, with ultrasonographic and radiographic findings. The utility of ultrasound in the diagnosis of this pediatric tumor is emphasized.

Sonographic characteristics of epidermoid cyst of testicle.

The ultrasonographic characteristics of an epidermoid cyst of the testicle are presented. Since these findings are similar to other published case reports, preoperative sonographic diagnosis of this lesion may be possible.

Perineural invasion in transitional cell carcinoma and the effect on prognosis following radical cystectomy.

OBJECTIVES: The relationship between perineural invasion and prognosis has been demonstrated to be poor in a number of malignancies. This has not been evaluated in the bladder. We performed a study to determine the occurrence of nodal metastases, extranodal metastases, and disease-free survival in patients with perineural invasion (PNI) and/or angiolymphatic invasion (ALI) in transitional cell carcinoma of the bladder (TCCB) from radical cystectomy specimens. METHODS: A retrospective review of 27 patients treated with radical cystectomy for TCCB was conducted. Comparisons were performed between three groups: PNI with or without ALI (PNI +/- ALI, 12 patients), ALI alone (8 patients), and a control group (no PNI or ALI) (7 patients). RESULTS: The mean patient age was 70 years (range 49 to 83). The overall median follow-up period was 11 months (range 1 to 32). PNI +/- ALI was predominantly found in Stage T3b disease (14 of 20 [70%] cases). The overall 1-year disease-free survival was 48%, 67%, and 83% for the PNI +/- ALI, ALI alone, and control groups, respectively. Nodal metastases (for all stages combined) were found in 6 of 12 (50%), 3 of 8 (38%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. Similarly, extranodal metastatic disease was found in 5 of 12 (42%), 4 of 8 (50%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. The percentage of deaths for the PNI +/- ALI, ALI only, and control groups were 33%, 50%, and 14%, respectively. CONCLUSIONS: In TCCB, perineural invasion with or without angiolymphatic invasion and angiolymphatic invasion alone are associated with a higher incidence of nodal and extranodal metastases and death.

1,25-Dihydroxy-16-ene-23-yne-vitamin D3 and prostate cancer cell proliferation in vivo.

OBJECTIVES: 1,25-Dihydroxyvitamin D can inhibit the proliferation of prostate cancer cells, but its clinical use is limited by hypercalcemia. We examined the effects of a "noncalcemic" vitamin D analogue, 1,25-Dihydroxy-16-ene-23-yne-cholecalciferol (16-23-D3), on the proliferation of human prostate cancer cells in a mouse model. METHODS: Twenty-four athymic nude mice were inoculated with human prostate carcinoma cells from the PC-3 cell line. Twelve mice (experimental group) received injections of 1.6 micrograms of 16-23-D3 on alternate days over a 22-day period. Twelve mice (control group) received sham injections. Tumor volumes, pathologic findings, and terminal serum calcium levels were compared between groups. RESULTS: The relative increase in tumor volume was significantly lower in the experimental than in the control group in the first interval following treatment (P < 0.01). Mean tumor volumes in the experimental group were approximately 15% smaller than in the control group. Serum calcium levels did not differ between groups. CONCLUSIONS: 16-23-D3 showed modest antiproliferative effects on prostate cancer cells in this model without evidence of drug-induced hypercalcemia. These findings support the concept that vitamin D analogues can inhibit the proliferation of human prostate cancer cells in vivo.

Seminal vesicle cystadenoma: a case report and literature review.

Primary tumors of the seminal vesicle are rare; most reported cases are carcinomas, with occasional reports of primary seminal vesicle sarcoma and an uncommon group of mixed epithelial-stromal tumors. The latter have been variably reported in the literature as cystadenoma, phyllodes tumor, and mullerian adenosarcoma-like tumor. We describe a 37-year-old man who presented with symptoms of bladder outlet obstruction and was found to have a pelvic mass. Resection of the mass yielded a biphasic tumor characterized by cystically dilated glandular spaces admixed with spindle-shaped stromal cells. There was no significant cytologic atypia or mitotic activity. The histologic features are most consistent with the reported cases of cystadenoma. The patient is alive, with no evidence of disease, 6 months after surgery. This case adds to the gradually growing body of literature on mixed epithelial-stromal tumors of the seminal vesicle.

Simultaneous radical nephrectomy and repair of abdominal aortic aneurysm.

OBJECTIVES: The combination of abdominal aortic aneurysm repair with other intra-abdominal surgery is controversial. Most studies have shown that a variety of procedures can be performed at the same time as an aneurysm repair with little change in mortality or complication rates. We conducted a retrospective study to determine if aneurysm repair could be safely and effectively combined with radical nephrectomy. METHODS: We studied 10 patients who underwent combined abdominal aortic aneurysm repair and radical nephrectomy during a 4-year period. Results from this group were compared to a separate control group of 10 patients who underwent radical nephrectomy alone and another of 12 patients underwent abdominal aortic aneurysm repair alone, during the same time period. RESULTS: The overall mortality was 10% and significant complications occurred in an additional 10% of patients. Minor, self-limiting complications occurred in 30% of patients. There were no aortic graft infections that occurred in the entire series of patients at 18 months of mean follow-up. There were no remarkable differences in the entire series of patients and the combined values in a separate group of control patients who had undergone either procedure alone. CONCLUSIONS: Simultaneous radical nephrectomy for presumed renal cell carcinoma can be safely combined with repair of abdominal aortic aneurysm in selected patients.

Interferon-induced reversible acute renal failure with nephrotic syndrome.

Although there has been considerable experience with interferons in clinical trials during the past decade, acute renal failure as a side effect of interferon treatments has rarely been reported. We report a case in which acute renal failure with nephrotic syndrome was associated with therapy with two types of interferons. We note incomplete return of renal function upon withdrawal of therapy.

Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis.

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.

A cost containment strategy for radical retropubic prostatectomy: Results from implementation of a clinical pathway program.

Health care costs from the management of prostate cancer are estimated at $1.5 billion per year. As the number of radical prostatectomies being performed increases, a simultaneous rise in these costs can be expected. However, diminishing resources and the expanding managed care environment necessitate measures to curtail and even reduce these inflationary trends in health care expenditure. With this in mind, we established a collaborative clinical pathway for patients undergoing radical retropubic prostatectomy at our institution. The goals of the pathway were to reduce patient costs and hospital stay and to promote efficient use of resources for the procedure. We studied 71 patients who underwent radical retropubic prostatectomy and were managed according to the pathway during the first year of its implementation (July 1994 through July 1995). Outcome variables for these patients were compared with those of a group of 65 patients who underwent an identical procedure during the previous year (July 1993 through June 1994) before implementation of the pathway. Outcome parameters that were compared included hospital charges, length of stay (LOS), operating room (OR) time, units of packed red cells transfused, morbidity, and mortality. The overall hospital charges since implementation of the pathway decreased by 17.2% when corrected for inflation (p ≤ 0.006). LOS also decreased from a mean of 6.4 days to 5.2 days. There was no significant change in OR time. Overall complications remained unaffected (12.3% vs 12.6%). Based on these results, we conclude that establishment of an individualized, procedure-oriented clinical pathway for patients undergoing radical retropubic prostatectomy can result in significant reduction in patient costs without appreciable effect on morbidity and mortality.

Routine frozen section of pelvic lymph node specimens prior to radical retropubic prostatectomy is unnecessary in patients with prostate specific antigen.

Our prospective study was designed to evaluate the routine use of frozen section of pelvic lymph node specimens prior to radical prostatectomy in patients with pre-biopsy prostate specific antigen (PSA) levels less than 20 ng/ml. Included in our study were 241 patients who had clinically localized disease on digital rectal examination, a negative preoperative metastatic work-up, and a pre-biopsy serum PSA of less than 20 ng/ml. If a palpable abnormality of pelvic lymph nodes was detected at the time of surgery, specimens were sent for frozen section analysis. Lymphatic specimens that were palpably normal were sent for permanent section only. Ten (4.1%) of the 241 patients had pelvic lymph node metastases demonstrated by permanent section. Of the patients with lymph node metastasis, 50% had Gleason scores of 8-10 on their needle biopsy specimens. None of these patients had frozen section analysis of their lymph nodes. Frozen section failed to detect lymph node metastasis in all cases analyzed. Routine frozen section analysis of pelvic lymphadenectomy specimens in patients with clinically localized prostate cancer, Gleason score 2-7 on the needle biopsy, and prebiopsy PSA of less than 20 ng/ml is unnecessary.

Evaluation of computerized tomography for staging of clinically localized adenocarcinoma of the prostate.

We conducted a retrospective review of 345 patients who underwent radical prostatectomy between 1991 and 1994 to assess the overall accuracy, sensitivity, and specificity of computerized tomography (CT) for detection of disease outside the prostate. In 139 patients who were eligible for study, the overall accuracy, sensitivity, and specificity were 51%, 79%, and 30%, respectively. For lymph node metastases only, the values were 89%, 7%, and 97%, respectively. For local extraprostatic extension, the values were 48%, 30%, and 83%, respectively. The overall positive predictive value of CT was 67% and the negative predictive value was 45%. CT has minimal to no utility in detecting extraprostatic disease in patients with clinically localized prostate cancer.