New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2.

Anticancer treatment with ifosfamide but not with its structural isomer cyclophosphamide is associated with development of renal Fanconi syndrome leading to diminished growth in children and bone problems in adults. Since both cytotoxics share the same principal metabolites, we investigated whether a specific renal uptake of ifosfamide is the basis for this differential effect. First we studied the interaction of these cytotoxics using cells transfected with organic anion or cation transporters and freshly isolated murine and human proximal tubules with appropriate tracers. Next we determined changes in membrane voltage in proximal tubular cells to understand their differentiated nephrotoxicity. Ifosfamide but not cyclophosphamide was significantly transported into cells expressing human organic cation transporter 2 (hOCT2) while both did not interact with organic anion transporters. This points toward a specific interaction of ifosfamide with hOCT2, which is the main OCT isoform in human kidney. In isolated human proximal tubules ifosfamide also interacted with organic cation transport. This interaction was also seen in isolated mouse proximal tubules; however, it was absent in tubules from OCT-deficient mice, illustrating the biological importance of this selective transport. Ifosfamide decreased the viability of cells expressing hOCT2, but not that of control cells. Coadministration of cimetidine, a known competitive substrate of hOCT2, completely prevented this ifosfamide-induced toxicity. Finally, ifosfamide but not cyclophosphamide depolarized proximal tubular cells. We propose that the nephrotoxicity of ifosfamide is due to its selective uptake by hOCT2 into renal proximal tubular cells, and that coadministration of cimetidine may be used to prevent ifosfamide-induced nephrotoxicity.

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.

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

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.

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.

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.

Prior vasorelaxation enhances diadenosine polyphosphate-induced contractility of rat mesenteric resistance arteries.

Low-threshold concentrations of diadenosine polyphosphates (ApnA: Ap3A, Ap4A, Ap5A, Ap6A) or ATP, which at basal vessel tone induce just measurable vasoconstrictions, induce up to ten times enhanced vasoconstrictions of previously relaxed (by acetylcholine or sodium nitroprusside or 8Br2 cGMP or isoproterenol or levcromakalim) pre-contracted rat mesenteric resistance arteries (MrA) in a microvessel-myograph. These enhanced vasoconstrictions were of similar magnitude for threshold concentrations of all ApnA.Possibly, the low concentrations of ApnA reverse the prior vasorelaxation by inhibiting a common vasorelaxation pathway, but obviously this is not due to inhibition of guanylate cyclase, which has been previously described to be inhibited by ApnA, because the enhanced vasoconstrictions can be observed with guanylate cyclase-independent vasorelaxants (8Br2 cGMP, isoproterenol or levcromakalim), too. The enhanced vasoconstrictions are endothelium-independent because after mechanical vascular de-endothelialization the results were identical. De-endothelialized vessels, which fail to relax by acetylcholine, showed no enhanced ApnA-induced vasoconstrictions, demonstrating that the mere prior vasorelaxation of the vessel is required to provide the enhanced vasoconstriction by ApnA. Furthermore, the enhanced contractility is not based on a potentiation of the phenylephrine contraction because it equally occurs with other agents used for arterial pre-contraction. Systemically applied ApnA considerably decrease arteriovascular resistance, resulting in hypotension. But here it is demonstrated that a preceding vasorelaxation enables the resistance arteries to generate a strong and persistent ApnA-induced vasoconstriction. Thus, in vivo at very low concentrations ApnA may serve to counteract severe conditions of hypotension (e.g., shock syndrome or anaphylaxis) by the constriction of resistance arteries.

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.

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.

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.

The endothelin axis in urologic tumors: mechanisms of tumor biology and therapeutic implications.

Endothelin (ET)-1 and its receptors ET-A and ET-B, referred to commonly as the endothelin axis, have been identified in various human cancers, especially gynecologic tumors, such as breast cancer or ovarian cancer, but also including urologic tumor entities. They play a key role in tumor growth and progression by influencing critical cancer pathways, such as apoptosis, angiogenesis and proliferation. In prostate cancer, overexpression of the ET-A receptor increases with tumor progression, and clinical trials with selective ET-A receptor antagonists, such as atrasentan (ABT-627), have shown promising early results. In preclinical models of bladder cancer, overexpression of the ET axis has been demonstrated and ET-targeting agents are under investigation. This paper reviews the role of the ET axis in human cancers and focuses on preclinical and clinical studies in urologic tumor entities to further define the role of ET-targeting agents as targeted molecular therapy.

Neoplasia of the kidney--a rare event during pregnancy.

Sarcomas of the kidney during pregnancy are very rare and should be treated by an interdisciplinary team with respect to the actual trimester. Decisions regarding treatment have to be made with the patient and her family.

Expression of the endothelin axis in bladder cancer: relationship to clinicopathologic parameters and long-term survival.

OBJECTIVES: Endothelin-1 (ET-1) and its receptors ET(A)R and ET(B)R, referred to as the Endothelin-axis, play an emerging role in cancer. We examined the ET-axis immunohistochemically in invasive bladder cancer. METHODS: Tumor specimens from 157 patients after cystectomy were stained immunohistochemically for ET-1, ET(A)R and ET(B)R. After semiquantitative analysis the staining results were correlated with clinicopathological parameters and survival rates. RESULTS: Overexpression of ET-1, ET(A)R and ET(B)R was identified in 26.8%, 58.8% and 76.9% of cases, respectively. No association with TNM staging and histologic grading was found. However, patients with ET(B)R expression tended to have organ-confined tumors (p=0.16) and no vascular invasion (p=0.09), the latter being statistically significant in the subgroup of G3 tumors (p=0.02). ET(B)R overexpression was associated with favorable disease-free survival (p=0.04). CONCLUSIONS: The ET-axis is overexpressed in bladder cancer, ET(B)R predominating in this entity and being associated with a more favorable prognosis. Further studies are warranted to elucidate the role of the ET-axis as a molecular target in bladder cancer.