W. de Riese

Metastatic renal cell carcinoma (RCC): Spontaneous regression, long-term survival and late recurrence

AbstractWe report 4 cases of metastatic renal cell carcinoma (RCC) with long-term survival either following radical nephrectomy alone or in combination with radioor hormonal therapy.Two patients with lymph node metastases showed a long-term survival of 12 or more years following radical tumour nephrectomy (with lymphadenectomy) and radiotherapy. One of them exhibited a histologically proven tumour recurrence nearly 12 years after primary surgical treatment and died shortly later; the other one is still without any evidence of metastatic disease.Two other patients exhibited spontaneous regression of pulmonary metastases: one regression occurred after radical tumour nephrectomy alone, the other one after successful primary hormonal treatment and subsequent radical tumour nephrectomy.The following important aspects are emphasized:1.Renal cell carcinoma is a very unpredictable tumour. Once the diagnosis of renal cell carcinoma is proved, a patient can never be considered cured.2.Although adjuvant palliative nephrectomy has produced contradictory results in several reports, radical tumour nephrectomy either alone or in combination with other adjuvant therapies such as radiotherapy, hormonal or immunological treatment, can be worthwhile. Cases with long-term survival and spontaneous regression of distant metastases are proof of this. Besides, if carefully selected, the mortality rate of different adjuvant therapies is not significantly higher in patients with metastatic disease than in patients without metastases. The world literature on this subject is reviewed.

Prostate-specific antigen—comparative clinical appreciation of a serodiagnostic measure after 8 years of experience

SummaryIn a prospective study, prostate-specific acid phosphatase/prostate-specific antigen (PSAP/PSA) serum levels were simultaneously determined in 696 patients with benign prostatic hyperplasia (BPH), 202 patients with newly diagnosed, untreated prostate cancer (p-Ca), and 414 patients with previously treated p-Ca; in 165 of the 202 patients with newly diagnosed p-Ca, sampling was continued at 3-month intervals after the onset of various tumor-specific therapeutic modalities over a period of 3 years. The titers of the latter group were compared with the independently assessed individual clinical disease activity. A positive correlation could not be established between PSAP/PSA serum levels and either lesser differentiation or volume of tumor burden. PSA proved to be more than twofold more sensitive than PSAP in indicating malignancy and residual or recurrent neoplastic activity. No diagnosis of either p-Ca or progression of tumor at short-term follow-up was indicated exclusively by PSAP. However, at long-term follow-up of patients under treatment, exclusive indication of biologically active p-Ca by PAP in 0.7%–2.2% of cases requires simultaneous serial determination of both antigens for currently optimal monitoring. Considering the disadvantageous impacts inherent in its tissue specificity, PSA proved to be a most valuable tool, superior to PAP, as an immunochemical parameter in p-Ca.

Proliferative behaviour and cytogenetic changes in human renal-cell carcinoma

SummaryFrom 1986 until 1990, in vivo proliferation rates (PRs) in 110 patients with renal-cell carcinoma (RCC) were immunohistochemically determined by the Ki-67 assay. It could be demonstrated that the PRs of RCCs range between only 1% and 15%. Due to its low proliferative kinetics in vivo, tumor cytogenetic investigations of this malignancy remain rare. During short-term in vitro culture, the PRs of this neoplasm increased (21%–82%). Therefore, 36 untreated human RCCs were cultured in vitro for cytogenetic analysis using the G-banding technique. In all, 77.8% (28/36) of the renal malignancies investigated exhibited an aberration of chromosome 3, which seems to serve as a marker for this malignancy. Whereas tumor stage showed no correlation with PR, tumor grade exhibited a strong correlation with this parameter. According to the data presented herein, immunohistochemical determination of the tumor-specific PR using the monoclonal antibody Ki-67 is a practicable, reliable and reproducible method that complements conventional histological tumor grading and staging. This parameter appears to be useful in identifying RCC patients at high risk, especially at early stages that are identical in tumor stage and grade.

Adenocarcinoma in extrophy of the bladder: A case report and review of the literature

There have been 81 cases of carcinoma in extrophied bladder described previously. We describe another such case. It demonstrates the problem of early diagnosis of carcinoma in extrophy of the bladder and the therapeutic consequences of an early cystectomy. In accordance with current literature we illustrate the theories on oncogenesis, and review the cases previously published.

Immunotherapy of advanced renal cell cancer using subcutaneous recombinant interleukin-2 and interferon-α

SummaryThe combined administration of subcutaneous recombinant human interleukin-2 (rIL-2) and interferon-α (rIFN-α) was studied in a phase II trial on patients with advanced progressive renal cell cancer. Safety, tolerance and clinical response rate of this outpatient treatment protocol were assessed in 29 evaluable patients who received a total of 47 cycles, each consisting of s.c. rIL-2 at 14.4–18 million IU m−2day−1 on days 1 and 2, followed by 6 weeks of combined administration of s.c. rIL-2 at 3.6–4.8 million IU m−2 day−1 on 5 days a week, and s.c. rIFN-α at 3–6 million units m−2 three times weekly over a period of 6 consecutive weeks. In patients exhibiting stable or regressive disease upon combined IL-2 and rIFN-α, the therapy was continued. The overall response rate was 31% (95% confidence limits = 15%–51%), with 6 out of 29 patients achieving partial remission (PR, 21%) and 3 patients complete remission (CR, 10%). In addition, 12 patients presented with stable disease. The median duration of response was 8.5 months in PR and 19+ months in CR. Long-term treatment using this regimen was associated mainly with moderate (WHO grade I–II) toxicity including fevers, chills, malaise, nausea and/or vomiting, anorexia and transient local inflammation at the injection sites. No toxic deaths occurred. Altered thyroid function was observed in more than half the patients. The combination regimen resulted in a significant increase in peripheral blood eosinophils and natural killer cells (P<0.005). Up-on treatment, 14 patients developed non-neutralizing activity against rIL-2, and 2 of these developed specific neutralizing antibodies after consecutive cycles; no anti-rIFN-2b antibodies were detected. In summary, subcutaneous long-term outpatient treatment with low-dose rIL-2 and rIFN-α is feasible, with moderate toxicity, and results in an objective tumor response rate comparable to that obtained previously with high-dose rIL-2 i.v. regimens.

Single potential analysis of cavernous electrical activity

SummaryRecording of cavernous electric activity was performed in 178 patients with erectile dysfunction and in 37 normal patients. In 34/37 normal patients, potentials of a uniform shape were recorded during flaccidity: At cut-off frequences of 0.5–500 Hz, the length was 8–18 (mean 12.8, SD 2.8), the amplitude 250–750 (mean 444, SD 109) μV, and the polyphasity 8–22 (mean 13.8, SD 3.3). In impotent patients with upper motor neuron lesions or peripheral lesions, specific types of potentials were observed. In 11/14 impotent patients with insulin-dependent diabetes for over 20 years and clinical findings of cavernous myopathy, potentials showed low amplitude, irregular shape, and slow depolarizations. In 51% of the consecutive impotent patients, abnormal findings of cavernous electric activity were recorded. Our clinical study suggests that single potential analysis of cavernous electric activity (SPACE) may be useful in the diagnosis of cavernous autonomic neuropathy and cavernous smooth muscle myopathy.

Current clinical relevance of immunotherapy in metastatic renal cell cancer

SummaryExisting compilations of data recorded in clinical trials involving cytokines as single compounds and in combination with each other and with cellular immuno-effectors or chemotherapeutic agents are analyzed. Antitumor activity for interferon alpha (IFN-α) and for interleukin-2 (IL-2) could be established at 14.5% and 13.7%, respectively, when used in single-agent regimens with considerable toxicity for IL-2 at high, intravenous doses. When IL-2 is combined with cellular effectors, these side effects together with the problems associated with the complexity of culture techniques when adding LAK (lymphokine-activated killer) cells or CTILs (cytotoxic tumor-infiltrating lymphocytes) impact unfavorably on future clinical application, and this combination must be considered investigational. IFN-α or IL-2 coupled with a chemotherapeutic agent only exhibited a limited advantage over single cytokine administration. The most promising combination seems to be IFN-α combined with IL-2, giving improved prospects for nearly 30% of the patients with metastatic renal cell cancer (RCC), simultaneously allowing for significant reduction of toxicity and for an outpatient treatment. A precise assessment of the underlying immunologic mechanisms is needed, as are controlled prospective and randomized trials comparing the various cytokines with each other and with conventional approaches in single and combination regimens with the ultimate purpose of defining the role of biotherapy within a clinical strategy for metastatic RCC before it can be considered a standard treatment modality.

In vitro sensitivity testing of human renal cell carcinoma with cytostatic agents and interferon alpha-2a

SummarySamples of 38 human renal cell carcinomas (RCC) were subjected to routine histopathological examination but also to in vitro sensitivity testing with mitomycin C, vinblastine and interferon Alpha-2a at various concentrations corresponding to serum titers recommended to be effective in vivo, employing a monolayer assay. Extending earlier in vitro studies, both tumor cell kill rates (TCKR) and proliferation rates (PR) were assessed. Following in vitro preparation the tumor cell cultures were simultaneously exposed to the anticancer drugs listed above. The proliferation rates were determined immunocytochemically using the monoclonal antibody Ki-67. Nine (23.7%) of the tumors investigated revealed temporary and limited response with respect to either TCKR or PR. Improvement of this percentage could only be obtained by increasing drug concentration to titers with toxicity intolerable for in vivo administration. The in vivo data presented correspond to clinical temporary and limited remissions in patients with metastatic RCC ranging up to 25%.

Effects of Cytokines on Clonogenic Growth of Primary Renal Cancer Cells: An in vitro Phase II Study

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF), granu-locyte colony-stimulating factor (G-CSF), and interleukin-3 (IL-3) are glycoproteins critically involved in the regulation of proliferation and differentiation of hemato-poietic precursor cells. However, there also is experimental evidence that proliferation of certain types of tumor cells may be stimulated by cytokines. The purpose of our study was to evaluate the effects of human recombinant GM-CSF, G-CSF, and IL-3 on clonogenic proliferation of primary renal cancer cells in vitro. Material and Methods: A capillary soft agar cloning system was used and the cells were incubated with cytokines for 14-28 days. Final concentrations were .1 ng/ml to 1,000 ng/ml for each cytokine. Results: Of a total of 35 tumor specimens, 20 specimens (57%) showed adequate growth and were evaluable for response. After incubation with GM-CSF, only two specimens (10%) showed a concentration-dependent stimulation of clonogenic growth. Stimulation was also observed in one specimen each incubated with G-CSF and IL-3 (5%). Inhibition of growth was observed in one specimen (5%) incubated with GM-CSF and G-CSF and in two specimens (10%) exposed to IL-3. No synergistic or additive effects were found in 18 specimens tested with combinations of cytokines. Conclusion: GM-CSF, G-CSF, and IL-3 do not significantly modulate growth of freshly explanted renal cancer cells in vitro. Chemotherapy followed by administration of these cytokines may thus be a safe approach for this tumor type.

Intrascrotal metastases from renal cell carcinoma

This is an up-to-date report about two patients suffering respectively from testicular and epididymal metastases of a renal adenocarcinoma in the condition following tumour nephrectomy in anamnesis. It is a survey on literature including the number of cases published.