Karl Heinz Kurth

Urinary Cytokines During Intravesical Bacillus Calmetteguerin Therapy for Superficial Bladder Cancer: Processing, Stability and Prognostic Value

PURPOSEnAn accurate prognostic indicator to identify nonresponding patients with superficial transitional cell carcinoma of the bladder at an early stage of intravesical bacillus Calmette-Guerin (BCG) therapy is urgently needed.nnnMATERIALS AND METHODSnThe processing conditions and stability of several BCG induced urinary cytokines were analyzed, as was the possible correlation between these cytokines (indicating immune responsiveness to BCG) and bladder tumor recurrence. We studied 23 patients with superficial transitional cell carcinoma of the bladder. Monitoring was performed by serial collection of urine during the first 24 hours after each of the 6 consecutive weekly intravesical BCG instillations. Baseline pre-therapy cytokine levels were 3.9 +/- 4.7 pg./mumol creatinine for interleukin-6 and 0.1 +/- 0.2 pg./mumol creatinine for tumor necrosis factor-alpha (all measured by enzyme-linked immunosorbent assay). To investigate the correlation between interleukin-2 and bladder tumor recurrence, patients were stratified into 2 groups based on an early (6 months or less) or late (greater than 6 months) recurrent tumor. For each patient the highest cytokine value measured during the 6-week BCG treatment course was evaluated.nnnRESULTSnThe results were positive if the level in urine exceeded 0.34 units interleukin-2 per mumol. creatinine. A significant correlation between urinary interleukin-2 and tumor recurrence was found (p = 0.003, 23 patients). Of the studied cytokines obtained from BCG treated patients, interleukin-1 beta, 2 and 6 but not tumor necrosis factor-alpha were stable in urine at 4C and 20C. At 37C all cytokines were unstable. Interferon-gamma could only be detected in immediately dialyzed urine and its occurrence correlated most with that of interleukin-2. Processing of urine by centrifugation to remove leukocytes immediately after collection was not required for reliable measurements of interleukins-2 and 6. Based on these results interleukins-2 and 6 were preferred for extensive monitoring of the BCG induced immune reaction.nnnCONCLUSIONSnOur study provides significant evidence for a correlation between urinary cytokine induction and clinical response following intravesical BCG therapy. Particularly, monitoring of interleukin-2 may have the potential for prognostic value provided that strict precautions regarding urine collection, such as maximal 2-hour sampling and immediate cooling, are taken.

Quality of life and treatment of hormone resistant metastatic prostatic cancer

72 patients with hormone resistant, progressing prostatic cancer completed a self-administered questionnaire to assess subjective morbidity and quality of life before they were entered into a phase III trial of estramustine (34) vs. mitomycin (38). At least one post-treatment assessment was available in 43 patients. This considerable degree of non-compliance is explained by practical problems related to completion and collection of the questionnaires in these rapidly deteriorating patients. Doctors underestimated subjective morbidity (pain, decreased performance status, nausea) in 30-50% of the cases. Decreased functional status, fatigue and pain were identified as the most frequent major morbidities before study entry. In most patients, treatment did not reduce this morbidity. The routine application of self-administered quality of life questionnaires has considerable practical problems but yields clinically worthwhile information about subjective morbidity. Simple but relevant monitoring of subjective morbidity by the patient should be mandatory in cancer trials where palliation is a major endpoint.

URINARY INTERLEUKIN-2 MONITORING DURING PROLONGED BACILLUS CALMETTE-GUERIN TREATMENT: CAN IT PREDICT THE OPTIMAL NUMBER OF INSTILLATIONS?

PURPOSEnIn patients with superficial bladder cancer treated with a first 6-week instillation course of bacillus Calmette-Guerin (BCG) the induction pattern of urinary interleukin (IL)-2 has been described, and the levels of urinary IL-2 were associated with the clinical response to BCG treatment. We evaluated urinary IL-2 kinetics in patients with recurrent superficial bladder tumor receiving a second or third 6-week BCG instillation course. To our knowledge there have been no studies of prolonged BCG treatment and urinary cytokine responses.nnnMATERIALS AND METHODSnUrinary IL-2 was determined in 12 patients with superficial transitional cell carcinoma of the bladder receiving a complete (6-week) second or third BCG instillation course and in 3 patients receiving 3 BCG instillations during a maintenance schedule at month 3. Urinary IL-2 was determined with an enzyme-linked immunosorbent assay using an oligoclonal system.nnnRESULTSnOf 12 patients 10 had a urinary IL-2 positive response during the subsequent BCG course and at week 1 urinary IL-2 was already increased. Comparing the urinary IL-2 kinetics observed during a second or third with a first course, urinary IL-2 tended to be higher during the first and lower during the last weeks. If the interval between subsequent courses was short (12 months or less) significantly higher urinary IL-2 levels at weeks 1 and 2, and a lower level at week 6 were observed.nnnCONCLUSIONSnDuring a repeat BCG instillation course urinary IL-2 reached a maximum at an earlier week, especially if the interval between the subsequent courses was short. Since an association between urinary IL-2 levels and response to BCG treatment during an induction course has been observed, these immunological data argue in favor of a limited number of instillations during prolonged BCG therapy which could reduce side effects as well as costs.

Progression in Untreated Carcinoma of the Prostate Metastatic to Regional Lymph Nodes (Stage T0 to 4,N1 to 3,M0,D1)

PURPOSEnWe attempt to contribute to the understanding of the natural history of prostate cancer metastatic to lymph nodes.nnnMATERIALS AND METHODSnA total of 61 patients with node-positive prostate cancer was prospectively followed without adjuvant treatment for an average of 41 months. The impact of T and P categories, grade, tumor volume and prostate specific antigen change on interval to progression was studied in a univariate and multivariate analysis.nnnRESULTSnMedian interval to progression was 18 months, and correlated with grade and prostate specific antigen doubling time. Changes in prostatic volume with time were not predictive.nnnCONCLUSIONSnOur study provides insight into the natural history of node-positive disease and identifies relevant prognostic factors that may be used for treatment decisions.

Molecular pathology of non-invasive urothelial carcinomas (part I)

An international consultation on the diagnosis of non-invasive urothelial neoplasms was held in Ancona, Italy in May 2001. Besides histology and problems of classification, one group of experts (Committee no. 3) discussed the molecular pathology and cytometry of non-invasive urothelial carcinomas. In the following first part, special immunohistochemical and molecular markers for stratifications in bladder cancer were discussed including different cytokeratins (clone 34βE12, CK 20), cell proliferation markers (Ki67/MIB-1, PCNA, AgNOR, DNA-cytometry), tumor suppressor genes and oncogenes (p53, p21, erb-B2, bcl-2), different receptor expressions of epidermal growth factor and vascular endothelial growth factor and others. These molecular markers were analyzed in diagnosis of urothelial carcinomas, recurrences, progression and response to treatment.