[Metastatic renal cell carcinoma: primary and follow-up treatment]. / Metastasiertes Nierenzellkarzinom: Erstlinien- und Sequenztherapie.

Systemic treatment of metastatic renal cell carcinoma has changed fundamentally in recent years. So-called targeted therapy gives patients with incurable renal cell cancer the chance of prolonged survival with acceptable quality of life and manageable side effects. Several tyrosine kinase inhibitors and mTOR inhibitors have been evaluated in various clinical settings within prospective trials. Therefore, recent medical guidelines are able to give recommendations for the management of advanced renal cell carcinoma in daily practice. The optimal therapeutic sequence of the available substances has not been defined until now; however recent data recommend the use of a tyrosine kinase inhibitor as the first line treatment. Besides standard treatment, new approaches are currently being evaluated in clinical trials.

The genetic make-up of renal cell tumors.

Recent developments in (molecular genetics have led to a better understanding of renal tumor biology. The current knowledge of the genetics of benign as well as malignant renal tumors is discussed briefly. This knowledge may, in the near future, be used to more accurately diagnose these tumors and also to optimalize individually based therapy.

Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine.

OBJECTIVE: To assess the involvement of the multidrug resistance-associated protein 1 (MRP1) and the glutathione pathway in the multidrug resistant (MDR) phenotype of prostate cancer in vitro. MATERIALS AND METHODS: Chemoselection of human prostate cancer cell lines PC3 and DU145 with etoposide resulted in the resistant cell lines PC3-R and DU-R. Resistance against etoposide, doxorubicin and vincristine, and its reversal with leukotriene D4 antagonists MK-571 and zafirlukast, and buthionine sulfoximine (BSO), was assessed using tetrazolium-dye viability assays. Western blot analysis of MRP1 expression and glutathione content were measured, and MRP1 function assessed in fluorescence assays. RESULTS: MRP1 was increased in the MDR models; the glutathione content was significantly higher in PC3-R but there was no increase in glutathione in DU-R. Adding non-toxic doses of MK-571, zafirlukast or BSO significantly increased the sensitivity of the MDR models to cytotoxic drugs. MRP1 function was inhibited with MK-571 in the MDR models. CONCLUSION: MRP1 and glutathione mediate MDR in newly developed prostate cancer models.

Recurrence after radical prostatectomy for organ-confined prostate cancer.

BACKGROUND: Some patients from our radical prostatectomy (RPx) series with organ-confined (pT2) prostate cancer and negative surgical margins show a PSA (prostate specific antigen) relapse. Aim of the study was to analyze this cohort of patients that otherwise would have been considered to be cured. PATIENTS AND METHODS: Since the introduction of PSA measurement in the follow-up after RPx, 475 pelvic lymph node dissections with subsequent RPx were performed in our department from 1988 to 1997. Of these, 227 were classified as pT2, 34 (15%) exhibited positive surgical margins, and 4 others were excluded due to an inadequate follow-up. Of the remaining 189 patients (study cohort), 19 (10%) developed a biochemical progression, defined as a minimum of 2 consecutive PSA measurements > or = 0.1 ng/ml. Only in one of them a G3 tumor was present. Median follow-up was 19.1 months. RESULTS: The Kaplan-Meier analysis of biochemical progression showed that after 1, 2 and 5 years, 95% (confidence interval (Cl) 91-99%), 91% (Cl 86-96%), and 77% (Cl 55-89%) of the patients were free of progression, respectively. This means that roughly one fourth of pT2 tumors will become progressive despite negative surgical margins. These 19 patients were subdivided into 4 groups: 1: biopsy-proven local recurrence (n = 2); 2: suspected local recurrence defined as slowly rising PSA < or = 2 ng/ml, but negative biopsies (n = 12); 3: distant metastasis proven by radiologic imaging (n = 1); 4: suspected distant metastasis defined as rapidly rising PSA > 9 ng/ml without direct radiologic evidence (n = 4). Preoperatively all patients from groups 3 + 4 had negative bone scans and 4/5 had preoperative PSA values < 10 ng/ml. In total 7 patients with proven recurrence or with proven metastasis had positive biopsies. CONCLUSION: A pathological diagnosis of organ-confined prostate cancer (pT2) and a meticulous analysis of negative surgical margins do not exclude the occurrence of local relapses in 7% (14/189), and there is evidence for suspect hematogenic spread of PC cells in at least 2% (4/189) of patients.

Multidrug resistance in prostate cancer.

Advanced hormone-refractory prostate cancer remains a therapeutic challenge, because all available pharmaceutical concepts have been ineffective in improving cancer-specific survival. Failure of chemotherapy may be caused by multidrug resistance (MDR) mechanisms protecting cancer cells against cytotoxic drugs, and the question arises whether prostate cancer is also using MDR principles resulting in resistance against chemotherapeutic agents. In consequence, an array of diverse pathways known to lead to MDR such as MDR1, MRPs, glutathione, and apoptosis have been examined and partially established at varying degrees in hormone-refractory prostate cancer. Thus, evidence keeps accumulating for the involvement of some MDR mechanisms in the chemoresistance of prostate cancer in vitro and in vivo. For some of them, e.g. MRP1, functional expression appears to be probable. This lends credit to the idea that reversal, circumvention, or overcoming of MDR pathways in advanced prostate cancer may be feasible and will lead to new avenues with improved treatment efficacy in otherwise intractable disease.

Rational selection of a control arm for randomised trials in metastatic renal cell carcinoma.

OBJECTIVE: Immunotherapy, and only immunotherapy, has reproducible, albeit limited efficacy in metastatic renal cell cancer (MRCC). Further improvement is warranted and progress will have to be investigated in randomised clinical trials, because the variable natural history of this disease precludes firm conclusions outside the context of controlled clinical studies. Currently, there is no general accepted standard arm to compare for those randomised clinical protocols. This needs to be established, which is the goal of this project. MATERIALS AND METHODS: Interferon-alpha (IFN-alpha) or interleukin-2 (Il-2) are registered for the use in MRCC. Taking this regulatory affair into consideration, a systematic literature research using Medline Sources was carried out to identify large controlled clinical studies in MRCC, in which one or both of the registered drugs were involved. Scientific value of the trials was weighed, and the applicability, efficacy, and safety of the control arm was analysed. RESULTS: 13 large controlled studies qualified for this purpose, and a total of 3065 patients were included. IFN-alpha monotherapy, the combination of IFN-alpha and Il-2, and the combination of IFN-alpha, Il-2 and 5-fluorouracil (5-FU) were used as a standard treatment in decreasing frequency, respectively. There is no valid scientific proof that a combination of immunotherapies prolongs survival over monotherapies, but the combination of surgery and immunotherapy leads to a clear survival benefit over immunotherapy alone. IFN-alpha monotherapy has considerable less side effects than Il-2 based regimens. CONCLUSION: An appealing safety profile, the applicability in an outpatient regimen, the possibility of less stringent selection criteria, and the proven life prolonging effect will make adjuvant monotherapy, in particular IFN-alpha monotherapy, after a tumournephrectomy currently the control-arm of choice in randomised trials for MRCC.

The plication procedure for penile curvature: surgical outcome and postoperative sexual functioning.

OBJECTIVE: This study evaluates the patients' judgement of the surgical outcome of the plication procedure, as described by Schröder and Essed, and the postoperative sexual functioning of patients with congenital curvatures and Peyronie's disease. PATIENTS AND METHODS: Of 98 patients treated for penile curvatures between 1985 and 1996, 85 patients received postoperatively a 'Questionnaire Assessing the Outcome of Surgery' and a short version of the 'Questionnaire for Screening Sexual Dysfunctions'. RESULTS: 28 patients with congenital curvatures and 31 with Peyronie's disease were evaluated. 75% of the patients with congenital curvatures and 58% of the patients with Peyronie's disease were satisfied with the result. Patients treated for Peyronie's disease reported diminished penile length and inability to have sexual intercourse more often than patients with congenital curvatures (90 vs. 64%, and 29 vs. 0%). After correction for age, patients with Peyronie's disease were less satisfied with their present sex life, had more frequent erectile problems and more trouble with considerable sexual desire than a group of 42 controls. For patients with Peyronie's disease satisfaction with the result was positively correlated with satisfaction with their present sex life and negatively correlated with the frequency of erectile problems. For patients with congenital curvatures satisfaction with the result was negatively correlated with both a postoperative curvature and a repeat operation. CONCLUSIONS: Some patients with Peyronie's disease may not benefit from surgical correction (alone). Because of the occurrence of sexual problems, future evaluation of the role of pre- and postoperative sexological counselling in achieving better results is recommended.

[The value of tumor nephrectomy in metastatic renal cell carcinoma]. / Stellenwert der Tumornephrektomie beim metastasierten Nierenzellkarzinom.

In the case of an organ-confined RCC, tumor nephrectomy is the undisputed therapy of choice even though overall 5-year survival has not surpassed the 60% threshold. Further improvement will most likely have to await the development of more effective systemic treatment strategies. For an exclusively surgical therapy of metastatic RCC, tumor nephrectomy, sometimes in combination with metastasectomy, can be applied. However, more commonly used is a multimodality approach consisting of a cytoreductive operation followed by immunotherapy. Alternatively, one may select immunotherapy first followed by adjuvant nephrectomy in the case of a response, or one may proceed directly to immunotherapy only. Long-term survival does not exceed 5-10%, and patient selection appears to have a higher prognostic impact than any treatment strategy available. Concepts and progress in the field clearly are of increasing value for modern oncologic urologists. The current standard, a multimodality treatment of metastatic RCC, in which an operation becomes necessary at a certain point in time, easily justifies a central role for the urologic surgeon.

Principles of nephrectomy for malignant disease.

For many years the prevailing belief was to advocate'radical' nephrectomy via a transperitoneal approach as the standard surgical procedure for renal cell carcinoma (RCC). because the early control of the renal vessels before manipulating the kidney should minimize the likelihood of disseminating tumour cells during surgery. This philosophy was based on retrospective data which were never confirmed in a controlled trial. Since then,evidence has accumulated that some patients maybe better served by an extraperitoneal (translumbar)approach, providing similar oncological efficacy with the added advantage of reduced morbidity. However,these results are again either retrospective or statistically insignificant, and therefore do not allow firm conclusions. Nevertheless, if there is any difference in the possible intraoperative dissemination of tumour, depending on the type of surgical approach, it will be small, requiring analysis in a large randomized multicentre trial. The treatment of choice for disease that is not disseminated is surgery, although the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvements will probably have to rely on the development of more effective systemic therapy and the application of combined treatments to counter the relatively many patients presenting with advanced stages. Concepts and progress in this field appear to be of major interest for modern uro-oncologists after the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade.

A phase II trial of methotrexate-human serum albumin (MTX-HSA) in patients with metastatic renal cell carcinoma who progressed under immunotherapy.

INTRODUCTION: Renal cell carcinoma (RCC) has a poor prognosis when metastasized to distant sites, although immunotherapy may offer a prolongation of survival in selected patient groups. Unfortunately, no treatment options remain when immunotherapy fails. In this phase IIa trial the tolerability and efficacy of the antifolate drug methotrexate-human serum albumin (MTX-HSA) were evaluated in patients with metastatic RCC who progressed after first-line immunotherapy. PATIENTS AND METHODS: A total of 17 patients started treatment, and 14 (12 men, 2 women) were evaluable for response according to the phase IIa Gehan design. Patients had had prior tumor nephrectomy, were in relatively good general condition, had no impairment of renal, liver or bone marrow function, and had progressive metastatic disease after treatment with interferon-alpha (IFN-alpha) with or without cis-retinoic acid (EORTC protocols 30951 and 30947). MTX-HSA was given once a week intravenously on an outpatient basis at a dose of 50 mg/m(2). The treatment interval was prolonged in those patients who had not yet recovered from previous toxicities. RESULTS: Toxicity was manageable, relatively mild to moderate and reversible in most cases. Grade 2/3 mucositis (10/17) and grade 3 elevated transaminase levels (4/17) were most frequent, and in only one patient was a grade 4 thrombocytopenia reported. Of three inevaluable patients, one discontinued treatment due to drug-related toxicities. The mean administration interval was 12.1 days, and 7 of 14 evaluable patients had treatment intervals of 1 or 2 weeks. No objective responses were seen, although eight patients had stable disease (stabilization >2 months) for up to 8 months (median 121 days). CONCLUSION: MTX-HSA was generally well tolerated and can be given on an outpatient basis, but no objective responses were seen in patients with metastatic RCC who had progressed after previous immunotherapy.

Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.

BACKGROUND: Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone. METHODS: We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5x10(6) IU/m(2) subcutaneously three times per week) started 2-4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat. FINDINGS: 40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0.60, 95% CI 0.36-0.97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0.54, 0.31-0.94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects. INTERPRETATION: Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status.

Urologic approaches to metastatic renal cell carcinoma.

The treatment of choice for nondisseminated disease is surgery. However, the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvement will most likely have to await the development of a more effective systemic therapy and the application of combined treatment modalities to counter the relatively high number of patients presenting with advanced stages. Treatment options in metastatic disease include nephrectomy alone, sometimes in combination with metastasectomy in selected cases, or cytoreductive surgery followed by immunotherapy. Alternatively, one may apply immunotherapy initially and perform adjuvant nephrectomy in the case of a response, or proceed with immunotherapy as a monotherapy. Nevertheless, long-term survival rates range merely from 5 to 10%, depending strongly on patient selection criteria. Concepts and progress in this field appear to be of major interest for modern urooncologists following the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade.

Early versus deferred hormonal treatment for asymptomatic prostate cancer.

There are two different clinical scenarios in which a decision on hormonal therapy either initially after diagnosis of deferred until the occurrence of signs and symptoms for presently asymptomatic prostate cancer is needed: A more recently described cohort of men with prostate cancer who underwent definitive therapy for putatively curable disease experiencing a rising PSA (biochemical relapse / progression), and a more classical group of men with prostate cancer who were unwilling or unfit to undergo local therapy with curative intent. Long-term hormonal treatment will expose patients to the risk of substantial adverse side effects such as muscle wasting, chronic fatigue, osteoporosis and others, in addition to an overall increase in treatment costs. On the other hand, a potential prolongation of survival and a delay in the development of clinical symptoms may serve as arguments for early treatment. A number of studies have been conducted in which early hormonal treatment delays the time to progression and reduces the cancer-related complication rate such as urinary obstruction and bone fractures. However, results on overall survival remain inconclusive and quality-of-life issues will become more and more important in light of the extended life span of patients with asymptomatic prostate cancer in recent years. Ongoing clinical trials such as EORTC 30991 are needed to provide further information on this important issue.

Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer.

PURPOSE: Advanced disseminated prostate cancer is highly resistant to cytotoxic chemotherapy. We identified proteins that may be involved in multidrug resistance in clinical prostate cancer. Expression of these proteins was examined in the context of tumor progression. MATERIALS AND METHODS: Paraffin embedded, formalin fixed prostate cancer specimens from archival sources of 3 distinct patient groups were examined. These groups were clearly distinct with regard to pathological stage and responsiveness to antihormonal therapy. Group 1 consisted of patients with organ confined prostate cancer treated with radical prostatectomy (early pathological stage T2N0M0). Group 2 patients had disseminated, early advanced prostate cancer and were treated with transurethral prostatic resection for urinary obstruction before receiving antihormonal therapy. Group 3 patients had disseminated prostate cancer with relapse despite antihormonal treatment (late advanced prostate cancer) and they underwent transurethral prostatic resection to relieve the symptoms of urinary obstruction. Immunohistochemical study was done to detect P-glycoprotein, multidrug resistance associated protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl-2, Bax, topoisomerase I, IIalpha and IIbeta, and Ki-67. RESULTS: Advanced tumors were distinguished from locally confined tumors because they exhibited significantly higher histological grade and proliferative activity. The expression of multidrug resistance associated protein, p53, topoisomerase IIalpha, Ki-67 and topoisomerase IIbeta was significantly related to a higher Gleason sum score. The number of cases expressing multidrug resistance associated protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl-2, topoisomerase IIalpha and Ki-67 was significantly increased in the group with advanced disseminated prostate cancer. Topoisomerase I and IIbeta were homogeneously and highly expressed at all stages of prostate cancer progression, while P-glycoprotein was not expressed in any tumors regardless of the patient group. CONCLUSIONS: Up-regulation of the expression of the drug transporters multidrug resistance associated protein and lung resistance protein, detoxifying enzyme glutathione-S-transferase pi, and apoptosis inhibiting proteins Bcl-2 and p53 may be an explanation of the resistance of disseminated progressive prostate cancer to chemotherapy. As shown by the up-regulation of Ki-67 and topoisomerase IIalpha, increased proliferation reflects the aggressiveness of metastatic prostate cancer. Research on agents that counteract multidrug resistance mechanisms and may sensitize prostate carcinoma to cytotoxic chemotherapy may possibly lead to more effective treatment of progressive disseminated prostate cancer.

Inhibition of apoptotic proteins causes multidrug resistance in renal carcinoma cells.

Renal Cell Carcinomas (RCCs) exhibit strong resistance to the most chemotherapeutic treatments probably due to the expression of various multidrug resistance (MDR) genes. Overexpression of P-glycoprotein (Pgp) is established as one such factor, but other mechanisms such as at-MDR, characterized by attenuated DNA-topoisomerase II (topoII) activity, may be functional as well. In addition, regulating proteins involved in apoptosis can exhibit multidrug resistant features. However, prevention of apoptosis as a mechanism of MDR has not yet been assessed in RCC, nor has the cytotoxicity of a variety of chemotherapeutic agents known to trigger apoptotic or necrotic cell death been tested in RCC in a systematic fashion. Using immunohistochemistry and Western blotting, Bcl-2 and Bax expression was determined in a panel of multidrug resistant RCC lines featuring Pgp and/or at-MDR. The results were related to apoptotic activity and kind of cell death in these cell lines, demonstrated by incubation with Hoechst 33342 and propidium iodide after treatment with various cytotoxic agents and quantitated by MTT. In the drug resistant sublines, some decreased Bax and strongly increased Bcl-2 expression was seen by immunohistochemistry indicating prevention of apoptosis as a distinct feature of MDR in RCC. This was confirmed by Western blotting. Sublines revealed significant resistance for all drugs, except for CC-313 and DiMIQ. However, these drugs induced necrotic cell death, in contrast to all other drugs tested, which induced apoptotic cell death. We conclude that, in chemoselected RCC sublines, multidrug resistance appears to be functional due to inhibition of apoptosis, apart from the MDR1 and at-MDR resistance mechanisms. CC-313 and DiMIQ are very potent cytotoxic agents in RCC, probably because they do not kill by induction of apoptosis.

Prognostic parameters for the management of advanced testis tumours.

The need for prognostic parameters in testicular germ cell tumours is sometimes questioned based on an overall cure rate of more than 80% of the patients regardless of tumour stage. However, the trend for an earlier and more accurate diagnosis amenable to curative treatment as well as the high effectiveness of standard Cisplatinum containing chemotherapy has masked the continuing need for intensifying therapy in patients with adverse risk factors. This intense treatment is often associated with worrysome morbidity and the assessment of prognostic factors, stage by stage, is warranted on which patient at risk can be identified and treated accordingly. Traditional prognostic factors, on which most classification systems are based, include large tumour volume, the presence of liver, bone or brain metastasis, grossly elevated tumour markers and an extragonadal primary site, particularly in the mediastinum. Novel prognostic factors are either (1) independent from the patient and his disease, (2) inherent on the patient's characteristics or (3) based on tumour biology. Clearly, the infrastructure and the experience of the treating uro-oncology unit (see 1) is decisive for treatment outcomes, and -at least-'difficult to treat' patients should be referred to properly resourced cancer centres. Patients with higher socio-economic status, willing to travel and well educated enough to be worried about their diseases status apparently gain access to expert centres more easily (see 2), translating into an upgrade on prognosis. Finally, biologic factors (see 3) such as beta-human chorionic gonadotrophin or MAGE epitopes in seminoma or the percentage of embryonal carcinoma components orvascular invasion mayor may not inversely influence the prognosis and need further assessment in prospective trials. However, the search for even better (molecular) biologic factors is speeding up because more complex treatment decisions such as in advanced testicular cancers rely on a more precise determination of prognosis, enabling a more tailored selection of individualized therapeutic options.

A phase II study of temozolomide in hormone-refractory prostate cancer.

INTRODUCTION: Hormone-refractory disseminated prostate cancer is a major oncological problem. Preclinical studies with temozolomide, an oral alkylating agent, in prostate cancer have shown encouraging results. In phase I studies the safety of temozolomide in non-prostate cancer patients has been demonstrated. Based on these results, a phase II study of temozolomide in patients with metastatic disease who had developed progressive symptomatic disease while on antiandrogen therapy, was initiated. METHODS: A group of 18 patients started a 5-day temozolomide regimen, with a 28-day treatment cycle. Response parameters (prostate-specific antigen, bone scan, quality of life questionnaire) and toxicity (common toxicity criteria for international studies) were recorded at regular intervals. RESULTS: Of the 18 patients, 16 were evaluable by completing two or three cycles. All patients developed progressive disease within two cycles, except one who had progressive disease at the end of cycle 3. Of the 16 evaluable patients, 11 developed new bone metastases (bone scan), 1 developed lung metastases, 4 had progressive disease as reflected by a 25% increase in serum PSA together with subjective progression, and 7 and 5 had progressive disease as reflected by decreased quality of life and increased pain score, respectively. Toxicity was limited to nausea and vomiting, which was effectively treated with antiemetic medication, and anemia and thrombocytopenia, which returned to normal values within 1 week. DISCUSSION: Treatment with temozolomide was generally well tolerated, with occasionally moderate toxicity. As all patients developed progressive disease the results are rather discouraging. Temozolomide is ineffective for the treatment of patients with symptomatic progressive hormone-refractory prostate cancer.

Immunotherapy of renal cell carcinoma. A critical appraisal from a urologist's point of view.

Treatment of choice for nondisseminated disease is surgery. However, the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvement will most likely have to await the development of a more effective systemic therapy and the application of combined treatment modalities to counter the relatively high number of patients presenting with advanced stages. Treatment options in metastatic disease include nephrectomy, sometimes in combination with metastasectomy in selected cases, alone or cytoreductive surgery followed by immunotherapy. Alternatively, one may apply immunotherapy initially and perform adjuvant nephrectomy in the case of a response, or proceed to immunotherapy as a monotherapy. Nevertheless, long-term survival ranges merely from 5 to 10% depending strongly on patient selection criteria. Concepts and progress in this field appear to be of major interest for modern uro-oncologists following the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade.

Chemosensitivity of prostate cancer cell lines and expression of multidrug resistance-related proteins.

The aim of this study was to obtain insight into the role of the multidrug resistance (MDR) phenomenon in hormone-independent progressive prostate cancer. Using immunocytochemistry and Western blotting we determined the expression of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi), Bcl-2, Bax, topoisomerase (Topo) I, II alpha and II beta in the human prostate cancer cell lines PC3, TSU-Pr1, DU145 and LNCaP derivatives LNCaP-R, LNCaP-LNO and LNCaP-FGC. Proliferative activity was assessed by immunocytochemistry. MTT assays were used to determine the sensitivity to etoposide, doxorubicin and vinblastin. Pgp was not expressed in any of the cell lines. MRP was variably expressed. GST-pi was expressed in TSU-Pr1, PC3 and DU145. The expression of Bcl-2 was restricted to TSU-Pr1, whereas Bax was found in all cell lines. Topo II alpha was expressed at the highest level in the rapidly proliferating cell lines TSU-Pr1 and DU145. Topo I and II beta were equally expressed. Resistance profiles varied among the cell lines, with TSU-Pr1 being the most sensitive and LNCaP-LNO relatively resistant. Multiple MDR proteins were expressed in prostate cancer cell lines and may well influence response to chemotherapy. Future functional studies, using chemo-selected MDR models, may further help to determine the mechanism or combination of mechanisms underlying the resistance of prostate cancer to chemotherapy.

[Lymphatic metastases in renal cell carcinoma. What is the value of operation and adjuvant therapy?]. / Lymphknotenmetastasen beim Nierenzellkarzinom. Was bringen Operation und adjuvante Therapie?

PURPOSE: Management of organ-confined RCC is primarily surgical. 5-year survival rates of all stages improved from 40% in the 1950th to 50% in the 60th, and stagnate at 60% in recent series. Paramount use of ultrasound in modern medicine has been claimed to contribute significantly to an earlier detection of RCC thus better amenable for radical operation. Other factors may have been strategies and general hospital care. However, it remains unclear whether an extended lymph node dissection as suggested by Robson in a seminal paper in the 1960th bears any therapeutic value. MATERIAL AND METHOD: The relevant literature including results of our institution were screened to support or to discard Robson's hypothesis that extended lymph node dissection improves treatment results for RCC. RESULTS: Retrospective data are contradictory with older studies claiming a benefit whereas more recent studies show no difference. The only prospective randomized study (EORTC 30881) revealed no difference, not even a trend, in an initial analysis. Long-term follow-up has not been published. However, the incidence of positive lymph nodes has declined from approximately 30% at the time of Robson's studies to 3.3% in the treatment arm of EORTC 30881. Hence, the clinical importance of a lymph node dissection for RCC has at least epidemiologically strongly diminished. Adjuvant (immuno)-therapy for RCC is investigational with all studies so far showing no advantage. An authoritative study randomizing in high risk patients between adjuvant or no further treatment has not been published. CONCLUSIONS: Lymph node dissection for RCC is diagnostic and improves pathologic staging. Morbidity associated with the procedure appears to be acceptable, but any therapeutic value remains unproven. Adjuvant therapy for N+ disease should be restricted to controlled clinical studies.