Yves Dittmar

Thrombin-mediated hepatocellular carcinoma cell migration: Cooperative action via proteinase-activated receptors 1 and 4

Proteinase‐activated receptor‐1 (PAR1), a thrombin receptor and the prototype of a newly discovered G‐protein‐coupled receptor subfamily, plays an important role in tumor development and progression. In this study, we documented the expression of the thrombin receptors PAR1, PAR3, and PAR4 in permanent hepatocellular carcinoma (HCC) cell lines and primary HCC cell cultures. Stimulation of HCC cells with thrombin and the PAR1‐selective activating peptide, TFLLRN‐NH2, increased transmembrane migration across a collagen barrier. This effect was blocked by the PAR1 antagonist SCH 79797, confirming that the PAR1 thrombin receptor subtype is involved in regulating hepatoma cell migration. In addition, the PAR4‐selective agonist, AYPGKF‐NH2, also stimulated HCC cell migration whilst the PAR4 antagonist, trans‐cinnamoyl‐YPGKF‐NH2, attenuated the effect of thrombin on HCC cell migration. PAR1‐ and PAR4‐triggered HCC cell migration was blocked by inhibiting a number of key mediators of signal transduction, including G proteins of the Gi/Go family, matrix metalloproteinases, ERK/MAPKinase, cyclic AMP‐dependent protein kinase, Src tyrosine kinase, and the EGF receptor kinase. Our data point to a cooperative PAR1/PAR4 signaling network that contributes to thrombin‐mediated tumor cell migration. We suggest that a combined inhibition of coagulation cascade serine proteinases, the two PARs and their complex signaling pathways may provide a new strategy for treating hepatocellular carcinoma. J. Cell. Physiol. 211: 699–707, 2007.

New methods for clinical pathways—Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM)

PurposeClinical pathways (CP) are nowadays used in numerous institutions, but their real impact is still a matter of debate. The optimal design of a clinical pathway remains unclear and is mainly determined by the expectations of the individual institution. The purpose of the here described pilot project was the development of two CP (colon and rectum carcinoma) according to Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM).MethodsBPMN is an established standard for business process modelling in industry and economy. It is, in the broadest sense, a computer programme which enables the description and a relatively easy graphical imaging of complex processes. t.BPM is a modular construction system of the BPMN symbols which enables the creation of an outline or raw model, e.g. by placing the symbols on a spread-out paper sheet. The thus created outline can then be transferred to the computer and further modified as required. CP for the treatment of colon and rectal cancer have been developed with support of an external IT coach.ResultsThe pathway was developed in an interdisciplinary and interprofessional manner (55 man-days over 15 working days). During this time, necessary interviews with medical, nursing and administrative staffs were conducted as well. Both pathways were developed parallel. Subsequent analysis was focussed on feasibility, expenditure, clarity and suitability for daily clinical practice. The familiarization with BPMN was relatively quick and intuitive. The use of t.BPM enabled the pragmatic, effective and results-directed creation of outlines for the CP. The development of both CP was finished from the diagnostic evaluation to the adjuvant/neoadjuvant therapy and rehabilitation phase. The integration of checklists, guidelines and important medical or other documents is easily accomplished. A direct integration into the hospital computer system is currently not possible for technical reasons.ConclusionBPMN and t.BPM are sufficiently suitable for the planned modelling and imaging of CP. The application in medicine is new, and transfer from the industrial process management is in principle possible. BPMN-CP may be used for teaching and training, patient information and quality management. The graphical image is clearly structured and appealing. Even though the efficiency in the creation of BPMN-CP increases markedly after the training phase, high amounts of manpower and time are required. The most sensible and consequent application of a BPMN-CP would be the direct integration into the hospital computer system. The integration of a modelling language, such as BPMN, into the hospital computer systems could be a very sensible approach for the development of new hospital information systems in the future.

Microbiology of the infected recurrent sacrococcygeal pilonidal sinus

The aim of the present retrospective single centre study was to define the changes in the microbiological flora of the recurring sacrococcygeal pilonidal sinus (PS). Microbiological findings of swab samples of abscess‐forming PS from 2000 to 2010 were evaluated. Within this time span, 73 swab samples were taken from primary sacrococcygeal pilonidal sinus (pPS) and 23 swab samples of patients with recurring sacrococcygeal pilonidal sinus (rPS). Our results show a statistically significant shift of the bacterial flora towards the gram‐positive range (P = 0·029) and a shift with tendency towards the aerobic range (P = 0·090). Pathogens of pPS are not always solely anaerobic or gram‐negative, and those of rPS not always aerobic or gram‐positive. Therefore, antibiosis preceding microbiological examination should cover both the aerobic and anaerobic bacteria as well as the gram‐positive and the gram‐negative spectrum.

Waiting time, not donor-risk-index, is a major determinant for beneficial outcome after liver transplantation in high-MELD patients

BACKGROUND Due to the increasing donor shortage, patients undergo liver transplantation actually mostly with high MELD-scores. In this study, we analyze high-MELD patients who underwent liver transplantation at a german single center. MATERIAL AND METHODS Since implementation of the MELD-score within the Eurotransplant region (December 2006) up to May 2011, 45 patients with a lab-MELD-score ≥ 36 underwent liver transplantation at our center. We correlated the 1-year-survival with donor data (especially the donor risk index, DRI), the time interval from reaching a lab-MELD-score ≥ 36 up to liver transplantation and the recipients state prior transplantation. RESULTS The overall 1-year-survival in our cohort is 68,8%. Waiting time of survivors was significantly shorter compared to non-survivors (MedianSurvivors: 2 days vs. MedianNon-survivors: 4 days; p=0.049). DRI showed no significant differences between both groups. Furthermore, the recipients state prior transplantation (dialysis, mechanical ventilation, catecholamines) showed no significant association with the outcome. CONCLUSIONS The outcome after liver transplantation in high-MELD patients is worse compared to that of patients with a marked lower MELD-score. Especially the time interval between reaching a lab-MELD score ≥ 36 to the transplantation is a major determinant for survival. Since the DRI is not associated with a worsened outcome, transplantation centers should accept even marginal organs for high-MELD patients to keep the waiting time as short as possible.

Liver Transplantation Utilizing Old Donor Organs: A German Single-Center Experience

INTRODUCTION Due to the current profound lack of suitable donor organs, transplant centers are increasingly forced to accept so-called marginal organs. One criterion for marginal donors is the donor age >65 years. We have presented herein the impact of higher donor age on graft and patient survival. PATIENTS AND METHODS Since 2004, 230 liver transplantations have been performed at our center, including 54 donor organs (23.5%) from individuals >65 years of age. We performed a retrospective analysis of recipient and graft survivals. RESULTS The overall 1-year mortality was 22.2% (12/54) among recipients of organs from older donors versus 19.5% among recipients whose donors were <65 years. When donor organs were grouped according to age, the 1-year mortality in patients receiving organs from donors aged 65-69 years was 30% (6/20); 70-74 years, 29.4% (5/17); and donors >75 years, 5.9% (1/17). There was no significant correlation between mortality rate and the number of additional criteria of a marginal donor organ. DISCUSSION The current lack of donor organs forces transplant centers to accept organs from older individuals; increasingly older patients are being recruited for the donor pool. Our results showed that older organs may be transplanted with acceptable outcomes. This observation was consistent with data from the current literature. It should be emphasized, however, that caution is advised when considering the acceptance of older organs for patients with hepatitis C-related cirrhosis.

Implantation of the Liver During Reperfusion of the Heart in Combined Heart-Liver Transplantation: Own Experience and Review of the Literature

BACKGROUND There are only a few reports about combined heart-liver transplantations. The surgical techniques differ widely, ranging from sequential implantation of the organs to simultaneous transplantations. We report our experience with simultaneous, combined heart-liver transplantations without using a veno-venous bypass demonstrating that this is a feasible surgical technique. METHODS Since 2005, we performed 4 combined heart-liver transplantations by implanting the liver during the reperfusion period of the newly implanted heart. We retrospectively reviewed patient clinical data and outcomes. RESULTS The mean operative time was 534 ± 247 minutes and the ischemia times for heart and liver were 190 ± 72 minutes (cold ischemia time for the heart), 98 ± 96 minutes (warm ischemia time for the heart), 349 ± 101 minutes (cold ischemia time for the liver), and 36.25 ± 3.5 minutes (warm ischemia time for the liver). Three patients were discharged from the hospital after an uneventful clinical course. One patient died due to multi-organ failure during the intensive care unit stay on the 23rd postoperative day. CONCLUSION We suggest that combined, simultaneous heart-liver transplantation without veno-venous bypass is a feasible surgical technique.

Stent migration to the ileum: a potentially lethal complication after Montgomery salivary bypass tube placement for hypopharyngeal stenosis after laryngectomy.

Montgomery salivary bypass tubes (MSBTs) have been used for decades in the treatment of stenoses and fistulae of the hypopharynx and the cervical esophagus. Generally, MSBT use is not associated with serious complications. Only a small number of cases with severe MSBT‐associated complications have been reported in the literature.

Post-operative internal hernia through an orifice underneath the right common iliac artery after Dargent's operation.

We report the case of a 39-year-old woman with ileus resulting from a small bowel incarceration underneath the right common iliac artery. The patient had a history of a radical trachelectomy with laparoscopic pelvic lymphadenectomy (“Dargent’s operation”) for cervical carcinoma. After dissection of the iliac vessels, a small bowel loop could slide underneath the common iliac artery. The hernia was closed by gluing a collagen patch over the right common iliac artery onto the retroperitoneal cavity. To our knowledge, such a case has not previously been reported in the medical literature.

Individualized treatment of gastric cancer: Impact of molecular biology and pathohistological features

Gastric cancer is one of the most common malignancies worldwide. The overall prognosis remains poor over the last decades even though improvements in surgical outcomes have been achieved. A better understanding of the molecular biology of gastric cancer and detection of eligible molecular targets might be of central interest to further improve clinical outcome. With this intention, first steps have been made in the research of growth factor signaling. Regarding morphogens, cell cycle and nuclear factor-κB signaling, a remarkable count of target-specific agents have been developed, nevertheless the transfer into the field of clinical routine is still at the beginning. The potential utility of epigenetic targets and the further evaluation of microRNA signaling seem to have potential for the development of novel treatment strategies in the future.

Liver transplantation for hepatocellular carcinoma - factors influencing outcome and disease-free survival.

Hepatocellular carcinoma is one of the leading causes of cancer-related death worldwide. Liver transplantation can be a curative treatment in selected patients. However, there are several factors that influence disease-free survival after transplantation. This review addresses the pre-, intra- and postoperative factors that influence the risk of tumor recurrence after liver transplantation.