Modulation of adhesion and growth of colon and pancreatic cancer cells by the histone deacetylase inhibitor valproic acid.

Histone deacetylase (HDAC) inhibitors belong to a promising class of antineoplastic agents which affect tumor growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro on preclinical colon and pancreatic cancer models. Human colon adenocarcinoma HT-29 and pancreatic carcinoma DanG cells were treated with 1 mM VPA for different time periods during cell proliferation MTT assays, and to evaluate the tumor cell adhesion to endothelial cell monolayers. Alterations of beta1 integrin subunits alpha1-6) were analyzed by flow cytometry and RT-PCR. VPA significantly caused growth arrest in tumor cells and prevented tumor cell attachment to the endothelium. HT-29 cell adhesion was blocked to a higher extent than the adhesion of DanG cells. VPA modified membranous integrin beta1 expression, quantity and quality (up- or down-regulation) which depended on the tumor type investigated. Furthermore, VPA diminished integrin coding mRNA in HT-29 but not in DanG cells. We conclude that VPA shifts the integrin beta1 subunit balance from a 'pathological' towards a 'physiological' expression pattern leading to reduced tumor growth and invasion. Further study is required to elucidate the molecular background of the post-transcriptional modifications of VPA in order to exploit the potential of this agent in the treatment of colon and pancreatic cancer.

Effect of procurement-related organ lesions on renal transplant outcome.

BACKGROUND: The purpose of our study was to examine the nature and incidence of renal injuries during organ procurement, to identify risk factors and to analyse the effects of organ lesions on the following transplantation. METHODS: All cadaveric kidney transplantations performed at our centre from 1996 to 2006 with an organ donated within the Eurotransplant (ET) region were retrospectively analysed. RESULTS: Five hundred and sixty-three renal grafts procured in 62 centres throughout the ET region were transplanted in the analysed period. One hundred and twenty (21.3%) kidneys were inadequately procured with 143 errors in total. The frequency of procurement errors did not differ significantly between kidneys procured by urologists and general surgeons (19.2% vs. 24.6%) nor when kidneys were procured alone or together with pancreas and/or liver (19.3% vs. 22.0%). Inadequate procurement lead to a discard rate of 0.2% and ultimately resulted in a surgical complication rate of 3.4%. Primary graft function (75.8% vs. 78.6%), three-yr graft survival (76.6% vs. 82.4%) and cumulated long-term graft survival were not significantly influenced by procurement errors. CONCLUSION: Additional measures to improve procurement quality are necessary. Nevertheless, adequate repair of organ lesions is possible and most organs can be successfully transplanted with very good short- and long-term results.

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.

[Quality of kidney procurement in Germany. Ten years experience and 486 renal allografts in a single centre]. / Qualität der Leichennierenentnahme in Deutschland. 10-Jahres-Erfahrungen mit 486 transplantierten Leichennieren an einem Zentrum.

BACKGROUND: Organ damage during organ procurement is believed to be an increasing problem among transplant centres. However, only very few published data are available. The purpose of our study was to examine the quality of kidney procurement in Germany. METHODS: We retrospectively analyzed all allograft renal transplants performed at our centre from 1996 to 2005. All kidneys were retrieved in Germany and allocated by Eurotransplant. RESULTS: From a total of 486 cadaveric kidneys, 103 (21.2%) were not correctly retrieved. Nevertheless, none of the organs had to be rejected. In 18 (3.7%), a technically insufficient organ retrieval was associated with a considerable extension of the surgical procedure or complications. CONCLUSIONS: Technically insufficient kidney procurement rarely results in clinical consequences. However, surgeons performing organ retrieval should be better trained. Whether adequate technical proficiency is achieved with ten supervised cases, as requested by the German Medical Association, remains to be determined. In our opinion, a further interdisciplinary course that trains surgeons in more refined techniques of organ procurement is desirable.

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, approximately 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.

Angiogenesis inhibition by angiostatin, endostatin and TNP-470 prevents cyclophosphamide induced cystitis.

Angiogenesis, the induction of vessel growth is involved in numerous physiological and pathological processes. While the anti-tumor effect of angiogenesis inhibitors has been extensively investigated in malignant tumors, there is very little information on the effect of angiogenesis inhibitors on inflammation induced angiogenesis. In this report, we utilized a murine model of acute chemically induced cystitis to investigate the ability of three different angiogenesis inhibitors, angiostatin, endostatin and TNP-470, to inhibit the angiogenesis stimulated by this injury. We demonstrate herein, that prophylactic application of the angiogenesis inhibitors led to a significant reduction of each of the inflammatory parameters that were measured. We conclude that anti-angiogenic therapy with angiostatin, endostatin and TNP-470 inhibits inflammation associated angiogenesis induced in this model. We also propose that anti-angiogenic agents may serve as a valuable addition to a standard cyclophosphamid chemotherapy regimen to help reduce the chemotherapy-related side effects while potentially adding an anti-tumor effect.

Da Vinci robot assisted Anderson-Hynes dismembered pyeloplasty: technique and 1 year follow-up.

In experienced hands, laparoscopic pyeloplasty is an effective alternative treatment for symptomatic ureteropelvic junction obstruction (UPJO). Although laparoscopic surgery can clearly benefit patients, laparoscopic pyeloplasty using conventional instrumentation is complex. The purpose of this report is to evaluate the feasibility of robot assisted laparoscopic surgery. Eleven pyeloplasties for UPJO were performed via a laparoscopic transperitoneal approach exclusively with the da Vinci Surgical System. The mean procedure time was 197 min (range 110-310 min). All operations were completed laparoscopically with no intraoperative complications and negligible blood loss. All patients recovered rapidly after surgery with excellent functional results at the 1 year follow-up. Our initial experience suggests that robot assisted Anderson-Hynes pyeloplasty is a safe and effective alternative to conventional laparoscopic surgery. In our opinion, robot assisted surgery will allow urologists to perform complex procedures with greater precision, confidence, and better results, as well as enable them to adapt the whole spectrum of laparoscopic procedures to their field.

Robotic technology and the translation of open radical prostatectomy to laparoscopy: the early Frankfurt experience with robotic radical prostatectomy and one year follow-up.

OBJECTIVE: Laparoscopic radical prostatectomy is a complex procedure and has been standardized only during the last years. The remote controlled da Vinci Surgical System has opened up a new era in minimally invasive surgery. We here present our initial experience with the translation of open retropubic radical prostatectomy to laparoscopic technique using da Vinci and a one year follow-up. METHODS: After a period of technical development and training on cadavers, 40 consecutive patients eligible for radical prostatectomy were treated. After port placement, the urologist took control of the 3D 30 degrees laparoscope and the two instrument arms at the da Vinci remote console to perform bilateral pelvic lymph node dissection, radical prostatovesiculectomy and urethrovesical anastomosis. RESULTS: The procedure was completed laparoscopically in all but two patients. Mean procedure time was 8.3 hours and mean intra-operative blood loss 570 ml. Learning curves associated with the use of the da Vinci Surgical System show that there is a 22-minute decrease in time required to perform the radical prostatectomy and lymphadenectomy for each case (p<0.0001). Patients recovered rapidly after surgery with early oncological and functional results that were similar to those obtained with our standard radical prostatectomy technique. CONCLUSIONS: Remote controlled robotic surgical systems are useful to translate open retropubic radical prostatectomy to laparoscopy. This new technology has the potential to equip the urologist with the microsurgical precision needed to preserve the delicate structural integrity of the pelvic floor in order to improve functional results without compromising the oncological outcome.

Serum levels of basic fibroblast growth factor reflect disseminated disease in patients with testicular germ cell tumors.

The potential role of angiogenesis stimulators in the pathogenesis of different tumor entities has been confirmed in several studies. We measured the serum levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in 51 patients with testicular germ cell tumors and in 39 healthy volunteers. Serum concentrations of bFGF, VEGF and PDGF-AB were determined by enzyme-linked immunosorbent assay. The median serum bFGF level for tumor patients was 3.46 pg/ml (range 0-61.6) compared to 0.7 pg/ml (0-11) in the control group (P<0.01). In patients with metastatic disease, the median serum bFGF level was 10.3 pg/ml (0-61.6) in contrast to 2.8 pg/ml (0-50) in patients with localized disease (P<0.01). The median serum VEGF and PDGF levels were 270 pg/ml (0-1,903) and 37,837 pg/ml (9,075-108,800), respectively, for tumor patients and 200 pg/ml (44-585) and 23,000 pg/ml (4,250-70,650) in the control group ( P<0.05). Our data suggest that angiogenesis, as reflected by serum concentrations of bFGF, VEGF and PDGF, plays a functional role in the growth and progression of testicular germ cell tumors.

Serum angiogenic activity: diagnostic relevance in renal cell carcinoma.

OBJECTIVE: Angiogenesis is essential for tumor growth and progression. However, reported data on angiogenic parameters in patients with renal cell carcinoma are contradictory. The objective of this study was to use serum to compare the systemic angiogenic activity in patients with renal cell carcinoma and to determine if pathologic stage and grade correlated to this angiogenesis parameter. METHODS: Serum of 28 patients with a newly diagnosed renal cell carcinoma, 28 healthy volunteers and 9 patients with bladder carcinoma were used for this study. All sera were tested in a 72-hour endothelial cell proliferation assay. In addition the serum concentrations of the angiogenesis stimulators basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) were determined using standard ELISA assays. RESULTS: The serum of renal cell carcinoma patients showed a median stimulation of human umbilical vein endothelial cells (HUVEC) of 89.79% (range 58.47-147.95%) and serum of healthy volunteers showed a median stimulation of 95.35% (range 74.64-141.77%) (p > 0.05). In contrast serum of patients with bladder carcinoma showed a median stimulation of 140.16% (range 64.82-200.16%) (p = 0.024). No correlations of the serum angiogenic activity and tumor stage or grade have been found in renal cell carcinoma patients. Furthermore, no correlations for serum bFGF and VEGF concentrations have been found. CONCLUSIONS: Serum angiogenic activity of patients with renal cell carcinoma did not differ significantly from healthy controls, while serum of patients with bladder carcinoma showed a significant increase in endothelial cell stimulation. Furthermore, bFGF and VEGF serum concentrations did not correlate to serum angiogenic activity in patients with renal cell carcinoma. Therefore, the determination of systemic angiogenic parameters, in case of renal cell carcinoma, might not lead to adequate data concerning prognosis or therapeutic effects.

Laparoscopic transperitoneal adrenalectomy using a remote-controlled robotic surgical system.

BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy is considered the standard method for removal of benign adrenal tumors. Although laparoscopic surgery provides clear patient benefit, laparoscopic adrenalectomy using conventional instrumentation is complex. Our objective was to evaluate whether the da Vinci trade mark Surgical System, a comprehensive robotic endoscopic surgical device, could be used effectively to perform laparoscopic adrenalectomy. PATIENTS AND METHODS: Through a transperitoneal approach, three right and one left adrenal tumors were removed in four patients using this method. RESULTS: There were no complications, and the clinical results were excellent. CONCLUSION: We demonstrate the feasibility of performing laparoscopic adrenalectomy exclusively by using robotic telepresent technology from a remote workstation. The da Vinci System enables conventionally trained urologic surgeons to perform complex minimally invasive procedures with ease and precision. Therefore, we are convinced that the system helps the urologist to adapt the whole spectrum of laparoscopic procedure in this field.

Reduced plasma levels of coagulation factors in relation to prostate cancer.

BACKGROUND: Prostate cancer has historically been associated with coagulation abnormalities. This study was undertaken to investigate the prevalence of abnormalities of coagulation factors in patients with prostate cancer before and after radical prostatectomy (RP). Because coagulation factors have been shown to be involved in tumor angiogenesis, the vascular density of the prostate tumors was assessed. METHODS: Plasma of 40 consecutive patients with histologically proven prostate cancer was investigated pre-RP and post-RP. The antigen level for antithrombin, plasminogen activator inhibitor-1, and heparin cofactor-II, and the plasma activity of antithrombin and plasminogen were determined by using immunologic and chromogenic assays. The values of these assays were compared with a group of 28 male, age-matched patients without any evidence of cancer and 18 patients with orthopedic interventions preoperatively and postoperatively. The vascular density of the prostate tumors was assessed by staining paraffin sections with an antibody to CD34. RESULTS: The median plasma antigen levels and/or activities of the investigated factors were below normal in the prostate cancer patients before RP. Furthermore, coagulation factors were significantly lower than in the age-matched control group and patients before and after orthopedic surgery. In prostate cancer patients, the median values of all investigated factors went up to normal levels within 2 weeks after RP, whereas postsurgical levels in orthopedic patients remained stable. No correlations to tumor parameters have been observed. CONCLUSION: We assume that the reduction of these coagulation factors is a principle concept in prostate cancer that needs further investigation.