Tumor percentage but not number of tumor foci predicts disease-free survival after radical prostatectomy especially in high-risk patients.

OBJECTIVE: To evaluate the predictive value of tumor volume (TV), tumor percentage (TP), and number of tumor foci (NF) in patients with prostate cancer. The prognostic relevance of TV, TP, and NF as predictors of biochemical recurrence (BCR) following radical prostatectomy (RPE) is controversial. PATIENTS AND METHODS: The cohort consisted of 758 referred subjects who underwent RPE between 2000 and 2005 at the University of Muenster. The mean time of follow-up was 62 months. TV, TP, and NF were estimated visually with the assistance of a pathologic mapping grid for embedded whole-mount RPE specimens. In addition, TV and TP were assessed in a categorized fashion by using quartiles as cutoff points. Subgroup analyses for high- and low-risk patients using univariate and multivariate Cox proportional hazard analyses for BCR were performed. RESULTS: TV, TP, and NF were strongly related to tumor stage, Gleason score, surgical margin status, and preoperative prostate-specific antigen (PSA). In univariate analysis, all pathologic parameters including TV, TP, and NF were predictive for BCR. In multivariate analysis, only TP, tumor stage, and PSA level were independent predictors. In subgroup analysis, TP was an independent predictor for BCR in the high-risk group but not in the low-risk group. CONCLUSIONS: TP, but not TV or NF, was found to be an independent predictor for BCR in patients after RPE. TP seems to be more relevant in high-risk patients (i.e., any of the following: > pT2, Gleason score > 6, or PSA > 20 ng/ml).

Phase 3 study of adjuvant radiotherapy versus wait and see in pT3 prostate cancer: impact of pathology review on analysis.

BACKGROUND: In a randomised trial, radical prostatectomy (RP) followed by adjuvant radiotherapy (aRT) was compared with RP alone in patients with pT3 pN0 prostate cancer with or without positive margin at local pathology (German Cancer Society trial numbers ARO 96-02/AUO AP 09/95). OBJECTIVE: A pathology review was performed on 85% of RP specimens of patients to investigate the influence of pathology review on the analysis. DESIGN, SETTING, AND PARTICIPANTS: Patients post-RP (n=385) were randomised before achieving an undetectable prostate-specific antigen (PSA) level to either wait and see (n=192) or 60Gy aRT (n=193). Of 307 patients with undetectable PSA after RP, 262 had pathology review. These results were included prospectively into the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement between local and review pathology was measured by the total percentage of agreement and by simple kappa statistics. The prognostic reliability for the different parameters was analysed by Cox regression model. Event-free rates were determined by Kaplan-Meier analysis with a median follow-up of 40 mo for the wait-and-see arm and 38.5 mo for the aRT arm. RESULTS AND LIMITATIONS: There was fair concordance between pathology review and local pathologists for seminal vesicle invasion (pT3c: 91%; κ=0.76), surgical margin status (84%; κ=0.65), and for extraprostatic extension (pT3a/b: 75%; κ=0.74). Agreement was much less for Gleason score (47%; κ=0.42), whereby the review pathology resulted in a shift to Gleason score 7. In contrast to the analysis of progression-free survival with local pathology, the multivariate analysis including review pathology revealed PSMs and Gleason score >6 as significant prognostic factors. CONCLUSIONS: Phase 3 studies of postoperative treatment of prostate cancer should be accomplished in the future with a pathology review. In daily practice, a second opinion by a pathologist experienced in urogenital pathology would be desirable, in particular, for high-risk patients after RP.

Laparoscopic adrenalectomy in urological centres - the experience of the German Laparoscopic Working Group.

OBJECTIVE: To evaluate the safety and feasibility of laparoscopic adrenalectomy (LA) performed in several German centres with different laparoscopic experience, as LA has become the gold-standard approach for benign surgical adrenal disorders; however, for solitary metastasis or primary adrenal cancer its precise role is uncertain. PATIENTS AND METHODS: The data of 363 patients who underwent a LA were prospectively collected in 23 centres. All centres were stratified into three groups according to their experience: group A (<10 LAs/year), group B (10-20 LAs/year) and group C (>20 LAs/year). In all, 15 centres used a transperitoneal approach, four a retroperitoneal approach and four both approaches. Demographic data, perioperative and postoperative variables, including operating time, surgical approach, tumour size, estimated blood loss, complications, hospital stay and histological tumour staging, were collected and analysed. RESULTS: The transperitoneal approach was used in 281 cases (77.4%) and the retroperitoneal approach was used in 82 patients (22.6%). In all, 263 of 363 lesions (72.5%) were benign and 100 (27.5%) were malignant. The mean (sd) operating time was 127.22 (55.56) min and 130.16 (49.88) min after transperitoneal and retroperitoneal LA, respectively. The mean complication rates for transperitoneal and retroperitoneal LA were 5% and 10.9%, respectively. CONCLUSION: LAs performed by urologists experienced in laparoscopy is safe for the removal of benign and malignant adrenal masses. LA for malignant adrenal tumours should be performed only in high-volume centres by a surgeon performing at least >10 LAs/year.

Combined immunochemotherapy in selected patients with metastatic renal cell carcinoma: HLA class II genotype can help to predict response to therapy.

A number of new agents have been approved for systemic therapy of metastatic renal cell carcinoma (mRCC) recently. Thereby, prognostic factors may aid in predicting the effectiveness of various treatment modalities in individual cases. Aim of this study was to determine the value of human leukocyte antigen (HLA) class II characteristics in predicting response of mRCC to combined immunochemotherapy (ICT). A retrospective study of 29 patients with mRCC treated with ICT was performed: 17 patients (group A) with long-term remission and 12 (group B) with progressive disease after ICT. DNA was used for high resolution typing of HLA-DRB1, -DRB3, -DRB4, -DRB5, -DQA1, and -DQB1. Statistical evaluation started with Classification and Regression Trees analysis. The assignment of single alleles to the groups was then aggregated to create a classification on a patients' basis. Finally, the accuracy of this test algorithm was evaluated. HLA-DRB1 (DRB1*0301*0401*0402*0407*1101*1501=progression) was the strongest discriminator between the 2 groups. The test algorithm defined all patients with at least one of these DRB1 alleles to be progressive after ICT. Thus, 12 of 12 patients of group B could have been identified as progressive (sensitivity=100%). However, only 10 of 17 patients of group A would have been identified as responding (specificity=58%). Thus, the test had a positive and negative predictive value of 63% and 100%, respectively. Approximately 5% to 10% of all patients with mRCC are able to benefit from ICT with long-term remission. HLA class II characteristics may aid in identifying this small subgroup of patients with mRCC.

Negative predictive value of systematic ultrasound-guided prostate biopsy: which tumours do we miss?

BACKGROUND: The aim of the study was the determination of the negative predictive value of sextant core prostate biopsy. PATIENTS AND METHODS: Prostate cancer was diagnosed in 126 patients by systematic ultrasound-guided sextant biopsy and was subsequently treated with radical prostatectomy. The prostatectomy specimens were examined histopathologically using the whole-mount section technique. RESULTS: 81 patients were diagnosed with unilateral and 45 with bilateral prostate cancer after biopsy. In 15/81 patients, the diagnosis of unilateral disease was confirmed by the whole-mount sections; 66 patients turned out to have bilateral disease. In 14/66 cases, the missed tumour foci were diminutive. In the remaining 52 patients, an erroneous diagnosis of unilateral prostate cancer had been made after biopsy, although the missed tumour foci were not diminutive. The negative predictive value of sextant core biopsy with respect to unilateral disease was 36%. CONCLUSION: An unexpectedly high number of tumour foci are missed by systematic ultrasound-guided sextant prostate biopsy.

Prognostic factors of papillary renal cell carcinoma: results from a multi-institutional series after pathological review.

PURPOSE: We examined papillary renal cell carcinoma prognostic variables and validated the 2002 UICC TNM staging system in a multicenter analysis. MATERIALS AND METHODS: From 10 urological institutions in Germany followup data were collected on a total of 675 patients with papillary renal cell carcinoma. Central pathological review was done to validate external histopathological diagnoses. The Kaplan-Meier method was used to derive cumulative cancer specific and overall survival, and the log rank test was used to compare the curves of 2 or more groups. For multivariate analysis of prognostic factors Cox regression analysis was done. All proportional hazard assumptions were systemically verified using the Grambsch-Therneau test. RESULTS: Cancer specific survival was significantly related to TNM stage and histological grading on univariate and multivariate analyses. Five-year cancer specific survival in pT1b cases was significantly shorter than in pT1a cases (90.0% vs 98.3%, p = 0.017). No significant difference was found between pT1b and pT2 tumors. Patients with pT3 or greater disease were at high risk for metastasis (50.6%) while metastatic disease associated with pT2 or less tumors occurred in 7.8% (p <0.0001). After metastatic disease was present the prognosis was poor with 7.2% 5-year cancer specific survival. Age was associated with poor prognosis in the subgroup with pT3 or greater tumors on univariate analysis (p = 0.026) but not on multivariate analysis. CONCLUSIONS: In its current form the 2002 UICC TNM staging system is not applicable to papillary renal cell carcinoma. Clinical and radiological followup should be offered at frequent intervals to patients with venous thrombus and/or locally advanced disease. The role of age remains unclear but should not be underestimated in risk stratification after surgery.

Multimodality treatment paradigms for renal cell carcinoma: surgery versus targeted agents.

For decades, advanced renal cancer was almost resistant to systemic therapy. Only a few patients with metastatic disease derived clinical benefit from immunotherapy after nephrectomy. Recent advances in understanding the molecular biology of advanced and metastatic renal cancer led to the development of several targeted agents that showed impressive anti-tumor efficacy and prolongation of progression-free survival. The integration of these drugs into clinical practice did not only revolutionize the management of renal cancer, but also created controversy about the necessity, patient selection for and timing of the extirpation of the primary tumor, as well as metastasectomy. Data from ongoing preclinical investigations, including basic science and translational research, are presented and carried forward into multimodal considerations to optimize clinical efficacy of concomitant surgical treatments in the era of targeted agents. In addition to these analyses, this article highlights available clinical data regarding the disputable importance of surgical treatment approaches and explores the need of multimodality treatment paradigms within interdisciplinary decision making.

Endothelin-A-receptor antagonism with atrasentan exhibits limited activity on the KU-19-19 bladder cancer cell line in a mouse model.

PURPOSE: The endothelin axis consists of endothelin-1 (ET-1) and its two receptors, ET(A)- and ET(B)-receptor (ET(A)-R and ET(B)-R). In several tumor entities, the ET(A)-R plays a significant role as a drug target. In our study, we investigated whether inhibition of ET(A)-R with atrasentan leads to an antitumor effect in urinary bladder carcinoma as well. MATERIALS AND METHODS: Twenty nude mice with thymic aplasia were subcutaneously administered 2 x 10(6) KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection, ten animals were treated with atrasentan (2.5 mg/kg BW intraperitoneally), and another ten animals were treated with placebo. During treatment, absolute tumor growth and relative growth rate over time were determined. After the end of treatment, the mitosis and necrosis rates, microvessel density, and receptor density in the tumor tissue were analyzed by immunohistochemistry. In addition, the expression intensities of ET-1, ET(A)-R, and ET(B)-R were evaluated semiquantitatively and compared between the groups. RESULTS: No significant differences between the active-treatment and placebo groups were detected, either with respect to absolute tumor growth (P = 0.333) or mitosis rate (P = 0.217). In the analysis of the necrosis rate and receptor density for ET(A)-R, a trend toward higher values in the active-treatment group (mean necrosis rate = 63.67%, receptor density: 1.417) than in the placebo group (mean necrosis rate = 46.25%, receptor density: 1.270) was found; however, neither difference was statistically significant (P = 0.08 and 0.219, respectively). CONCLUSIONS: ET(A)-R blockade with atrasentan in a bladder cancer xenograft model shows no significant antitumor effect.

Pre-treatment global quality of health predicts progression free survival in metastatic kidney cancer patients treated with sorafenib or sunitinib.

PURPOSE: Our goal was to prospectively evaluate self-reported quality-of-life (QoL) during second-line therapy in 51 consecutive patients with cytokine-refractory kidney cancer treated with sorafenib or sunitinib. METHODS: QoL was assessed by the EORTC QoL questionnaire QLQ-C30 at baseline and at weeks 4, 6, 10, 12 and 16. RESULTS: Global QoL deteriorated significantly during the first 4 weeks of treatment (P < 0.0001). Patients experienced a reduction of their role, cognitive, and social function (all P < 0.0001). In addition, fatigue (P < 0.0001), nausea/vomiting (P = 0.003), and pain (P < 0.0001) as well as dyspnoea (P < 0.0001), insomnia (P = 0.026), appetite loss (P = 0.013), and diarrhoea (P < 0.0001) increased significantly. After 16 weeks, fatigue (P < 0.0001), pain (P = 0.015), appetite loss (P = 0.002) and diarrhoea (P = 0.038) were still influenced by the therapy, while all functional scales recovered. Global QoL at baseline was predictive of overall response (P = 0.006) and progression free survival (PFS) (P < 0.0001). A better physical function at baseline, a better ECOG performance status, and a low risk profile according to MSKCC risk groups correlated with a longer PFS (all P < 0.0001). No significant differences regarding QoL were found between sorafenib and sunitinib during the study period. CONCLUSIONS: Second-line therapy with sorafenib or sunitinib does not adversely affect patients global QoL after 16 weeks of treatment. Evaluation of baseline QoL can help to further stratify patients into risk groups predicting overall response and PFS.

Prospective comparison of sorafenib and sunitinib for second-line treatment of cytokine-refractory kidney cancer patients.

OBJECTIVES: It was the aim of this study to investigate the clinical differences between the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib as second-line treatment for cytokine-refractory kidney cancer patients. METHODS: Twenty consecutive patients received continuous treatment of oral sorafenib at a dose of 400 mg twice daily in 6-week cycles. Sunitinib was administered to the remaining 20 patients at 50 mg once daily in repeated 6-week cycles consisting of daily therapy for 4 weeks, followed by a 2-week off-treatment period. We correlated best treatment responses and progression-free survival (PFS) with either TKI treatment. Adverse events were evaluated and differences were compared between both treatment groups. RESULTS: In the sorafenib group, 2 (10%) patients showed a partial response (PR) and 4 (20%) patients had progressive disease (PD) versus 6 (30%) PRs and 3 (15%) PDs in the sunitinib group, respectively (p = 0.195). The median PFS was 6.4 months for sorafenib and 7.4 months for sunitinib (p = 0.969). In contrast to gender, age and the number of prior cytokine therapy cycles, the Eastern Cooperative Oncology Group performance status (p = 0.024) and the Memorial Sloan-Kettering Cancer Center risk groups for second-line treatments (p = 0.015) were independent predictive parameters of PFS. Gastrointestinal symptoms were found to occur with greater frequency in the sunitinib group (p = 0.03). CONCLUSIONS: Both TKIs showed comparable clinical benefits. The Eastern Cooperative Oncology Group performance status and the Memorial Sloan-Kettering Cancer Center risk groups can help determine which patients might benefit from alternative drug treatments.

The prognostic impact of pelvic lymph node metastasis and lymphovascular invasion on bladder cancer.

OBJECTIVES: To present long-term results of a single-center series of patients undergoing bilateral pelvic lymphadenectomy and radical cystectomy for bladder cancer and to analyze the impact of pelvic lymph node metastasis and lymphovascular invasion on clinical outcome. METHODS: Between 1986 and 2005 833 patients were treated with bilateral pelvic lymphadenectomy and radical cystectomy at our institution. 614 of them with valid clinical follow-up information and no neoadjuvant therapy could be evaluated. RESULTS: Disease-free and overall survival in the entire cohort was 56.7% and 49.5% at 5 years and 52.4% and 38.2% at 10 years, respectively. 28.1% of all patients had pelvic lymph node metastasis. We found organ-confined tumor stages (or=pT3) and positive pelvic lymph nodes had a significantly shorter overall survival than those without lymph node metastasis (P < 0.0001). In the subgroup of or=pT3) (P = 0.004) and lymphovascular invasion (P = 0.001) were independent prognostic parameters. CONCLUSIONS: According to the present series, survival for patients with

Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate.

Recent studies have shown that intraductal prostate carcinoma (IDC-P) should be considered as a separate lesion distinct from prostatic intraepithelial neoplasia (PIN). The purpose of the present study was to analyze the genetic relationship between benign prostatic tissue, PIN, invasive cancer, IDC-P, and extracapsular tumor tissue to get further information about the role of IDC-P in the development of prostate cancer. One hundred five radical prostatectomy specimens were investigated immunohistochemically, 77 cases were analyzed by PCR for LOH of the tumor suppressor genes TP53 and RB1, and 11 cases of IDC-P and 10 cases of PIN were investigated using comparative genomic hybridization (CGH). At CGH analysis, IDC-P showed several chromosomal imbalances in contrast to PIN, where no changes were found. We could demonstrate a significant increase of LOH for TP53 or RB1 from benign tissue to PIN. LOH of both TP53 and RB1 were frequently found in IDC-P (52%), followed by extracapsular tumor tissue (44%), invasive cancer (24%), PIN (19%), and benign prostatic tissue (17%). Increased immunohistochemical expression was found in invasive cancer for TP53, RB1, and for PTEN. Decreased expression could be demonstrated in extracapsular tumor tissue and in IDC-P. Our results indicate that IDC-P in general follows the genetic pathway from normal epithelium over PIN lesion. IDC-P represents a separate prostatic lesion and should be graded as a poorly differentiated carcinoma.

VEGF-C, VEGF-D and Flt-4 in transitional bladder cancer: relationships to clinicopathological parameters and long-term survival.

BACKGROUND: Our aim was to determine the role of the lymphangiogenic markers VEGF-C, VEGF-D and Flt-4 in transitional bladder cancer. MATERIALS AND METHODS: Archival cystectomy tumor blocks of 286 patients were selected for construction of a tissue microarray (TMA). Paraffin sections were assessed immunohistochemically using polyclonal antibodies against VEGF-C, VEGF-D and Flt-4. Staining results were evaluated semiquantitatively and analyzed for their association with various clinicopathological factors. RESULTS: There was no association of VEGF-C with histopathological parameters or clinical outcome. Patients with VEGF-D overexpression had higher pathological tumor stages (p =0.021) and regional lymph node metastasis (p=0.008). Furthermore, they had a significantly reduced disease-free survival (p=0.042). Overexpression of Flt-4 was particularly present in the subgroup of G3 and G4 tumors (p=0.001) and was associated with a shorter disease-free survival (p=0.041). In multivariate analysis, only tumor stage and lymph node metastasis were independent prognostic parameters. CONCLUSION: Targeting VEGF-D and Flt-4 could be a useful tool to predict and control progression of bladder cancer.

The role of the endothelin axis and microvessel density in bladder cancer - correlation with tumor angiogenesis and clinical prognosis.

Endothelin-1 (ET-1) and its receptors, entothelin-A (ETAR) and endothelin-B (ETBR), commonly referred to as the endothelin (ET)-axis, are involved in tumor biology and growth. We investigated the effects of the ET-axis on microvessel density (MVD) and the clinicopathological parameters of patients with invasive bladder cancer. Paraffin tumor sections of 120 patients who had undergone radical cystectomy were assessed immunohistochemically using mono- and polyclonal antibodies for ET-1, ETAR, ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Transitional cell carcinomas (MVD=23.7) were better vascularized than squamous cell carcinomas (MVD=17.8, p=0.04). Organ-confined tumors (MVD=32.2) were better vascularized than T3- and T4-tumors (MVD=21.2, p=0.02) and ET-1 was overexpressed in this subgroup (p=0.027). Patients with metastatic regional lymph nodes (MVD=20.9) tended to have less MVD than patients without regional lymph node metastases (MVD=24.1) (p=0.15). The account of MVD did not reveal any significant differences in disease-free or overall survival. Organ-confined tumors and ET-1 overexpression are associated with upregulated microvessel density. These results suggest that MVD and ET-1 could be considered good prognostic factors.

Expression of the Endothelin-axis in the different histologic subtypes of renal cell carcinoma: a tissue microarray analysis.

Endothelin-1 and its receptors ETAR and ETBR, commonly referred to as the Endothelin-axis, are emerging to play a role in cancer. The Endothelin-axis has been shown to be involved in proliferation, angiogenesis and metastasis in various human tumours. To assess the role of the Endothelin-axis in renal cell carcinoma, we analysed its expression in archival tumour tissue of 183 patients. Representative tumour blocks were selected for constructing a tissue microarray. Paraffin sections were assessed immunohistochemically using monoclonal and polyclonal antibodies for Endothelin-1, ETAR and ETBR. Staining intensities were analysed semiquantitatively and the results were correlated with various histopathologic factors. Overexpression of Endothelin-1, ETAR and ETBR was identified in 12.8%, 84.1% and 93.3% of cases, respectively. No association with pathological tumour stage and histologic grading was found. Papillary renal cell carcinomas expressed highly significantly more Endothelin-1 than clear cell renal cell carcinomas (34.5% vs. 6.7%, p<0.001), while there was no difference between ETAR- and ETBR-expression in these histologic subtypes. However, ETAR tended to be overexpressed in the subgroup of G3-tumours (p=0.044). Studies are underway assessing the role of the Endothelin-axis and its potential use as a molecular target in renal cell carcinoma.

Multiorgan failure 17 years after initial stone therapy: forgotten ureteral stent in a horseshoe kidney.

We report on the case of a 44-yr-old white man who was referred as an emergency from a local hospital to the medical intensive care unit (ICU) at our institution for progressive multiorgan failure of unknown cause. The CT scan of the abdomen showed a horseshoe kidney with extensive stone formation in both kidneys and the urinary bladder. A massively calcified double pigtail ureteral stent could also be seen in the left upper urinary tract. The stent had been placed prior to extracorporeal shock wave lithotripsy (ESWL) therapy 17 years previously. Three weeks later, after conservative treatment for heart failure and septic complications, the massively enlarged hydronephrotic left part of the horseshoe kidney was exposed and heminephroureterectomy was performed. Moreover, a right-sided pyelotomy was performed. Midline vesicotomy allowed extraction of the remaining bladder stone including the rest of the forgotten pigtail stent. The patient recovered rapidly after surgery and was discharged after 2 wk with all drains removed.

The dual serotonin and noradrenaline reuptake inhibitor duloxetine for the treatment of interstitial cystitis: results of an observational study.

PURPOSE: We report an observational study to evaluate the efficacy and tolerability of duloxetine for interstitial cystitis. MATERIALS AND METHODS: A total of 48 women were prospectively treated for 2 months following an uptitration protocol to the target dose of 2 x 40 mg duloxetine per day. Patients received the target dose for 5 weeks. The efficacy of duloxetine treatment was assessed at week 8. The primary end point was a change in the overall well-being evaluated by a patient reported global response assessment. Secondary end points were changes in pain and urgency (visual analog scales), frequency and functional bladder capacity (48-hour voiding log), and changes in overall symptom severity (O'Leary-Sant index). RESULTS: There were 5 patients (10.4%) who were identified as responders and 17 patients (35.4%) who dropped out of the study exclusively due to side effects, with nausea present in all dropouts. No severe adverse events were reported. All 5 responders reported onset of symptom improvement but not until they had reached the target dose. Regarding secondary outcome parameters, duloxetine treatment did not result in statistically significant improvement of symptoms. Maximum urinary flow rate and residual volume were influenced more prominently in patients at the target dose, however, the changes did not appear to be clinically meaningful. CONCLUSIONS: Treatment of interstitial cystitis with duloxetine did not result in significant improvement of symptoms. The drug administration was safe but the tolerability of the drug was poor mainly due to nausea occurring with the starting dose of 20 mg per day. Based on the preliminary data of this observational trial we currently cannot recommend duloxetine as a therapeutic approach for interstitial cystitis.

Metallothionein in bladder cancer: correlation of overexpression with poor outcome after chemotherapy.

We examined metallothionein (MT) expression in bladder cancer and its relationship to clinicopathologic factors, survival data, and outcome of chemotherapy. In 97 patients who underwent radical cystectomy for bladder cancer, 34 of whom received cisplatin-based chemotherapy, MT expression was evaluated immunohistochemically. Results were correlated with histopathologic data, survival rates, and outcome of chemotherapy. MT overexpression was present in 33 patients (34.0%): strong in 7 (7.2%) and focal in 26 (26.8%). Overexpression was an independent prognostic factor and was significantly associated with poor survival. Patients undergoing chemotherapy showed worse survival if their tumours were MT-positive than if they were MT-negative. MT overexpression predicts unfavorable survival in bladder cancer patients. In those treated with cisplatin chemotherapy, survival is significantly poorer if tumours express MT. Our results show that MT overexpression may mediate resistance to alkylating agents. Therefore, further studies are warranted to define those patients who need a more aggressive therapy.

Histologic subtype of metastatic renal cell carcinoma predicts response to combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil.

OBJECTIVES: Combined immunochemotherapy with interleukin 2 (IL-2), interferon alpha (IFN-alpha), and 5-fluorouracil (5-FU) is an established first-line therapy for metastatic renal cell carcinoma (RCC). However, data on histologic parameters predictive of clinical benefit are rare. In this study, we evaluated the response to immunochemotherapy in the main histologic subtypes of renal cell carcinoma and performed a subgroup analysis of inoperable patients. METHODS: From 164 patients treated with one or two cycles of combined immunochemotherapy, radical nephrectomy had revealed 22 cases of papillary RCC (pRCC; 13.4%) and 131 cases of clear cell RCC (ccRCC; 79.9%). In the remaining 11 (6.7%) their disease was inoperable. The overall response rates were evaluated according to World Health Organization criteria. RESULTS: For ccRCC and inoperable disease, responses of 34.4% and 27.3% after one cycle and 28.8% and 16.7% after two cycles, respectively, were noted. In contrast, no patient with pRCC showed any response after two cycles of combined immunochemotherapy. CONCLUSIONS: No objective response was seen in patients with pRCC. Hence, the use of immunotherapeutic agents must be questioned in this histologic subtype.