Martin Gerber

Surgery for Metastatic Urothelial Carcinoma with Curative Intent: The German Experience (AUO AB 30/05)

BACKGROUND Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients. OBJECTIVE We report the combined experience and outcome of patients undergoing resection of UCM gained at 15 uro-oncologic centers in Germany. DESIGN, SETTING, AND PARTICIPANTS Retrospective survey of 44 patients with distant UCM of the bladder or upper urinary tract who underwent complete resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008. INTERVENTION Resected metastatic sites were the following: retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). Systemic chemotherapy was administered in 35 of 44 patients (79.5%) before and/or after UCM surgery. MEASUREMENTS Overall, cancer-specific and progression-free survival from time of diagnosis and metastasectomy of UCM. RESULTS AND LIMITATIONS Median survival from initial diagnosis of UCM and subsequent resection was as follows: overall survival, 35 mo and 27 mo; cancer-specific survival, 38 mo and 34 mo; and progression-free survival, 19 mo and 15 mo. Overall 5-yr survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up of 8 mo. Seven patients without disease progression survived for >2 yr and remained free from tumor progression at a median follow-up of 63 mo. No significant prognostic factors could be determined due to the limited patient number. CONCLUSIONS Long-term cancer control and possible cure can be achieved in a subgroup of patients following surgical removal of UCM. Metastasectomy in patients with disseminated UCM remains investigational and should only be offered to those with limited disease as a combined-modality approach with systemic chemotherapy.

Expression of human beta-defensins 1 and 2 in kidneys with chronic bacterial infection

BackgroundConstitutive expression and localization of antimicrobial human β-defensin-1 (HBD-1) in human kidneys as a potential mechanism of antimicrobial defense has been previously reported. Inducible expression of human β-defensin-2 (HBD-2) has been described in various epithelial organs but not for the urogenital tract.MethodsWe investigated the gene- and protein expression of HBD-1 and HBD-2 by reverse transcriptase-polymerase chain reaction, and immunohistochemistry in 15 normal human kidney samples and 15 renal tissues with chronic bacterial infection. Additionally, cell culture experiments were performed to study HBD gene expression by real-time RT-PCR in response to inflammatory cytokines TNFα and IL-1β as well as lipopolysaccharide from Gram-negative bacteria.ResultsConstitutive HBD-1 gene- and protein expression was detected in normal renal tissue and kidneys with chronic infection. As a novel finding, inducible HBD-2 gene- and protein expression was demonstrated in tubulus epithelia with chronic infection but not in normal renal tissue. In pyelonephritic kidneys HBD-1 and HBD-2 expression showed a similar pattern of localizaton in distal tubules, loops of Henle and in collecting ducts of the kidney. Furthermore, real-time RT-PCR of kidney derived cell lines stimulated with inflammatory agents TNF-α, IL-1β and LPS revealed a strong increase in relative HBD-2 transcription level and also a slight increase in relative HBD-1 transcription level.ConclusionsUpregulated HBD-2 expression in renal tubulus epithelium indicates a role of a wider range of human defensins for antimicrobial host defense in the urogenital tract than previously recognized.

Coordination chemistry and function of the catalytic metal ion in liver alcohol dehydrogenase

A physicochemical characterization of the metal binding center of the active site of the dimeric enzyme horse liver alcohol dehydrogenase (HLADH) has been performed by replacing the zinc ion by various metal ions, e.g. Co, Ni, Cd, Cu. These metal ions have served as spectroscopic and kinetic probes to study the binding of coenzymes, substrates and inhibitors. The metal replacement is performed in two steps. First, the catalytic zinc ions are removed by treatment of crystal suspensions with chelating agents resulting in a species H4Zn(n)2-HLADH (where n denotes the non-catalytic zinc ions which remain in situ). Secondly, the H4Zn(n)2-HLADH can be reconstituted with different metal ions in a crystal suspension or in solution to yield Me(c)2Zn(n)2-HLADH (where c denotes the catalytic metal ion). X-ray crystallographic investigations have shown: (i) in H4Zn(n)2-HLADH only the catalytic zinc ion has been removed without any gross changes in the tertiary structure of HLADH or the ligand sphere of the catalytic metal ion; (ii) on binding NADH to H4Zn(n)2-HLADH, the transition from an ‘open’ to a ‘closed’ conformation occurs analogous to the native enzyme; and (iii) in Co(c)2Zn(n)2-HLADH the cobalt ion has been inserted into the active site accepting a coordination geometry very similar to the zinc ion in the native enzyme. The kinetics and the mechanism of the reconstitution of H4Zn(n)2-HLADH with Co(II), Zn(II) and Ni(II) has been shown to be a two-step process: The spectroscopic characterization of binary and ternary complexes of Me(c)2Zn(n)2-HLADH with coenzymes and/or inhibitors (substrates) has demonstrated that changes of the electronic structure of the catalytic metal ion during enzymatic turn-over are of fundamental importance. A novel kind of interaction of the catalytic metal ion with the coenzyme was noted: the rate of coenzyme dissociation and, therefore, the enzymatic turn-over depends on the kind of metal present in the active site. Concerning the interaction of the catalytic metal ion with non-protein ligands, we conclude: (a) previous conclusions drawn from measurements of the proton relaxation enhancement of the cobalt-bound ligand protons are invalid, since the cobalt ion is not a suitable relaxation probe in this protein; (b) the metal ion acts as a Lewis acid on inner-sphere bound aldehydes; and (c) the coordination number of the catalytic metal ion in binary and ternary complexes of LADH is a matter of controversy. Finally, we point out that previous postulated mechanisms for LADH are premature since the assignment of ionizing groups controlling catalysis is not firmly established. In particular, we have shown by 1H NMR spectroscopy of Co(c)2Zn(n)2-HLADH that the δ(NH) value of the metal ligand His-67 controls the acid-base equilibrium with pKa = 9.2 in the free enzyme. This possibility has never been considered in any previous mechanism.

Alcohol dehydrogenase from leuconostoc mesenteroides: molecular properties in comparison with the yeast and horse liver enzymE

Abstract 1. 1. Leuconostoc mesenteroides alcohol dehydrogenase is an acidic protein (pI =4.1) with a mol wt of 135,000 consisting of 4 identical subunits. 2. 2. It contains 2 Zn atoms and 5 cysteine residues per subunit. 3. 3. Thermal stability increases with increasing ionic strength. 4. 4. One NADPH molecule is bound per subunit. NADPH is bound about 10 times more strongly than NADH. Fluorescence spectra of bound coenzymes show characteristic blue shifts and intensity enhancements compared to those of free NAD(P)H. 5. 5. A comparison of molecular properties between horse liver-, yeast- and L. mesenteroides alcohol dehydrogenase shows the closer relationship of Leuconostoc ADH to yeast ADH.

Complete resection of urothelial cancer metastases with curative intent

BACKGROUND Recent publications suggest that a subgroup of patients can benefit from surgical removal of transitional cell carcinoma (TCC) metastases in addition to systemic chemotherapy. We report the combined experience and outcome of patients undergoing resection of TCC metastases at 15 uro-oncologic centers in Germany. MATERIALS AND METHODS Forty-four patients with distant metastatic TCC of the bladder or upper urinary tract underwent resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008 in an attempt to be rendered free of disease. RESULTS The resected metastatic sites consisted of retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). The treatment sequence included systemic chemotherapy in 35/44 (79.5%) patients before and/or after surgery. Median survival times from initial diagnosis of metastatic TCC and subsequent resection were as follows: overall survival, 35 and 27 months, respectively; cancer-specific survival, 38 and 34 months, respectively; and progression-free survival, 19 and 15 months, respectively. Overall 5-year survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up time of 8 months. Seven patients without disease progression survived for more than 2 years and remain free from tumor progression at a median of 63 months. CONCLUSION The results in this selected cohort confirm that long-term cancer control and possibly cure can be achieved in a subgroup of patients following surgical removal of TCC metastases. However, prospective data to identify patients most likely to benefit from this aggressive therapeutic approach are lacking. Therefore, metastasectomy in patients with disseminated TCC remains investigational and should be offered only to those with limited disease as a combined-modality approach with systemic chemotherapy.

Metastasenchirurgie in kurativer Absicht beim Urothelkarzinom

BACKGROUND Recent publications suggest that a subgroup of patients can benefit from surgical removal of transitional cell carcinoma (TCC) metastases in addition to systemic chemotherapy. We report the combined experience and outcome of patients undergoing resection of TCC metastases at 15 uro-oncologic centers in Germany. MATERIALS AND METHODS Forty-four patients with distant metastatic TCC of the bladder or upper urinary tract underwent resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008 in an attempt to be rendered free of disease. RESULTS The resected metastatic sites consisted of retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). The treatment sequence included systemic chemotherapy in 35/44 (79.5%) patients before and/or after surgery. Median survival times from initial diagnosis of metastatic TCC and subsequent resection were as follows: overall survival, 35 and 27 months, respectively; cancer-specific survival, 38 and 34 months, respectively; and progression-free survival, 19 and 15 months, respectively. Overall 5-year survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up time of 8 months. Seven patients without disease progression survived for more than 2 years and remain free from tumor progression at a median of 63 months. CONCLUSION The results in this selected cohort confirm that long-term cancer control and possibly cure can be achieved in a subgroup of patients following surgical removal of TCC metastases. However, prospective data to identify patients most likely to benefit from this aggressive therapeutic approach are lacking. Therefore, metastasectomy in patients with disseminated TCC remains investigational and should be offered only to those with limited disease as a combined-modality approach with systemic chemotherapy.

Metastasenchirurgie in kurativer Absicht beim Urothelkarzinom@@@Complete resection of urothelial cancer metastases with curative intent

BACKGROUND Recent publications suggest that a subgroup of patients can benefit from surgical removal of transitional cell carcinoma (TCC) metastases in addition to systemic chemotherapy. We report the combined experience and outcome of patients undergoing resection of TCC metastases at 15 uro-oncologic centers in Germany. MATERIALS AND METHODS Forty-four patients with distant metastatic TCC of the bladder or upper urinary tract underwent resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008 in an attempt to be rendered free of disease. RESULTS The resected metastatic sites consisted of retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). The treatment sequence included systemic chemotherapy in 35/44 (79.5%) patients before and/or after surgery. Median survival times from initial diagnosis of metastatic TCC and subsequent resection were as follows: overall survival, 35 and 27 months, respectively; cancer-specific survival, 38 and 34 months, respectively; and progression-free survival, 19 and 15 months, respectively. Overall 5-year survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up time of 8 months. Seven patients without disease progression survived for more than 2 years and remain free from tumor progression at a median of 63 months. CONCLUSION The results in this selected cohort confirm that long-term cancer control and possibly cure can be achieved in a subgroup of patients following surgical removal of TCC metastases. However, prospective data to identify patients most likely to benefit from this aggressive therapeutic approach are lacking. Therefore, metastasectomy in patients with disseminated TCC remains investigational and should be offered only to those with limited disease as a combined-modality approach with systemic chemotherapy.