[Systemic treatment of metastatic renal cell carcinoma: change of paradigms after introduction of targeted therapy]. / Systemische Behandlung des metastasierten Nierenzellkarzinoms: Paradigmenwechsel nach Einführung der zielgerichteten Therapie.

INTRODUCTION: The goal of this work was to describe the change of treatment paradigms for metastatic renal cell carcinoma (mRCC) since 2006. PATIENTS AND METHODS: We retrospectively investigated all mRCC patients who were treated with targeted therapy between June 2006 and June 2012 at the University of Münster. RESULTS: In all, 50 of 158 (31.6 %) patients were initially treated with immunotherapy. The most often used second line treatment after immunotherapy was sorafenib (29 patients, 58.0 %). The first line treatment chosen for therapy-naïve patients was sunitinib (68 patients, 63.0 %). There was no statistically significant difference between the two groups (572 vs. 554 days, p = 0.745). A total of 77 patients had synchronous metastasis (48.8 %), 55 of whom underwent cytoreductive nephrectomy. There was a significant survival benefit in favor of surgically treated patients (510 vs. 186 days, p = 0.002). CONCLUSION: After introduction of the new agents treatment paradigms have changed substantially. Immunotherapy is used only rarely. Cytoreductive nephrectomy may continue to be regarded as standard treatment until prospective data are available.

Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib.

PURPOSE: To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). PATIENTS AND METHODS: Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodothyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. RESULTS: Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analysis, the ECOG status (P < 0.0001) as well as MSKCC criteria (P = 0.003) and response to therapy (P < 0.0001) were associated with progression-free survival (PFS). Twenty-one of 66 (31.8%) evaluable patients developed hypothyroidism during treatment. Of those patients, 8/21 (38.1%) were treated with So and 13/21 (61.9%) with Su. Response rate in this subgroup was 49.2%. Hypothyroidism was associated with a longer PFS (16.0 ± 0.8 months vs. 6.0 ± 0.8 months, P = 0.032). Most patients [16/21 (76.2%)] developed abnormal TSH values during the first 4 weeks of treatment. Hormone replacement with l-thyroxine did not have an influence on survival. In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, P = 0.018) and hypothyroidism (P = 0.01) were independent prognostic parameters. CONCLUSIONS: The development of hypothyroidism during treatment might be useful as a predictor of PFS for mRCC patients undergoing treatment with targeted agents.

[Cyclooxygenase-2-expression in bladder cancer: tumor-biological and clinical implications]. / Cyclooxygenase-2-Expression beim Harnblasenkarzinom: Tumorbiologische und klinische Bedeutung.

PURPOSE: Cyclooxygenase-2 (Cox-2) contributes to the carcinogenesis of human tumors by various mechanisms. As Cox-2-expression has been found in most human neoplasms, selective Cox-2-inhibitors could be used as a molecular targeted therapy, and first clinical trials have already been initiated. Moreover, Cox-2-inhibitors have been shown to add to the activity of conventional cytotoxic therapies in experimental and clinical studies. We analyzed Cox-2-expression in bladder cancer and its implications on clinical parameters. MATERIALS AND METHODS: Cox-2-expression was evaluated immunohistochemically in 157 patients undergoing radical cystectomy. Sixty-two patients had received cisplatin-based treatment during follow-up, either as adjuvant therapy or for metastatic disease. Cox-2-expression was correlated with clinical and pathological parameters, survival data and outcome of chemotherapy. RESULTS: Cox-2 was expressed in 83.4 % of tumors. No association was found with TNM-staging and histological grading, but a significant relation to the histologic subtype (transitional vs. squamous cell carcinoma, p = 0.038) was present. Survival analysis showed no impact of Cox-2-expression on overall or disease-free survival. However, a subgroup of chemotherapy patients demonstrated a significant correlation of strong Cox-2-expression with worse overall survival time (p = 0.01). CONCLUSIONS: Cox-2-expression was found in the majority of invasive bladder tumors. For patients who underwent chemotherapy, a significant relation of Cox-2-expression and worse overall survival was demonstrated. Cox-2 seems to be an interesting molecular target for the diagnosis and therapy of bladder cancer. Further experimental and clinical studies are warranted to elucidate whether Cox-2-inhibition can serve as an additive therapy to chemotherapy of bladder cancer.

In vitro electrostimulation-induced urethral relaxation in the guinea pig is blocked by prazosin.

The purpose of this study was to characterize the electrostimulation-induced relaxation in guinea pig urethral rings. From sacrificed male guinea pigs, urethral rings were cut between the bladder neck and the penile crura and mounted in an in vitro bath. The drop in baseline tension in response to electrical stimulation (rectangular pulses of 0.8-msec pulse duration, a frequency of 3, 5, 10, and 20 Hz, and 75-mA current) was measured in the presence of various pharmacologic agents. In urethral tissue precontracted with 10(-5) norepinephrine, a significant relaxation of 34.8% was found at 10 Hz. This relaxation was not affected by the addition of neuropeptide Y (NPY, 10(-8)-10(-6) M), 10(-6) M atropine, 10(-5) M alpha-beta-methylene-adenosine,5'-triphosphate (alpha-beta-methylene-ATP, a purinergic antagonist), and tolazoline (alpha2 antagonist, 10(-8)-10(-4) M). However, with the alpha1 antagonist prazosin (5 x 10(-8)-5 x 10(-7) M), no relaxation occurred. The tissue response was of neurogenic origin as it was blocked by 10(-7) M tetrodotoxin. Norepinephrine-precontracted urethral rings of male guinea pigs exhibit a relaxation response at 10 Hz that is alpha1-adrenergic, non-cholinergic, non-purinergic, and independent of NPY.

Urethral relaxation after electrostimulation in the guinea pig is independent of nitric oxide.

PURPOSE: To investigate whether the relaxation of the striated urethral sphincter in guinea pigs is mediated by nitric oxide. MATERIALS AND METHODS: After sacrifice, urethral rings were cut between the bladder neck and the penile crura and mounted in an in vitro bath. Maximal isometric tension obtained at 1, 3, 10 and 25 Hz electrical stimulation (Tmax) for 5 to 30 sec was measured. RESULTS: Tmax at 25 Hz was not changed by pretreatment with 10(-4)M nitroprusside or 10(-4)M NG-nitro-L-arginine. In urethral tissue precontracted with 10(-4)M noradrenaline, a significant relaxation of 16-25% was found at 10 Hz. This relaxation could not be prevented by pretreatment with 10(-4)M NG-nitro-L-arginine and was not enhanced by the presence of 10(-3)M L-arginine. CONCLUSION: Noradrenaline-precontracted urethral rings of male guinea pigs exhibit a maximal relaxation at 10 Hz, which does not depend on nitric oxide.