Keyhole limpet hemocyanin for carcinoma in situ of the bladder: a long-term follow-up study.

OBJECTIVE: Keyhole limpet hemocyanin (KLH) is a nonspecific immunomodulator, demonstrated to be clinically effective in superficial bladder cancer. The present study investigated the clinical efficacy of intravesical KLH in patients with carcinoma in situ (CIS) with a long-term follow-up. METHODS: Thirteen patients with CIS grade III were treated with intravesical instillations of KLH, 20 mg for 6 weeks, then monthly for 1 year and bimonthly for 2 subsequent years. Patients not responding to 2 courses of KLH were treated with bacillus Calmete-Guérin (BCG, 81 mg Connaught strain). RESULTS: The follow-up period ranged from 12 to 84 months. Two patients were free of tumor after KLH instillations with a follow-up of 66 and 82 months, respectively. All patients who did not respond to the primary KLH course, but to the 'rescue' instillation of BCG, experienced recurrences after 42, 48, 56 and 60 months after the first KLH instillation treatment. Three patients with recurrent CIS and who were not cystectomized had recurrences after prolonged remission (4-5 years). Patients progressing despite KLH and BCG instillations underwent cystectomy. CONCLUSIONS: KLH demonstrates efficacy and induces long- term remissions against CIS in a limited number of cases. In the present study, most patients with CIS progressed over time whatever the substance instilled, whether KLH or BCG. CIS remains a very aggressive neoplasm requiring a lifelong follow-up. Further studies are necessary to define the precise role of KLH in patients with CIS.

Efficacy of prophylactic Immucothel in patients pretreated with conventional drugs to prevent recurrence of superficial bladder carcinoma.

OBJECTIVES: Fifty patients enrolled in clinical trials with Immucothel((R)) were reevaluated for their disease-free intervals. METHODS: Of the 37 evaluable patients, 16 had received mitomycin C, 3 bacillus Calmette-Guérin, 3 Adriamycin and 15 miscellaneous pretreatments prior to Immucothel. They thus served as their own controls. RESULTS: Although their prognosis was worse at the time when Immucothel therapy was started than at the time of initiation of pretreatment, the mean recurrence-free intervals of all patients increased from 17.0 months under pretreatment to 35.1 months under Immucothel. CONCLUSION: The difference was statistically significant (Wilcoxon matched-pairs signed-ranks test).

PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer.

OBJECTIVE: To assess the effectiveness of PC-SPES, a dietary supplement containing eight herbal extracts, which is a popular alternative therapy among patients with hormone-refractory prostate cancer; anecdotal reports claim that this agent provides relief of metastatic pain, improvements in quality of life and reduction of prostatic specific antigen (PSA) level. PATIENTS AND METHODS: Sixteen men treated for advanced metastatic prostate cancer (stage D3) with either orchidectomy or a luteinizing-hormone releasing hormone agonist, with or without anti-androgen, were enrolled into a prospective clinical trial to evaluate the possible toxic and beneficial effects of PC-SPES. After hormone-ablative therapy had failed, and with established disease progression, all patients received supplemental treatment with PC-SPES (2.88 g daily) for 5 months. Hormonal therapy was continued throughout the trial to avoid the known withdrawal effect of anti-androgen on PSA levels. RESULTS: The supplemental intake of PC-SPES was associated with significant (P<0.05-0.01) improvements in quality-of-life measures, reductions in patient's pain ratings (P<0.05-0.01), and a decline in PSA levels (P<0.01), with no major side-effects. CONCLUSIONS: These results support the anecdotal reports of the beneficial effects of PC-SPES as a comparable alternative to current management regimens in hormone-refractory prostate cancer. However, no conclusions can be drawn about the long-term effects of this new herbal therapy.

[Effectiveness and tolerance of 1 dosage forms (subcutaneous and intramuscular) of decapeptyl depot in patients with advanced prostate carcinoma]. / Wirksamkeit und Verträglichkeit von 2 Applikationsformen (s.c. und i.m.) von Decapeptyl Depot bei Patienten mit fortgeschrittenem Prostatakarzinom.

The intramuscular (i.m.) administration of Decapeptyl Depot has been approved in Germany for the treatment of advanced hormone dependent prostate cancer since July 1990. In this study a reformulated Decapeptyl Depot, administered as a first-line endocrine therapy, was injected intramuscularly (i.m.) or subcutaneously (s.c.) every 28 days for 6 months. At 12 different hospitals, 52 prostate cancer patients were treated, whereby 25 patients received a s.c. injection and 27 patients a i.m. injection. Testosterone was measured as the main parameter: after 28 days, both the s.c. and the i.m. application form of Decapeptyl Depot successfully reduced initial testosterone levels of at least 2.3 ng/ml to steady-state castration levels below 1.2 ng/ml, maintaining this complete suppression for the entire length of the trial (168 days). Decapeptyl Depot was well tolerated and very acceptable to the patients in both groups. Side effects were few and predictable, being largely associated with decreased testosterone concentrations. No cumulation in triptorelin serum levels was observed within the 6 months of treatment. Decapeptyl Depot, administered subcutaneously or intramuscularly was effective and safe in the treatment of patients with advanced prostate cancer.

A multicentric, placebo-controlled, double-blind clinical trial of beta-sitosterol (phytosterol) for the treatment of benign prostatic hyperplasia. German BPH-Phyto Study group.

OBJECTIVE: To report the results of a double-blind, placebo-controlled trial to evaluate Azuprostat, a beta-sitosterol, in patients with symptoms of outlet obstruction caused by benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: A randomized, double-blind and placebo-controlled clinical trial was conducted to assess the efficacy and safety of 130 mg free beta-sitosterol (phytosterol) daily, using the international prostate symptom score (IPSS) as the primary outcome variable. In total, 177 patients with BPH were recruited for 6 months of treatment in 13 study centres. In addition to the relative difference in the IPSS, changes in quality of life, peak urinary flow rate (Qmax) and post-void residual urinary volume (PVR) were recorded. The drug used in the trial consisted of a chemically defined extract of phytosterols, derived for example from species of Pinus, Picea or Hypoxis, with beta-sitosterol as the main component. RESULTS: There were significant (P < 0.01) improvements over placebo in those treated with beta-sitosterol; the mean difference in the IPSS between placebo and beta-sitosterol, adjusted for the initial values, was 5.4 and in the quality-of-life index was 0.9. There were also significant improvements in the secondary outcome variables, with an increase in Qmax (4.5 mL/s) and decrease in PVR (33.5 mL) in favour of beta-sitosterol when adjusted for the changes after placebo. CONCLUSION: These results show that beta-sitosterol is an effective option in the treatment of BPH.

Antibody response to keyhole limpet hemocyanin (KLH) treatment in patients with superficial bladder carcinoma.

The dynamics of specific KLH-antibody production after intracutaneous and intravesical instillation was analysed. Nine patients (male, n = 7; female, n = 2, mean age 68.6 years, range 47-75) with primary superficial carcinomas of the bladder were intracutaneously immunized with 1 mg Keyhole limpet hemocyanin (KLH) after the complete resection of the tumors. Treatment was continued for 6 consecutive weeks, monthly for one year and thereafter bimonthly for 2 subsequent years, consisting of 20 mg KLH in 20 ml saline introduced intravesically. The antibodies against KLH in patient sera were determined by means of a specially developed direct enzyme-linked immunosorbent assay (ELISA; according to H. von der Kammer, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany). Blood was taken for antibody-titer examination before treatment and 8 weeks after treatment. The KLH-antibody titer increased significantly (Mann-Whitney-Test P = 0.02) after KLH therapy in bladder cancer patients, however the level varied considerably from patient to patient. 6 of 9 patients (67%) presented increased serum antibody titers to KLH after immunotherapy. 4 patients (44.4%) remained free of tumor during the established follow-up period of 10-45 months (median 30.7 months). One patient without increased antibody titer to KLH was free of tumor, 2 patients however, suffered from tumor recurrence after the KLH course. 2 patients presented with tumor recurrence in spite of increased antibody titers. No evidence of tumor progression occurred in patients with recurrence after KLH therapy. 4 of 5 patients (80%) without tumor recurrence presented with a positive skin test. Of patients with tumor recurrence, 50% had a negative skin test. 44.4% KLH-treated patients had tumor recurrence The recurrence rate was 1.6. The time to recurrence was 8.75 months. KLH instillation did not induce major side effects. Positive skin test reactivity and KLH antibody response were more commonly seen in responding patients (i.e. those who remained tumor free after therapy) than in non-responders. The production of KLH antibodies, apparently is the biological response to the antigen stimulus of KLH.

Immunohistological findings in patients with superficial bladder carcinoma after intravesical instillation of keyhole limpet haemocyanin.

OBJECTIVE: To determine whether keyhole limpet haemocyanin (KLH) instilled intravesically improves the local cellular response within the bladder wall of patients suffering from superficial bladder carcinoma. PATIENTS AND METHODS: Twelve patients (10 men and two women, mean age 67 years, range 42-85) with superficial carcinomas of the bladder were treated for 6 consecutive weeks and then monthly for 1 year with 20 mg KLH in 20 mL saline instilled intravesically after complete resection of the tumours. Biopsies were taken for immunohistochemical examination before treatment and again 6 weeks, 3, 6 and 9 months after treatment. Six patients with no evidence of cystitis or malignant bladder disease acted as a control group. Immunofluorescent staining of the biopsies was performed using monoclonal antibodies to the T-cell markers CD4 and CD8, and to CD14 (monocytes), CDw15 (granulocytes), CD19 B-cells (Pan-B), CD68 (macrophages) and HLA-DR. Anti-KLH antibody-producing plasma cells were detected using a standard technique. A semiquantitative analysis of locally infiltrating cell types was performed. RESULTS: After treatment with KLH the increase of CD8+ suppressor cells was less pronounced than that of CD4+ helper cells. The T-helper/inducer to T-suppressor/cytotoxic cell ratio thus altered from 0.8:2.0 before treatment to 1.6:2.3 afterwards. Hence, the number of T-helper cells had increased considerably, whereas there was only a moderate increase in the number of T-suppressor cells. This cellular ratio could be detected for 9 months after KLH therapy. The numbers of activated HLA-DR+ immune cells in the submucosa and among urothelial cells also increased after KLH instillation. The degree of mononuclear cell infiltration of the submucosa increased considerably, but granulocyte infiltration was only moderate. Lymph follicles with enhanced B-lymphocyte counts were also detected. CONCLUSION: Immune-cell infiltration into the urothelium and enhanced activation (expression of class II antigens) suggests distinct processes of cellular antigen recognition, which could be detected for up to 9 months after the beginning of KLH therapy. This may represent a basic functional mechanism of KLH therapy.

Effect of keyhole limpet hemocyanin (KLH) and bacillus Calmette-Guérin (BCG) instillation on carcinoma in situ of the urinary bladder.

Patients with histologically verified carcinoma in situ (CIS) of the urinary bladder (13 primary and 8 secondary CIS) were treated with intravesical instillations of Keyhole Limpet Hemocyanin (KLH) (20 mg KLH weekly for 6 weeks, then monthly for 1 year or bimonthly for 2 subsequent years. Patients, non-responding to 2 courses of KLH were then treated with regular Bacillus Calmette-Guerin instillations (120 mg BCG-Connaught strain). The follow-up period ranged from 10 to 54 months (mean 23.5 months). 7 patients (33%) were free of tumor after the first therapeutical KLH course and 4 patients (19%) presented a complete-remission after the second KLH course (total primary response: 52%). 5 patients (24%) remained free of tumor during the established follow-up period (mean 31.7 months) and no evidence of further tumor progression occurred in patients after two courses of KLH treatment. However, 2 patients (9.5%) had to be cystectomized after KLH instillations because of progressive disease or tumor recurrence. 8 patients (38%) had to be radically cystectomized because of CIS persistence or progression after KLH and subsequent BCG treatment. Altogether 9 patients (42.8%) presented long-term remissions, with a mean duration of 31.3 months. Instillations of KLH did not induce major side effects; however, instillations of BCG caused severe dysuria in 60% and fever in 40% of patients.

Efficacy of local Bacillus Calmette-Guérin treatment in superficial bladder cancer relapsing under Keyhole-Limpet Hemocyanin immunotherapy.

The efficacy of local immunotherapy with Keyhole-Limpet Hemocyanin (KLH) and Bacillus Calmette-Guérin (BCG) in preventing recurrence of superficial bladder cancer (stages pTa to pT1; grades 1 to 3) was checked in 96 patients. All tumours were resected and all patients were presumed to be free of malignant disease at initiation of prophylactic KLH instillations. Before starting KLH instillations (20 mg/administration week for 6 weeks, followed by regular (bi)monthly instillations for 3 years altogether) all patients were intracutaneously immunized with 1 mg KLH. Tumour relapse under this therapeutic schedule was the indication for BCG instillations (120 mg BCG-Connaught; administration in analogy to KLH treatment). This study has proved that (1) prophylactic KLH treatment reduced superficial bladder cancer relapse rate after surgical intervention without considerable local/systemic side effects and (2) local BCG-administration was therapeutically effective in relapsing/progressive disease under KLH treatment. There were, however, pronounced side effects.

Influence of propionibacterium avidum KP-40 on the proliferation, maturation, emigration and activity of thymocytes and monocytes.

Inactivated cells of Propionibacterium avidum KP-40 could be shown to induce thymocyte proliferation and maturation in BALB/c-mice after intraperitoneal administration of the optimal immunomodulating dosage (1 mg per mouse). The increase in thymus weight and thymocyte numbers per mg organ weight was most pronounced and statistically significant 10 days after P. avidum KP-40 administration. Determinations of lymphatic subsets revealed a considerable up-regulation of mature cells expressing helper/inducer (L3T4+) or cytotoxic/suppressor (Lyt-2+) phenotypes and immature cells presenting both L3T4+/Lyt-2+ antigens. Obviously, P. avidum KP-40 administration accelerated murine thymocyte proliferation and maturation. Counts of BALB/c-mouse peripheral blood lymphocytes (PBL) and monocytes (PBM) revealed statistically significant increases after P. avidum KP-40 administration with peak values after 6-10 days. The determination of activated PBL (expressing interleukin-2 receptors) or PBM (expressing MAC-3 antigens) proved that P. avidum KP-40 induced a potent immunostimulation since counts of these cells were significantly enhanced after P. avidum KP-40 treatment.

Urinary interleukin-1 alpha levels are increased by intravesical instillation with keyhole limpet hemocyanin in patients with superficial transitional cell carcinoma of the bladder.

Intravesical instillation of keyhole limpet hemocyanin (KLH) is a possible treatment for decreasing tumor recurrence after transurethral resection (TUR) in patients with superficial transitional cell carcinoma of the bladder (stages pTa-pT1, grades 1-3). Our study confirms the theory that instillation of KLH stimulates production of cytokines, resulting in their secretion in urine. Interleukin-1 (IL-1) stimulates the immune cascade through a domino effect and is produced mainly by activated macrophages. The instillation program was started 5-7 days after TUR of primary superficial cell carcinoma. 20 mg KLH in 20 ml of 0.9% NaCl was instilled into the bladder each week for 6 consecutive weeks and then monthly for 1 year. When KLH is instilled into the bladder, IL-1 alpha is secreted in the urine. A specific enzyme-linked immunosorbent assay (ELISA) was used for analysis. The ELISA for IL-1 alpha was established in our laboratory and showed a detection limit of 5 pg/ml. This IL-1 alpha ELISA deviation amounts to 3-7% within a series of measurements, and 5-15% from series to series. In the therapy group the IL-1 alpha secretion ranged from 0 to 30,905 pg/24 h and in the control group from 0 (collection period) to 2,472 pg/4 h. IL-1 alpha production increased significantly after KLH instillation in bladder cancer patients; however, the level varied considerably from patient to patient. Maximum production was achieved within a period of 4-8 h, decreasing within 24 h. There was a striking difference between the amount of IL-1 alpha produced over the 24-hour period in the control group and that of the KLH group. 8 of 14 patients (57%) who responded to KLH therapy had higher urine IL-1 alpha levels after 6 weeks of KLH treatment than those who failed to respond within 12 months, but the levels were not of statistical significance. The secretion of IL-1 alpha in urine is the biological response of the bladder to the antigen stimulus of KLH. No IL-2 was detected in the urine samples. It remains to be determined whether no IL-2 cytokine was present, or whether the amount was smaller than the minimal detection limit required for the ELISA.

Melanotic neuroectodermal tumor of infancy (MNTI) in the epididymis. A case report with immunohistological studies and special consideration of malignant features.

Melanotic neuroectodermal tumors of infancy (MNTI) are uncommon, usually benign neoplasms, most frequently found in the maxilla. These tumors are extremely rare in the epididymis. Only 18 cases with this site of origin are documented. We report on the third epididymal MNTI with some morphological characteristics of malignancy but favorable clinical outcome. The 2 cm large tumor of a 6-month-old male infant showed large epitheloid cells in the center and small neuroblastoma-like cells at the periphery. Despite invasion of lymphatics there is no evidence of relapse or metastases during 4 years of follow-up. Immunohistochemically, the large tumor cells were distinctly positive for cytokeratin, vimentin, GFAP, the melanoma marker NKI-C3, NSE, and S100. The small tumor cells were only slightly positive for GFAP, NKI-C3, NSE, and S100 but they were negative for cytokeratin and vimentin. Neurofilament and chromogranin could not be proved in the tumor.

[Adjuvant immunotherapy with keyhole limpet hemocyanin in category PT 2 N+ and PT 3-4, No-N+, Mo renal cell carcinoma]. / Adjuvante Immuntherapie mit Keyhole Limpet Hemocyanin (KLH) beim Nierenzellkarzinom der Kategorie PT 2 N+ und PT 3-4, No-N+, Mo.

This study was a prospective randomized trial to compare adjuvant immunotherapy with Keyhole Limpet Hemocyanin (KLH) after radical nephrectomy. From January 1983 to December 1988, 50 patients underwent radical nephrectomy for category PT 2 N+ and PT 3-4, No-N+, Mo renal cell carcinoma. Postoperatively 25 patients were given adjuvant treatment with the biological response modifier, Keyhole Limpet Hemocyanin (KLH), and 25 patients were in the control group. In each group 2 patients were lost to follow-up. The mean follow-up time was 55 months. Adjuvant treatment with KLH did not appear to improve the prognosis in renal cell carcinoma patients. The 5-year survival rate was 60% in the KLH group and 56.5% in the control group. Progress was seen in 9/23 in the KLH group, 10/23 in the controls. The median survival in patients showing progress was 27 and 28 months in the two groups, respectively. Studies with a combination of low dose cyclophosphamide and KLH revealed a positive immunostimulating effect, which may provide the rationale for further research concerning different KLH doses, schedules or therapeutic combinations.

[Urothelial cancer of the upper urinary tract]. / Das Urothelkarzinom des oberen Harntrakts.

Uretero-nephrectomy with bladder cuff was performed in 61 patients with renal pelvis and ureter carcinoma between 1982 and 1987. A retrospective study was done on 54 patients, with a mean follow up of 56.9 months. The 5-year survival was 61.6%. The average age was 68.8 years with a male-to-female ratio of 1.7:1. Macrohaematuria was the most frequent symptom, occurring in 77.7% of the patients. In 92.5% of the urothelial tumours the diagnosis was confirmed by intravenous pyelogram (IVP) and retrograde pyelography. Between grade G1 and G3 and stage pTa and pT3-4 a statistically significant difference (P < 0.05) in the 5-year survival rate could be seen, as expected.

The potential use of prostatic secretory protein of 94 amino acid residues (PSP94) as a serum marker for prostatic tumor.

The serum concentrations of prostatic secretory protein of 94 amino acid residues (PSP94) as well as those of prostate-specific antigen (PSA) were determined in 40 patients with established prostatic carcinoma, prior to transurethral resection of the prostate. In a comparison with a control group of healthy men (n = 40) and a group of patients with histologically established benign prostatic hyperplasia (n = 40) no significant differences in PSP94 serum concentrations between the groups were observed. Similarly, correlations of PSP94 serum concentrations with prostatic carcinoma stages or grades were not detected. In contrast, and as expected, PSA behaved as a prostate tumor marker of known sensitivity and specificity. A correlation of PSP94 and PSA concentrations in sera of patients with benign prostatic hyperplasia and/or prostatic carcinoma could not be verified. PSP94 apparently does not fulfill the criteria of a serum marker for monitoring adenomas and/or carcinomas of the prostate.

[Combination therapy with recombinant interferon alpha-21 (rIFN alpha 2a) and recombinant interleukin 2 (rIL-2) in metastatic renal cell cancer]. / Kombinationstherapie mit rekombinantem Interferon alpha-2a (rIFN alpha 2a) und rekombinantem Interleukin-2 (rIL-2) beim metastasierten Nierenzellkarzinom.

Sixteen patients with histologically-proven metastatic renal cell carcinoma (RCC) were treated after nephrectomy with a daily continuous 24-hour i.v. infusion of recombinant human interleukin-2 (rIL-2) at a dosage of 18 x 10(6) IU/m2 daily for 5 days per week and of recombinant interferon alpha-2a (rIFN-alpha 2a) 5 x 10(6) IU/m2 subcutaneously on days 2 and 4. The treatment cycles were repeated at 3-weekly intervals. Altogether 38 treatment cycles were given, but only 14/16 patients were evaluable for response rates. The main toxic side effects were fever, nausea, chills, anorexia, hypotension and hepatotoxic syndrome (Toxicity grades I-III, WHO). There were 3 objective responses among the 14 evaluable patients (21%); 2 patients have remained in complete remission for 12 and 8 months, respectively until now whilst 1 has shown a partial response for 21 months.

Clinical evaluation of a new prostate-specific antigen sandwich ELISA which employs four monoclonal antibodies directed at different epitopes of prostate-specific antigen.

A known radioimmunometric prostate-specific antigen (PSA) test based on monoclonal antibodies, as well as a new PSA-ELISA utilizing 4 monoclonal antibodies directed against different epitopes of PSA were compared in a clinical evaluation. For the investigation, collectives of patient sera from patients with independently diagnosed prostatic carcinoma (PCA) as well as benign prostatic hyperplasia (BPH) were employed. The results of the evaluation demonstrated that although the PSA immunoradiometric test and the PSA-ELISA yielded different numerical values for PSA serum concentrations, they possess comparable diagnostic sensitivities as well as specificities. The nonradioactive PSA-ELISA could therefore substitute the PSA-IRMA in a clinical routine diagnostic of PCA.

Pheochromocytoma of the urinary bladder.

A case of a pheochromocytoma of the urinary bladder is reported which was treated preoperatively with alpha-receptor-blocking agents. The tumor was operated transurethrally, followed by partial cystectomy.

Combined treatment (goserelin plus flutamide) versus monotherapy (goserelin alone) in advanced prostate cancer: a randomized study.

This study compared goserelin monotherapy with goserelin plus flutamide in the treatment of stage C or D prostatic cancer. Patients were stratified according to whether distant metastases were present or absent. After a mean follow-up of 33 months, combined treatment with goserelin and flutamide produced a higher response rate and a more rapid normalization of abnormal levels of prostatic acid phosphatase and prostatic specific antigen than treatment with goserelin alone. A more prompt relief of bone pain was also evident. An advantage, though not statistically significant, in terms of progression and survival was demonstrated in the combination group when metastases were present before the start of treatment. In both groups, the median for progression as well as the PCA-related and nonrelated death was not achieved during the study period.

[Acute hemorrhagic cystitis following chlordimeform poisoning ]. / Akute hämorrhagische Zystitis nach Intoxikation mit Chlordimeform.

A 19-year-old and a 50-year-old man who together had cleaned a water-tank as part of their duties in a tank protection and cleaning firm developed that same evening lower abdominal pain, dysuria and haematuria. Cystoscopy revealed haemorrhagic cystitis in both patients, a finding confirmed by bladder mucosa biopsy. 4-chlor-2 methylaniline (concentration less than 1 mg/l) was found in hydrolysed serum of both. This metabolite of the pesticide chlordimeform was also found in the urine of the 51-year-old patient (16 mg/l). The haematuria regressed within two days of the patients having increased their fluid intake. Dysuria improved within a week. It is likely that chlordimeform had previously been transported in the water-tank. In case of haemorrhagic cystitis possibly caused by occupational or other poisoning, serum and urine should always be obtained for toxicological tests.