Dietger Jonas

Robotic-assisted laparoscopic radical cystectomy and intra-abdominal formation of an orthotopic ileal neobladder.

PURPOSE To describe our technique of robotic-assisted laparoscopic radical cystectomy and intra-abdominal formation of an orthotopic neobladder (Hautmann) for treatment of transitional cell carcinoma of the bladder. METHODS We describe our surgical technique in the worldwide first attempt to perform a robotic-assisted laparoscopic radical cystectomy and completely intra-abdominal formation of an orthotopic neobladder. The DaVinci System (Intuitive Surgical, Mountain View, CA, USA) was utilized to perform the procedure. RESULTS Utilizing the DaVinci System the operation could be performed without any complications. Operating time was 8.5 hours, blood loss was 200 ml. The oncologic as well as the functional result of the reservoir were excellent. DISCUSSION We here demonstrated that sophisticated laparoscopic procedures like the intra-abdominal formation of an orthotopic neobladder are accomplishable with robotic assistance.

Robotic surgery in urology: fact or fantasy?

Advanced robotic surgery was first introduced into urology in 2000. The first studies showed the feasibility and safety of the daVinci (Intuitive Surgical Inc., Sunnyvale, CA) telemanipulator assistance in radical prostatectomy, pelvi‐ureteric junction obstruction, and radical cystectomy and neobladder formation. The miniature endowristed tools offer a potential advantage over standard laparoscopy in the accuracy of preparation and suturing. Other features are a three‐dimensional vision system and unimpaired hand‐eye coordination. Complex laparoscopic tasks are learned faster by using the robot, which may also explain the shorter training required for radical prostatectomy than for manual laparoscopy. This new and expensive technology has spread rapidly over the last 4 years. By 2004, ≈ 10% of radical prostatectomies in the USA will be robot‐assisted. Data on the functional and oncological outcomes are accruing but not yet conclusive. There will be a further spread of robotic surgery, routine telesurgery, smaller and more affordable systems, the introduction of virtual reality, all developments which have the potential to urological surgeons to improve.

Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy

BackgroundTumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment.MethodsTumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 μM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry.ResultsAdhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 μM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMFs effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes.ConclusionWe conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.

New molecular mediators in tumor angiogenesis

Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition.

Adrenal myelolipoma: Clinical, radiologic, and histologic features

The adrenal myelolipoma is a benign, endocrinologically inactive tumor whose histologic structure consists of mature adipose tissue with foci of hematopoietic cells. A case is presented of a seventy-one-year-old woman in whom the diagnosis was established preoperatively by means of sonography, computerized tomography, and magnetic resonance tomography. In a review of the literature, the radiologic profile is discussed, and based on the analysis of 59 surgically treated cases a therapy recommendation is given.

Renal transplantation in the elderly: surgical complications and outcome with special emphasis on the Eurotransplant Senior Programme

BACKGROUND The purpose of this retrospective study was to evaluate the results of the Eurotransplant Senior Programme (ESP) within our centre compared to elderly recipients >or=60 years from the regular Eurotransplant Kidney Allocation System (ETKAS), specifically focusing on surgical aspects. METHODS Data from 73 ESP patients (average donor/recipient age: 71.1/67.1) were compared with those from 51 patients (49.7/63.6) treated within the framework of the ETKAS program between the years 1999 and 2006. The mean follow-up was 39.5 months. RESULTS Cold ischaemic time (ESP versus ETKAS: 10.3 versus 15.0 h), duration of renal replacement therapy (42.2 versus 76.8 months), donor glomerular filtration rate (81.7 versus 109.9 ml/min/1.73 m(2)) and HLA mismatches (4.1 versus 2.4) were significantly different between the two groups (all P < 0.001). Primary graft function was seen in 74% ESP versus 69% of ETKAS patients (P > 0.05). The rate of surgical complications in the ESP versus ETKAS group was 47% versus 28% (P = 0.031) and the revision rate, 33% versus 24% (P = 0.259). Three-year patient and censored graft survival was 84% versus 92% and 85% versus 88% in the ESP and ETKAS group, respectively (all P > 0.05). Ninety-five percent of all deceased patients died with a functioning graft. CONCLUSIONS The donor and recipient pool has been markedly expanded through ESP with similar patient and graft survival compared to elderly recipients grafted according to ETKAS criteria. However, patients and their physicians should be aware of the high surgical complication rate in elderly recipients, particularly when receiving elderly donor kidneys. This might seriously influence postoperative patient management but ultimately does not compromise the transplant outcome.

The histone deacetylase inhibitor valproic acid alters growth properties of renal cell carcinoma in vitro and in vivo

Histone deacetylase (HDAC) inhibitors represent a promising class of antineoplastic agents which affect tumour growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro and in vivo on pre‐clinical renal cell carcinoma (RCC) models. Caki‐1, KTC‐26 or A498 cells were treated with various concentrations of VPA during in vitro cell proliferation 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays and to evaluate cell cycle manipulation. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. The anti‐tumoural potential of VPA combined with low‐dosed interferon‐α (IFN‐α) was also investigated. VPA significantly and dose‐dependently up‐regulated histones H3 and H4 acetylation and caused growth arrest in RCC cells. VPA altered cell cycle regulating proteins, in particular CDK2, cyclin B, cyclin D3, p21 and Rb. In vivo, VPA significantly inhibited the growth of Caki‐1 in subcutaneous xenografts, accompanied by a strong accumulation of p21 and bax in tissue specimens of VPA‐treated animals. VPA–IFN‐α combination markedly enhanced the effects of VPA monotherapy on RCC proliferation in vitro, but did not further enhance the anti‐tumoural potential of VPA in vivo. VPA was found to have profound effects on RCC cell growth, lending support to the initiation of clinical testing of VPA for treating advanced RCC.

De novo renal cell carcinoma of native and graft kidneys in renal transplant recipients

Study Type – Therapy (case series)

Chemoresistance induces enhanced adhesion and transendothelial penetration of neuroblastoma cells by down-regulating NCAM surface expression.

BackgroundDrug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). One explanation for the link between resistance and malignancy might be that resistance facilitates cancer progression and invasion. To investigate this hypothesis, adhesion, transendothelial penetration and NCAM (CD56) adhesion receptor expression of drug-resistant versus drug-sensitive NB tumor cells were evaluated.MethodsAcquired drug resistance was mimicked by exposing parental UKF-NB-2, UKF-NB-3 or IMR-32 tumor cells to increasing concentrations of vincristine- (VCR) or doxorubicin (DOX) to establish the resistant tumor cell sublines UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-3VCR, UKF-NB-3DOX, IMR-32VCR and IMR-32DOX. Additionally, the malignant behaviour of UKF-NB-4, which already possessed the intrinsic multidrug resistance (MDR) phenotype, was analyzed. UKF-NB-4 exposed to VCR or DOX were designated UKF-NB-4VCR or UKF-NB-4DOX. Combined phase contrast – reflection interference contrast microscopy was used to separately evaluate NB cell adhesion and penetration. NCAM was analyzed by flow cytometry, western blot and RT-PCR.ResultsVCR and DOX resistant tumor sublines showed enhanced adhesion and penetration capacity, compared to their drug naïve controls. Strongest effects were seen with UKF-NB-2VCR, UKF-NB-3VCR and IMR-32DOX. DOX or VCR treatment also evoked increased invasive behaviour of UKF-NB-4. The process of accelerated tumor invasion was accompanied by decreased NCAM surface and protein expression, and down-regulation of NCAM coding mRNA. Transfection of UKF-NB-4VCR cells with NCAM cDNA led to a significant receptor up-regulation, paralleled by diminished adhesion to an endothelial cell monolayer.ConclusionIt is concluded that NB cells resistant to anticancer drugs acquire increased invasive capacity relative to non-resistant parental cells, and that enhanced invasion is caused by strong down-regulation of NCAM adhesion receptors.

New histone deacetylase inhibitors as potential therapeutic tools for advanced prostate carcinoma

The anti‐epileptic drug valproic acid is also under trial as an anti‐cancer agent due to its histone deacetylase (HDAC) inhibitory properties. However, the effects of valproic acid (VPA) are limited and concentrations required for exerting anti‐neoplastic effects in vitro may not be reached in tumour patients. In this study, we tested in vitro and in vivo effects of two VPA‐derivatives (ACS2, ACS33) on pre‐clinical prostate cancer models. PC3 and DU‐145 prostate tumour cell lines were treated with various concentrations of ACS2 or ACS33 to perform in vitro cell proliferation 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays and to evaluate tumour cell adhesion to endothelial cell monolayers. Analysis of acetylated histones H3 and H4 protein expression was performed by western blotting. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. Tumour sections were assessed by immunohistochemistry for histone H3 acetylation and proliferation. ACS2 and ACS33 significantly up‐regulated histone H3 and H4 acetylation in prostate cancer cell lines. In micromolar concentrations both compounds exerted growth arrest in PC3 and DU‐145 cells and prevented tumour cell attachment to endothelium. In vivo, ACS33 inhibited the growth of PC3 in subcutaneous xenografts. Immunohistochemistry and western blotting confirmed increased histone H3 acetylation and reduced proliferation. ACS2 and ACS33 represent novel VPA derivatives with superior anti‐tumoural activities, compared to the mother compound. This investigation lends support to the clinical testing of ACS2 or ACS33 for the treatment of prostate cancer.