Biomedical subjects
Publications and source records attributed to G H Mickisch.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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.
Chemotherapy is the principal strategy to systemically challenge metastasized cancers of genitourinary origin. Unfortunately, the efficacy of chemotherapy is often hampered by multidrug resistance, the resistance to a variety of structurally and functionally distinct cytotoxic agents. Multidrug resistance can be either intrinsic or acquired, and can be caused by several mechanisms. The so-called classical multidrug resistance, mediated by the MDR1 gene product P-glycoprotein, has been held mainly responsible for inferring the multidrug resistance phenotype on urologic malignancies. However, several other multidrug resistance pathways have been identified. Multidrug resistance can be caused by the membrane-bound multidrug-resistance-associated protein, the detoxifying glutathione metabolism, the antiapoptotic protein BCL2, and changes in levels or activity of the topoisomerase enzymes. Strategies to overcome multidrug resistance of genitourinary tumors have arisen from the better understanding of the biologic and molecular mechanisms of multidrug resistance, and have been studied in experimental and clinical settings. However, attempts to modulate multidrug resistance in clinical renal cell, bladder, prostate, and testicular cancer have not been very rewarding so far, despite the optimism that had arisen from experimental data. Nevertheless, application of novel therapies to reverse multidrug resistance and to increase efficacy of chemotherapy for urologic cancers should be further pursued, within the setting of controlled clinical trials, to improve on current strategies.
Renal cell carcinoma (RCC) displays strong resistance against many chemotherapeutic drugs. Overexpression of P-glycoprotein (Pgp) appears to be part of this resistance. The involvement of another resistance mechanism, involving the decreased activity of DNA topoisomerase II (topoII), remains uncertain. By culturing the human RCC lines RC2 and RC21 in the presence of increasing concentrations of etoposide, we derived the variant sublines RC2E, RC21A and RC21E, that had acquired approximately 30-, 60- and 90-fold resistance to this drug respectively. RC2E, RC21A and RC21E were approximately 50-, 5- and 400-fold cross-resistant to doxorubicin respectively. RC2E and RC21E also showed cross-resistance (approximately 200- and 3500-fold respectively) to vinblastine. Quantitative differences in MDR1 and Pgp expression (elevated in RC2E and RC21E) and topoII alpha (reduced in RC21E and RC21A) were demonstrated using Western blotting and the reverse transcriptase/polymerase chain reaction. Decreased amounts of topoII alpha were reflected in a reduced activity of RC21A and RC21E as measured by unknotting phage P4 DNA. Qualitative changes of the topoII alpha gene, such as point mutations in the motif B/DNBS and DNA-binding regions, or differences in methylation status of the promoter gene of RC21E, were not found. These cell lines represent a model of a solid tumor in which overexpression of Pgp, a combination of increased Pgp and decreased topoII alpha, and a decrease of topoII alpha are represented.
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The past decade has seen the successful application of genetic techniques in the dissection of the most important phenotypes of cancer cells. In the case of drug resistance mechanisms, the elucidation of the genes involved in resistance to anticancer agents has led to new and unexpected information about tumor physiology and may well open therapeutic options by virtue of reversing clinical chemoresistance. The experimental characterization of defined multidrug resistance factors, such as P-glycoprotein, multidrug resistance associated protein, topoisomerase, or glutathione-S-transferase in urologic malignancies, is now relatively comprehensive, allowing for an initial analysis. Clinical studies on some of these concepts have been started and will be the subject of careful scrutiny. We expect that they will have a considerable impact on the way certain urologic anticancer strategies will be pursued in the future.