[Catheterizable continence mechanisms for various urinary diversion reservoirs: serosa lined and tapered ileum]. / Katheterisierbarer Kontinenzmechanismus für verschiedene Harnableitungsreservoire : Getapertes, seroserös eingebettetes Ileum.

In a retrospective multicenter study of four clinics perioperative complications as well as incontinence and stoma stenosis of serosa-lined tapered ileum as catheterizable continence mechanisms for different urinary diversions were analyzed. Between 2008 and 2012 a total of 40 patients received a continent catheterizablestoma, 15 (37.5%) in combination with continent vesicostomy and closure of the bladder neck due to postoperative incontinence and recurrent stenosis including radical prostatectomy, transurethral resection (TUR) of the prostate, bladder neck incision (n=11), neurogenic bladder with reduced capacity and incontinence (n=2), interstitial cystitis (n=1) and recurrent urethral tumor following ileal neobladder (n=1). Of the patients 25 (62.5%) received this continence mechanism in combination with a modified Mainz pouch I, in 19 patients as primary and in 6 patients as secondary efferent segment for trouble shooting. The complications were subdivided according the Clavien classification. In 29 patients information concerning continence and stenosis were obtained, the median follow-up was 25 months (range 1-111 months). In patients with continent vesicostomy (n=11) the incontinence rate was 9.1% (1/11) and the stenosis rate 18.2% (2/11). In 18 patients with an ileocecal pouch, incontinence and stenosis rates were 0% and 11.1% (2/18), respectively. The presented technique is a safe continence mechanism for various catheterizable continent urinary diversions for both primary and secondary indications.

Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99].

BACKGROUND: The second-line chemotherapeutic treatment for metastatic urothelial cancer (UC) after failure of cisplatin-based first-line therapy needs to be improved. Based on encouraging phase II data of gemcitabine and paclitaxel (Taxol) (GP), this trial was designed to compare a short-term (arm A) versus a prolonged (arm B) second-line combination chemotherapy of GP. PATIENTS AND METHODS: Of 102 randomized patients, 96 were eligible for analysis. Primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rates (ORR) and toxicity. RESULTS: Neither OS [arm A: 7.8 (95% CI: 4.2-11.4), arm B: 8.0 (95% CI: 4.9-11.1) months] and PFS [arm A: 4.0 (95% CI: 0-8.0), arm B: 3.1 (95% CI: 1.9-4.2) months] nor ORR (arm A: 37.5%, arm B: 41.5%) were significantly different. On prolonged treatment, more patients experienced severe anemia (arm A: 6.7% versus arm B: 26.7% grade III/IV anemia; P = 0.011). In six patients, treatment was stopped during the first cycle due to disease progression or toxicity. Two patients died due to treatment-related toxic effects. CONCLUSION: Due to rapid tumor progression and toxicity at this dosage and schedule in a multicenter setting, it was not feasible to deliver a prolonged regimen. However, a high response rate of ∼40% makes GP a promising second-line treatment option for patients with metastatic UC.

[Urethral reconstructive surgery]. / Die plastische Rekonstruktion der Harnröhre.

There is no technique which can be used in all types and localizations of urethral strictures. Urethral strictures occur in the majority of cases in the bulbar urethra. The success rate of urethroplasty is above 80% and results are much better compared to DVIU. Dorsal onlay shows a significantly better success rate than ventral onlay. If the graft bed has poor vascularization a flap should be used or a staged approach should be considered.

[Autotransplantation--a forgotten option?]. / Autotransplantation - eine vergessene Option?

Renal autotransplantation should be considered as an individual treatment in a number of renal or ureteral pathologies, such as ureteral strictures or transitional cell carcinomas of the upper urinary tract. Pyelovesicostomy offers the possibility of a complete ureteral resection and provides the opportunity for a follow-up cystopyeloscopy. In cases of careful patient selection and experience in vascular surgery autotransplantation should not become a forgotten option.

[Complete resection of urothelial cancer metastases with curative intent]. / 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.

Kidney's nightshift, kidney's nightmare? Comparison of daylight and nighttime kidney transplantation: impact on complications and graft survival.

BACKGROUND: Organ distribution and internal procedures often delay kidney transplantation into nighttime. Consequently, surgeons start the operation at a time different from normal working hours, and nighttime work is accompanied by higher incidence of complications. Surgical complications in kidney transplantation often require reoperation, and graft survival can be affected. The aim of our study was to evaluate the impact of the time starting transplantation had on complications and graft survival. METHODS: Between 1994 and 2004, a total of 260 patients underwent kidney transplantation. Of these, 166 of 260 (64%) operations were initiated between 8 a.m. and 8 p.m. (day-kidney) and 94 of 260 operations (36%) between 8 p.m. and 8 a.m. (night-kidney). Mean follow-up was 43 months (range, 0-121 months). RESULTS: Overall graft failure rate was 8.1% 12 months and 12.7% 60 months after engraftment, respectively. Nighttime operation was associated with a higher risk of graft failure. Twenty-four of 260 patients (9.1%) underwent reoperation within 30 days after transplantation. Reoperation rates (night-kidney: 16 of 94 patients [16.8%], day-kidney: 8 of 166 patients [6.4%]) differed significantly between both groups. Reoperation was associated with risk of graft failure (P < .05, Cox proportional hazard). CONCLUSIONS: Nighttime surgery enhances the risk for complications and graft failure. Delaying kidney transplantation of a night-kidney to the following day may be worthwhile, even risking prolonged cold ischemia time.

[The role of superselective transcatheter arterial embolisation in management of complications after kidney surgery]. / Radiologisch-interventionelle superselektive Embolisation - universeller Einsatz bei verschiedensten Blutungskomplikationen nach renaler Chirurgie.

PURPOSE: Transcatheter arterial embolisation (TAE) is replacing open procedures in terms of vascular malformations or traumatic haemorrhage. Furthermore, the role of TAE is established in post-surgery bleeding complications. We report on a number of patients with severe haemorrhage after kidney surgery and successful management by TAE. MATERIALS AND METHODS: Gross renal haemorrhage was observed after pyelocalicolithotomy and open kidney-sparing surgery. One patient developed a large arteriovenous fistula after kidney transplantation preceded by open biopsy. Technique of TAE: In all cases the bleeding vessel was located by transfemoral arteriography. Embolisation was performed by dropping platinum coils or gelfoam pellets. RESULTS: TAE stopped the haemorrhage in all patients and occluded the arteriovenous fistula in the renal allograft. No complications were observed. CONCLUSION: TAE can be considered as the treatment of choice for a widespread range of complications after kidney surgery. It should always be taken into consideration before open surgical revision.

Reducing recurrence and costs in superficial bladder cancer: preclinical evaluation of osmotic cytolysis by distilled water vs. mitomycin.

Transurethral resection followed by instillation of chemotherapeutic agents such as mitomycin is considered as standard therapy in recurrent superficial bladder cancer. However, incidence of bladder cancer is increasing, and contrariwise resources to finance the health care systems are decreasing. Therefore, effective alternatives to expensive chemotherapeutics are necessary. Recurrence of bladder cancer after transurethral resection is mostly promoted by reimplantation of dissolved tumour cells which are therapeutical purpose of any intravesically instillated agent. Monolayer cultures of human RT112, RT4, T24 and TCC SUP bladder cancer cells were incubated and exposed to mitomycin or distilled water. Cell survival was determined by microculture tetrazolium assay. Distilled water led to significant cytolysis in all tumour cells. This effect was comparable to exposition to mitomycin. Distilled water and mitomycin have comparable in vitro effects in bladder cancer cells. These findings have to be substantiated by an animal model emphasising the aspect of larger tumour cell compounds or possible damage to healthy bladder tissue.

Sudden death due to giant cell coronary arteritis.

An 89-year-old woman was found dead lying in her bed. Autopsy demonstrated a pronounced thickening of all coronary arteries except for the first 2-4 cm. Death was due to a recent myocardial infarction. Microscopically, the coronary arteries showed a substantial concentric thickening of all three layers with 90% narrowing. There was a dense transmural inflammatory infiltration with lymphocytes, macrophages, and numerous multinucleated giant cells. The CD68 positive giant cells were mostly located at the media-intima border in the vicinity of fragmented fibers of the lamina elastica interna. The aorta and its major branches including the carotid arteries, however, were free of inflammation and thickening. The findings were characteristic for giant cell arteritis, the equivalent of temporal Horton arteritis, but isolated involvement of the coronary arteries is exceptional.

Randomised phase II trial of gemcitabine and paclitaxel second-line chemotherapy in patients with transitional cell carcinoma (AUO Trial AB 20/99).

The objectives are to evaluate and compare the response and toxicity of a 3-weekly and a 2-weekly regimen of gemcitabine (Gem) and paclitaxel (Pac) second-line treatment in patients with transitional cell carcinoma (TCC). Between June 2000 and July 2001, 30 patients with progressive disease (PD) during first-line chemotherapy (n = 11) or relapse after adjuvant cisplatin-based chemotherapy of a metastatic or locally advanced TCC (n = 18) have been randomised to receive either six cycles (schedule A) of 3-weekly Gem (1000 mg/qm, days 1 and 8) and Pac (175 mg/qm, day 1) or 2-weekly treatment until disease progression (schedule B) with Gem (1250 mg/qm, day 1) and Pac (120 mg/qm, day 2). Restaging was performed after every 6 weeks by clinical imaging. Of 30 patients, one patient in schedule A and two patients in schedule B were not evaluable for response due to serious adverse events (SAEs) during the first cycle. The overall objective response (OR) was 44% (12 of 27) with eight complete remissions (CRs) and four partial remissions. Median time to progression (TTP) was 11 (3-41) months in schedule A and 6 (1-15+) months in schedule B. Median survival was 13 (5-46) months in schedule A and 9 (0-16) months in schedule B. Schedule A showed a significantly higher rate of CRs (7 vs. 1, p < 0.05). With a median number of six (1-6) cycles (A) and nine (1-23) cycles (B), TTP and survival were not significantly different. In schedule B, one patient had WHO grade IV anaemia and leucopenia. WHO grade III toxicities were seen in schedule A/B as follows: anaemia 3 (23%)/2 (16%) patients, leucopenia 5 (38%)/2 (16%), thrombocytopenia 0/2 (16%) and alopecia 10 (76%)/4 (32%). The combination of Gem and Pac is an effective second-line regimen in patients with mainly poor prognosis due to PD after cisplatin-based chemotherapy. Except for three SAEs (uncertainly therapy related), both regimens were tolerated well. The 3-weekly schedule with a nonsplit Pac dose showed a significantly higher complete response rate in our small study population and, thus, might be superior to the 2-weekly schedule.

Fatal hepatic haemorrhage in a child-peliosis hepatis versus maltreatment.

A 2.5-year-old boy with known myotubular myopathy (Spiro-Shy-Gonatas syndrome) and gonadorelin intake 9 months ante-mortem was found dead in his bed at home. At autopsy a ruptured subcapsular haematoma of the liver with resulting haemoperitoneum (600 ml) was found. Both lobes of the liver showed numerous circular blood foci <1 mm-2 cm in diameter. Signs of mechanical trauma such as bruising of the abdominal wall were absent. Histologically, the blood cysts were commonly connected to the sinusoids but did not have an endothelial lining and the reticular fibres showed ruptures. These pathomorphological findings are characteristic for peliosis hepatis and the cause of death was therefore determined to be exsanguination due to hepatic haemorrhage from peliosis hepatis instead of from mechanical trauma. To our knowledge this is the youngest casualty from peliosis reported so far.

Backstabbing--a report of an unusual case.

A case of a 25-year-old male with a deep knife stab injury in the back is reported. The stab wound penetrated the left thorax and the left lung was injured, a thoracotomy was performed and the patient survived. The injured man could not remember what had happened, his bag was missing and the incident was therefore considered to be due to a robbery. Further results of the police investigations and the forensic pathology inspection revealed an extremely unusual accident constellation.

Preclinical evaluation of a radiosensitizing effect of gemcitabine in p53 mutant and p53 wild type bladder cancer cells.

OBJECTIVES: Despite clinical use, the radiosensitizing effect of gemcitabine (2'2'-difluorodeoxycytidine) in human transitional cell carcinoma (TCC) has not been shown to date. We investigated gemcitabine as a radiosensitizer for human TCC cells. METHODS: Monolayer cultures of RT112 (G1, p53 wild type), RT4 (G1-G2, p53 wild type), T24 (G3, p53, mutant type), and SUP (G4, p53 mutant type) cells were incubated in medium with gemcitabine. Electron beam radiation was applied alone, simultaneous, or 3, 6, 12, and 24 hours after gemcitabine. Jurkat leukemia cells were used as controls for radiation toxicity. Cell survival was determined 6, 12, 24, 48, and 72 hours after radiation by microculture tetrazolium assay. DNA damage was evaluated by flow cytometric assessment of poly(ADP-ribose) polymerase, and apoptosis was determined by terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labeling and flow cytometric assessment after annexin-V and propidium iodide labeling. RESULTS: In all TCC cell lines, radiation alone caused only little and insignificant growth inhibitory effects at 10 Gy. Gemcitabine alone had a dose-dependent cytotoxic and apoptosis inducing effect on all TCC cell lines independent of p53 status. Assays combining radiation with gemcitabine in different dose and time schedules demonstrated no radiosensitizing effect in TCC cells. CONCLUSIONS: Gemcitabine is effective in TCC cell lines independent of p53 status. A radiosensitizing effect could not be demonstrated. Again, p53 status was not predictive of the radioresponse in the bladder cancer cell lines. Clinical studies with gemcitabine and radiotherapy might nevertheless yield different results but should be performed with utmost caution.

Mycotic cerebral vasculitis in a paediatric cardiac transplant patient excludes misadventure.

We present the case of a 10-year-old girl with cardiomyopathy who received a heart transplant. Due to organ rejection, the dosage of immunosuppressive agents was increased postoperatively. The patient complained of intermittent headaches in the following days and developed a haemorrhagic necrosis of the left thalamus. A week later, an oral dose of cyclosporin A was accidentally given intravenously, and 2 weeks later a recurrent subarachnoid haemorrhage of unknown origin was diagnosed. The clinical course was then characterised by progressive deterioration resulting in coma, fluctuating brain stem symptoms and the development of a massive cerebral oedema with subsequent brain death. A coroner's autopsy was instigated to investigate a claim of medical misadventure. Neuropathological investigations found a focal infiltration of fungal hyphae in the left posterior cerebral artery resulting in necrosis of the vascular wall and thus explaining the source of the recurrent subarachnoid haemorrhage which eventually resulted in the girl's death. Medical misadventure due to the administration of cyclosporin was not directly responsible for the death of this patient. This case illustrates that it is of paramount importance to copiously sample and investigate the basal cerebral arteries in cases of subarachnoid haemorrhage of unknown origin, in particular in a medico-legal context.

Effect of ethanol on dynamic visual acuity during vertical body oscillation in healthy volunteers.

Visual orientation is the most important sensory input during locomotion (e.g. walking, driving a car, riding a bicycle). We investigated dynamic visual acuity (DVA) during vertical body-oscillations (amplitude 5 cm; frequency 1.5 Hz) in 12 healthy subjects before and twice after ethanol consumption. During oscillation, vertical eye movements were recorded under two test conditions: with eyes closed (EC) and during DVA testing. A significant increase in vertical eye-amplitude after ethanol ingestion occurred only during EC tests, as a possible sign of vestibular hyperreaction. During vestibular stimulation alone (EC), ethanol did not affect the phase shift between stimulus and eye movements. However, when the subjects were given an additional visual stimulus (DVA), the post-alcohol phase shift rose significantly. Surprisingly, the post-alcohol phase shift values for the two test conditions showed no significant differences. After ethanol ingestion we found no changes in static visual acuity but a significant loss of DVA. Volunteers with a change of DVA threshold (DVAT) showed significantly (P = 0.004) higher post-alcoholic changes in the phase shift. In summary, low doses of ethanol disturbed the visually guided oculomotor response during fixation of an earth-fixed target while the observer was subject to linear vertical acceleration. This effect led to an increasing delay between the beginning of body and eye movements. The consequence was an increasing phase shift and thus a decrease in DVA during whole-body oscillation which was comparable to movements during human locomotion.

Reduction of DNA synthesis, pigment synthesis, pigmentation gene mRNA and resistance to UVB in human melanoma cells treated with analogues of a histamine (H2) agonist.

Two groups of S-[2-(N,N-dialkylamino)ethyl]isothiourea derivates which depigmented melanoma cells either with inhibition of tyrosinase (group 1, R = methyl, isopropyl) or without inhibition of tyrosinase (group 2, R = benzyl, phenyl) were studied. Treatment of human melanoma cells with non-lethal doses of group 1 drugs led to a reduction in the levels of mRNA for the pigmentation genes tyrosinase, tyrosinase-related protein-1 and Pmel 17. The group 1 drug S-[2-N,N-diisopropylamino)ethyl[isothiourea] (DINOR) (R = isopropyl) produced only moderate inhibition of DNA, RNA and protein synthesis in three cell lines during the first 24 hr of treatment, and there was no correlation between the extent of inhibition and long-term toxicity. A group 2 drug (R = benzyl) rapidly inhibited DNA synthesis in an amelanotic melanoma cell line (MM96E) sensitive to killing by the drug; association of the latter with inhibition of RNA or protein synthesis was less clear. MM96E cells were also sensitive to killing by reactive oxygen species. In pigmented melanoma cells (MM418), incorporation of [125I]thiouracil, a false precursor of melanin, increased during the first 24 hr of treatment with DINOR whereas a group 2 drug (R = phenyl) inhibited incorporation of [125I]thiouracil. Cells depigmented by treatment with drugs from either group suffered the same amount of DNA damage as pigmented cells after UVB irradiation, as judged by inhibition of DNA synthesis, but did not recover as well as pigmented cells, whether or not drug was present during recovery. The results suggested that (1) group 1 agents down-regulated message for several pigmentation genes, possibly at the transcriptional level; (2) the toxicity of group 2 drugs was related to reactive oxygen species; and (3) melanin protected cells from UVB by enhancing cellular recovery.

Dimaprit analogues inhibit tyrosinase via a disulphide breakdown product independently of the histamine H2 receptor.

Histamine displayed specific and saturable binding to membrane fractions of the human melanoma cell line MM96E (Kd = 72.4 nM and Bmax = 487 fmol/mg protein). There was weak competition with isothioureas that inhibit tyrosinase in intact cells: dimaprit (an H2 agonist) nordimaprit and S-[2-(N,N-diisopropyl)ethyl]isothiourea (DINOR). Under culture conditions, rapid, pH-dependent hydrolysis of the isothioureas occurred, with cleavage to urea and a thiol which spontaneously oxidised to the disulphide. The H3 agonist imetit, which also inhibited tyrosinase, behaved similarly. The disulphide breakdown product of DINOR but not the thiol inhibited tyrosinase activity in intact MM96E cells to a similar extent as DINOR itself. Isothioureas with more bulky substituents, however, were stable in culture and did not inhibit tyrosinase. The results show that (a) certain histaminergic drugs exert effects via a disulphide hydrolysis product independently of the histamine H2 receptor, and (b) beta-aminoethyldisulphides are depigmenting agents.

Inhibition of melanogenesis in human melanoma cells by novel analogues of the partial histamine (H2) agonist nordimaprit.

A series of analogues of the weak histamine (H2) agonist S-[2-(N,N-dimethylamine)ethyl] isothiourea (nordimaprit) was produced to investigate the possibility that bulky substituents on the tertiary amine of nordimaprit would enhance potency for depigmentation and killing of melanoma cells. Cell survival studies showed that neither an increase in lipophilicity nor an increase in size of these groups produced selective toxicity, with only the N,N-diisobutyl derivative being more effective than the N,N-diisopropyl derivative in killing the constitutively pigmented human melanoma cell line MM418. The most hydrophobic analogue, the N,N-dibenzyl derivative, was also the most toxic to all cell lines tested. The association of toxicity with lipophilicity was confirmed by the piperidine derivative having greater toxicity than the less hydrophobic morpholine analogue. The ability to decrease tyrosinase activity was lost when lipophilicity and size of the N-terminal groups were increased, but these analogues produced marked depigmentation, even greater than that found with either nordimaprit or the diisopropyl derivative. Surprisingly, an increase in tyrosinase activity was achieved, the most potent agent being the N-ethyl-N-anilino analogue which caused complete depigmentation (0.6% of control) and elevated tyrosinase activity (148%) in MM418 cells after 1 month of treatment. This indicates that nordimaprit and its derivatives possess two different mechanisms of depigmentation, the first being tyrosinase dependent and the second being tyrosinase independent. The latter pathway is yet to be elucidated but appears to require a high degree of hydrophobicity.