Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long‐term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long‐term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow‐up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post‐transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus‐based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus‐based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.     

Biobanking for research in surgery: are surgeons in charge for advancing translational research or mere assistants in biomaterial and data preservation?

Background

High-quality biospecimens of human origin with annotated clinical and procedural data are an important tool for biomedical research, not only to map physiology, pathophysiology and aetiology but also to go beyond in translational research. This has opened a new special field of research known as ‘biobanking’, which focuses on how to collect, store and provide these specimens and data, and which is substantially supported by national and European funding.

Purpose

An overview on biobanking is given, with a closer look on a clinical setting, concerning a necessary distinction from clinical trials and studies as well as a comparison of prospective sample collection with secondary use of archived samples from diagnostics. Based on a summary of possible use and scientific impact of human tissue in research, it is shown how surgical expertise boosts the scientific value of specimens and data. Finally, an assessment of legal and ethical issues especially from a surgical perspective is given, followed by a model of interdisciplinary biobanking within a joint ‘centre’ that as synergistic structure merges essential input from surgery as well as laboratory medicine, pathology and biometry.

Conclusion

Within the domain of biobanking, surgeons have to develop a better awareness of their role within translational research, not only on the level of medical faculties but also as nationally and internationally funded initiatives. Therefore, the authors suggest a platform for biobanking within the German association of surgeons in analogy to the existing special interest group for clinical trials.     

C‐type natriuretic peptide slows down wound healing but promotes angiogenesis in SKH1‐hr hairless mice

C‐type natriuretic peptide (CNP) is known to increase growth rate of endothelial cells in vitro. In addition, gene transfer of CNP into ischaemic muscle was shown to induce angiogenesis. So far, no study has addressed the effect of CNP on dermal wound healing. The ear wound model in mice was used in this study. The first group was treated with dsRed‐CNP plasmid, whereas the second group was transfected with the empty dsRed‐sine plasmid, lacking sequence coding for CNP. The third group was sham operated and treated with saline to serve as second control. Wound size was measured on days 0, 1, 3, 5, 7, 9, 11 and 14. On days 7 and 14 capillary density was analysed. Wound closure rate was significantly reduced in mice treated with CNP [dsRed‐CNP 73·3 ± 3·2% versus dsRed‐sine 94·5 ± 2·4% versus saline 92·1 ± 2·4%, n = 8 per group, analysis of variance (ANOVA) P < 0·001] at day 7 postop. Capillary density was found to be significantly higher in CNP‐treated mice (dsRed‐CNP 18·7 ± 3·9 versus dsRed‐sine 12·3 ± 2·7 versus control 10·1 ± 4·7, CD31⁺ capillaries per microscope field, ANOVA P = 0·018) at day 14 postoperative. CNP significantly reduces wound closure rate in hairless mice but promotes the development of new blood vessels. A possible explanation is the dual effect of CNP, inhibiting growth of fibromyoblasts but stimulating growth of endothelial cells. Thus, CNP may serve as a therapeutic approach to diseases caused by hyperfibrosis.     

PVA gel as a potential adhesion barrier: a safety study in a large animal model of intestinal surgery

Background

Intra-abdominal adhesions following surgery are a major source of morbidity and mortality including abdominal pain and small bowel obstruction. This study evaluated the safety of PVA gel (polyvinyl alcohol and carboxymethylated cellulose gel) on intestinal anastomoses and its potential effectiveness in preventing adhesions in a clinically relevant large animal model.

Methods

Experiments were performed in a pig model with median laparotomy and intestinal anastomosis following small bowel resection. The primary endpoint was the safety of PVA on small intestinal anastomoses. We also measured the incidence of postoperative adhesions in PVA vs. control groups: group A (eight pigs): stapled anastomosis with PVA gel compared to group B (eight pigs), which had no PVA gel; group C (eight pigs): hand-sewn anastomosis with PVA gel compared to group B (eight pigs), which had no anti-adhesive barrier. Animals were sacrificed 14 days after surgery and analyzed.

Results

All anastomoses had a patent lumen without any stenosis. No anastomoses leaked at an intraluminal pressure of 40 cmH₂O. Thus, anastomoses healed very well in both groups, regardless of whether PVA was administered. PVA-treated animals, however, had significantly fewer adhesions in the area of stapled anastomoses. The hand-sewn PVA group also had weaker adhesions and trended towards fewer adhesions to adjacent organs.

Conclusion

These results suggest that PVA gel does not jeopardize the integrity of intestinal anastomoses. However, larger trials are needed to investigate the potential of PVA gel to prevent adhesions in gastrointestinal surgery.     

Differential induction of apoptosis in undifferentiated and differentiated HL-60 cells by DNA topoisomerase I and II inhibitors

The effects of monocytic/macrophage and granulocytic differentiation induced by phorbol myristate acetate (TPA) and all-trans retinoic acid, respectively, were tested on the induction of apoptosis in human promyelocytic leukemia HL-60 cells treated with topoisomerase I and II inhibitors. Using a filter-binding assay, we observed a strong inhibition of DNA fragmentation induced by 3- and 24-hour continuous exposure to camptothecin, VP-16, VM-26, and m-AMSA in TPA- differentiated cells. The inhibition of the typical internucleosomal DNA fragmentation was confirmed by agarose gel electrophoresis. By contrast, drug-induced DNA fragmentation was not inhibited in retinoic acid-differentiated cells, and apoptosis occurred in these cells after 4 to 5 days in the absence of drug treatment. The TPA inhibitory effect was maximal after 24 hours of treatment and was correlated with differentiation, because phorbol dibutyrate ester was active, whereas 4- alpha-TPA, a nontumor promoter that does not induce differentiation, was not active. Using alkaline elution, we observed that TPA and retinoic acid differentiation were associated with changes in topoisomerase-mediated DNA breaks that were not correlated with their differential effects on drug-induced DNA fragmentation. Moreover, TPA also inhibited DNA fragmentation induced by vinblastine, cycloheximide, calphostin C, and x-rays. Using a cell-free system, we observed that DNA fragmentation was not inhibited in nuclei from TPA-differentiated cells. Rather, inhibition of apoptosis seemed to take place in the cytoplasm. We conclude that phenotypic changes associated with TPA- induced differentiation include inactivation of a cytoplasmic activity that can induce DNA fragmentation associated with apoptosis.     

Level of hospital care and outcome of gastric cancer: a population-based evaluation of the Munich Cancer Registry

Background

Gastric cancer accounts for 5 % of cancer deaths. Successful implementation of guideline-recommended treatment procedures should result in population-based outcome improvements despite the still poor prognosis. In this context, the objective of this study was to compare the outcome of gastric cancer by different levels of hospital care.

Materials and methods

Total of 8,601 patients with invasive gastric cancer documented between 1998 and 2012 by the Munich Cancer Registry were evaluated. Tumour and therapy characteristics and outcome were analysed in regard to five levels of hospital care: three levels were defined for general hospitals (level I–III), while university hospitals and speciality hospitals were grouped as separate classes. Survival was investigated using the Kaplan–Meier-method, computing relative survival, and by multivariate Cox proportional hazard regression.

Results

The average age differed between 66 years in university hospitals and 75 years in hospitals providing a basic level of care (level I). No survival differences were found for patients treated in different levels of hospital care in 75 % of the patient cohort, namely the M0 patients. A better survival could only be shown for patients with M1 at diagnosis when treated in a university or level III hospital compared to those treated in other hospitals.

Conclusion

The outcome difference of M1 patients is most likely caused by selection effects concerning health status differences and not by processes of health care attributable to level of hospital care. Thus, this study demonstrates and confirms appropriate treatment and care of gastric cancer over all levels of hospital care.     

Loss of liver transplant surgeons into alternate career paths

In Germany, long‐term commitment of surgeons to transplantation is rare. Most surgeons leave transplant surgery after a short stint and follow careers in other surgical fields. This rapid turnover of liver transplant surgeons may result in poor resource utilization and potentially compromise patient safety. In this report, we have analyzed the caseload and the careers of 25 surgeons in liver transplantation over a period of 22 years. The median time in liver transplantation was short. Of all surgeons who engaged in liver transplantation, the median time was 3.5 years. Surgeons who completed their training remained in the field for 7 years. Surgeons who prematurely stopped their training remained for 2 years. Individual total caseloads of transplant surgeons were relatively low. The median number of procedures was 40 for all surgeons, 153 for currently active surgeons, 51 for surgeons who completed training, 27 for surgeons currently in training, and a median of four liver transplantations for surgeons who prematurely stopped liver transplantation. The vast majority (75%) of surgeons prematurely quit liver transplantation to follow alternate surgical careers. Structural changes in academic transplant surgery have to be made to facilitate long‐term commitments of interested surgeons and to avoid “futile” transplant careers.     

Stent versus open surgery for acute and chronic traumatic injury of the thoracic aorta: a single-center experience

BACKGROUND: Traumatic injuries of the thoracic aorta have a high morbidity and mortality. Treatment options include either open surgery or endovascular stent graft implantation. METHODS: We have reviewed retrospectively all our patients treated for acute and chronic traumatic injury of the thoracic aorta and compared the outcome of the endovascular versus open therapy. Age, gender, severity of injuries, interventional delay, perioperative morbidity, 30-day mortality, length of intensive care, and overall hospital stay were evaluated. RESULTS: In all, 46 patients were treated over the past 14 years. Overall 30-day mortality was 16% in patients treated for acute or contained aortic ruptures (n = 31) and not significantly different after endovascular versus open repair (13.3% versus 18.8%). There was no mortality in the patients receiving elective stent grafting or open surgery for chronic posttraumatic aortic aneurysms (n = 15). Conversion and/or operative revision following stent graft implantation occurred in three patients (12.5%). Neurologic complications were absent in the stent graft group (0 of 24), whereas paraplegia (n = 2) or minor neurologic (n = 3) deficits developed following open surgery (5 of 22; 22.7%; p = 0.013). Length of intensive care and overall hospital stay were significantly shorter for patients after elective stent graft treatment compared with open surgery (p = 0.045). CONCLUSIONS: According to our midterm results, minimally invasive endovascular repair for patients with acute traumatic ruptures and chronic posttraumatic aneurysms is an equally effective treatment option compared with open surgery, with advantages regarding perioperative neurologic complications and duration of hospital stay under elective circumstances.