Hans Juergen Schlitt

Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion

Mesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and viability of MSC was examined by isolation and re-culture of intravenously infused MSC. C57BL/6 MSC (500,000) constitutively expressing DsRed-fluorescent protein and radioactively labeled with Cr-51 were infused via the tail vein in wild-type C57BL/6 mice. After 5 min, 1, 24, or 72 h, mice were sacrificed and blood, lungs, liver, spleen, kidneys, and bone marrow removed. One hour after MSC infusion the majority of Cr-51 was found in the lungs, whereas after 24 h Cr-51 was mainly found in the liver. Tissue cultures demonstrated that viable donor MSC were present in the lungs up to 24 h after infusion, after which they disappeared. No viable MSC were found in the other organs examined at any time. The induction of ischemia-reperfusion injury in the liver did not trigger the migration of viable MSC to the liver. These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer

BackgroundIn selected patients with peritoneal carcinomatosis from ovarian cancer prognosis can be improved by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsBetween September 1995 and February 1999, 19 patients (mean age 52 years, range 30–72 years) with peritoneal carcinomatosis from primary or recurrent epithelial ovarian carcinoma were operated with the aim of complete macroscopical cytoreduction. Surgery was followed by intraoperative HIPEC. The data was analyzed retrospectively.ResultsEleven patients had recurrent and 8 primary ovarian cancer. The median progression free interval was 18 months (range 6–36 months). Macroscopically complete cytoreduction was achieved in 9 patients. Cisplatin (n = 16) or mitoxantrone (n = 3) were used for the intraoperative chemotherapy. The median intraabdominal inflow temperature was 41.5°C. Complications occurred in seven patients. Most frequent complications were anastomotic leakage (2/19) and intraabdominal abscess formation (2/19). One patient died postoperatively. The mean (± SD) overall survival time was 33(± 6) months with a 5-year survival rate of 15%. The survival was found to be influenced by the completeness of cytoreduction (44 ± 11 vs. 25 ± 6 months, p = 0.40), tumor volume (54 ± 10 versus 16 ± 4, p = 0.002) and presence of lymph node (38 ± 8 vs. 20 ± 8 months, p= 0.2) or liver metastases (51 ± 9 vs. 21 ± 6 months, p = 0.06).ConclusionsCytoreductive surgery combined with HIPEC is feasible and is associated with a reasonable morbidity and mortality. Complete cytoreduction may improve survival in select group of patients with low tumor volume and no organ metastases.

Immunosuppression for liver transplantation

In the last few decades liver transplantation (LTx) has become a reliable life-saving procedure for patients with chronic end-stage liver diseases. LTx has an outstanding success rate in the first few years after allografting, especially considering that many patients are on the brink of survival at the time of transplantation. The success of LTx is owed to the pioneers who developed the surgical procedures and to researchers who discovered the medications to help prevent immunological rejection of allografts. However, several problems continue to impose serious limits on LTx today, including a shortage of donor livers, recurrence of disease (eg, hepatitis, hepatocellular cancer), preservation of long-term allograft function and the side effects of anti-rejection drugs. While the dilemma of organ shortage is not a focus of this review, we will address the latter issues as they relate to the “oldest” and “newest” approaches to immunosuppression, and discuss the prospect that recipients could potentially be made immunologically tolerant to liver transplants. Due to the critical shortage of organs, new strategies to preserve transplanted liver allografts for the longest possible time are of paramount importance.

Patient selection for a curative approach to carcinomatosis

Abstract:There is an increasing evidence showing that in selected patients with peritoneal carcinomatosis cytoreductive surgery and hyperthermic intraperitoneal chemotherapy may improve survival. Adequate patient selection is crucial to obtain a complete macroscopic cytoreduction, a leading predictor of patient outcome. However, selection is a very difficult process and is associated with a significant learning curve. Many selection criteria have to be assessed in each patient: performance status, comorbiditites, response to previous chemotherapies, histology grading, and presence of extra-abdominal or liver metastases, small bowel involvement, and tumor volume assessed by the peritoneal cancer index. All these factors have to be discussed interdisciplinary and with the patient to create an individualized treatment strategy. It is difficult to decide the relative importance of each selection criteria. However, completeness of cytoreduction, tumor volume, and histology grading are most important in many multivariate analysis independent prognostic factors. For appropriate selected patients with peritoneal carcinomatosis arising from appendiceal and colon cancer, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be considered standard of care.

Safety of Gastric Resections During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis

BackgroundCytoreductive surgery (CRS) including gastric resection combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can improve the prognosis of selected patients with peritoneal surface malignancies. Perioperative morbidity of this aggressive treatment strategy is high; however, overall mortality can be low in specialized centers. The aim of this study was to assess the safety of gastric resections with anastomosis during CRS and HIPEC.MethodsBetween 2005 and 2008, 204 patients underwent CRS and HIPEC at our tertiary referral centre. Of these, 37 procedures (male/female 24/13, median age 55xa0years) included gastric resections. The clinical data of all patients were introduced into a database and analyzed with respect to the morbidity associated with the gastric resections.ResultsOf all patients included, 16 had pseudomyxoma peritonei, 11 gastric carcinoma, 4 ovarian carcinoma, 3 malignant peritoneal mesothelioma, and 3 colon carcinoma. Twenty-seven patients had previous surgery (nxa0=xa022) and/or systemic chemotherapy (nxa0=xa018). Fifteen total gastrectomies, 3 subtotal gastrectomies, 12 distal gastrectomies, and 7 gastric wedge resections were performed during CRS. The overall postoperative morbidity was 45%; main surgical complications were pancreatitis (nxa0=xa06), abdominal abscess (nxa0=xa04), bile leakage (nxa0=xa02), and digestive fistula (leakage of ileorectostomy and small bowel perforation) (nxa0=xa02). However, no complications occurred at the site of the esophageal anastomosis (nxa0=xa015), gastric anastomosis (nxa0=xa015) or gastric suture (nxa0=xa07). No patient died postoperatively during the hospitalization period.ConclusionsCRS in combination with HIPEC is associated with high postoperative morbidity; however, anastomosis following total or subtotal gastrectomy is safe in experienced centers. No leakages related to gastric resections occurred in this high-risk patient group.

Delayed Visceral Arterial Hemorrhage Following Whipple’s Procedure: Minimally Invasive Treatment with Covered Stents

BackgroundDelayed visceral arterial hemorrhage caused by inflammatory vessel erosion represents a rare but life-threatening complication after pancreatic head resection. Therapeutic options include reoperation or endovascular minimally invasive techniques such as embolization or stent graft placement. The present article describes our experiences with implantation of newly developed low-profile stent grafts.MethodsThe findings of four patients with delayed visceral arterial hemorrhage are described. All patients were treated with placement of low-profile stent grafts. The patients’ medical records, radiological reports, and images were retrospectively reviewed. Technical success was defined as immediate cessation of hemorrhage. Clinical success was defined as hemodynamic stability.ResultsA total of seven stent grafts were implanted in four arteries. In detail, one stent graft was placed in the splenic artery of the first and second patients. In the third patient one stent graft was initially implanted in the common hepatic artery. The patient developed recurrent hemorrhages of the common hepatic artery, treated one time surgically and two times by deployment of a second and third stent graft. In the fourth patient two stent grafts were placed in the proper hepatic artery. Technical and clinical success was achieved at every procedure. Apart from recurrent hemorrhage of patient No. 3 there were no major complications.ConclusionsMinimally invasive therapy using low-profile stent grafts is an effective and safe procedure for the treatment of delayed visceral arterial hemorrhage following Whipple’s procedure. The technique is a promising alternative to standard procedures such as surgical repair or embolization.

Workload and quality of life of surgeons. Results and implications of a large-scale survey by the German Society of Surgery.

BackgroundQuality of life is of vital importance for patients undergoing surgery. However, little is known about the quality of life of surgeons who are facing a stressful and dramatically changing working environment. For this reason, this large-scale study investigated the quality of life (QL) of surgeons in Germany in the context of occupational, private, and system-related risk factors.MethodsThe study population consisted of attendees (surgeons, non-surgical physicians, medical students) of the nine major annual conferences of the German Society of Surgery between 2008 and 2009. Participants filled in a single questionnaire including study-specific questions (demographic variables, professional position, and occupational situation) and a standardized quality of life instrument (Profiles of quality of life of the chronically ill, PLC). Surgeons responses with regard to their professional situation and their quality of life were contrasted with those of the two controls (non-surgical physicians, medical students). Furthermore, PLC scores were compared with German population reference data and with reference data of several patient groups.ResultsIndividuals (3,652) (2,991 surgeons, 561 non-surgical physicians, 100 medical students) participated in this study. The average age of surgeons and non-surgeons was in the low forties. In terms of professional qualifications, the majority of surgeons were residents (30%) and the majority of non-surgeons consultants in private practice (38%). Sixty-eight percent of the surgeons, only 39% of the non-surgeons worked more than 60xa0h per week on average (pu2009<u20090.001). Surgeons regarded their administrative workload as high (67% vs. controls 57%, pu2009<u20090.001). Surgeons reported restrictions on their private and family life due to work overload, more so than non-surgeons (74% vs. 59%, pu2009<u20090.001). Of the surgeons, 40% regarded their quality of life as worse than that of the general public (non-surgeons, 22%; pu2009<u20090.001). A third (32%) of the surgeons considered their quality of life even lower than that of their patients (non-surgeons, 17%; pu2009<u20090.001). Responses to the PLC quality of life questionnaire confirmed these results, showing score values lower than those of the German population reference data and of several patient groups. Multiple regression analyses showed that the strongest and most consistent influence variable for a low quality of life on all eight quality of life scores were restrictions in private life (range of standardized beta weights betau2009=u20090.259 to 0.325), hierarchical and uncooperative working environment (betau2009=u20090.057 to 0.235), lack of opportunities for continuing education (betau2009=u20090.108 to 0.161), and inadequate salary (betau2009=u20090.036 to 0.172).ConclusionsImproving the working conditions for surgeons requires a concerted action of all relevant parties, including hospital administrators, insurance companies, and the German Society of Surgery. The present study clearly identified measures that should be taken.

Study protocol: a pilot study to determine the safety and efficacy of induction-therapy, de novo MPA and delayed mTOR-inhibition in liver transplant recipients with impaired renal function. PATRON-study.

AbstractBackgroundPatients undergoing liver transplantation with preexisting renal dysfunction are prone to further renal impairment with the early postoperative use of Calcineurin-inhibitors. However, there is only little scientific evidence for the safety and efficacy of de novo CNI free bottom-up regimens in patients with impaired renal function undergoing liver transplantation. This is a single-center study pilot-study (PATRON07) investigating safety and efficacy of CNI-free, bottom-up immunosuppressive (IS) strategy in patients undergoing liver transplantation (LT) with renal impairment prior to LT.Methods/DesignPatients older than 18 years with renal impairment at the time of liver transplantation eGFR < 50 ml/min and/or serum creatinine levels > 1.5 mg/dL will be included. Patients in will receive a CNI-free combination therapy (basiliximab, MMF, steroids and delayed Sirolimus). Primary endpoint is the incidence of steroid resistant acute rejection within the first 30 days after LT. The study is designed as prospective two-step trial requiring a maximum of 29 patients. In the first step, 9 patients will be included. If 8 or more patients show no signs of biopsy proven steroid resistant rejection, additional 20 patients will be included. If in the second step a total of 27 or more patients reach the primary endpoint the regimen is regarded to be safe and efficient.DiscussionIf a CNI-free-bottom-up IS strategy is safe and effective, this may be an innovative concept in contrast to classic top-down strategies that could improve the patient short and long-time renal function as well as overall complications and survival after LT. The results of PATRON07 may be the basis for a large multicenter RCT investigating the new bottom-up immunosuppressive strategy in patients with poor renal function prior to LT.nhttp://www.clinicaltrials.gov-identifier: NCT00604357

Living donor liver transplantation in adults in the MELD era in Germany – a multi‐center retrospective analysis

The aim of this analysis was to provide an update on the current trend in living donor liver transplantation (LDLT) for adult recipients in the model of end stage liver disease (MELD) era in Germany and to encourage a wider implementation of LDLT. We descriptively analysed the data of LDLTs in Germany from 15 December 2006 to 31 December 2009 using a multi‐center retrospective analysis via a questionnaire and data provided by Eurotransplant. Ten German centers performed LDLTs in adults. Eighty four transplantations in 50 male recipients and 34 female recipients were performed during the review period, ranging from 1 to 16 LDLTs per center. Hepatocellular carcinoma in cirrhosis (15/84) was the most common transplantation indication. The recipient mean lab‐MELD score was 15 (±8). Six re‐transplantations were necessary after initial LDLTs. The 1‐year patient survival was 81%. We obtained data of 79/84 donors. The incidence of complications was 30.4% (nu2003=u200324). There were no grade 5 complications according to the Clavien classification. LDLT is an established treatment option that may reduce the waiting time, provides high quality split liver grafts and should be advocated in the MELD era to reduce organ shortage and ‘death on the waiting list’.

Dual inhibition of Raf and VEGFR2 reduces growth and vascularization of hepatocellular carcinoma in an experimental model

Background and aimsActivation of the mitogen-activated protein kinase–extracellular-signal-regulated kinase (ERK) pathways plays an important role in the progression of hepatocellular carcinoma (HCC). Importantly, Raf kinases are principal effectors within this oncogenic signaling cascade. We hypothesized that concomitant inhibition of Raf and vascular endothelial growth factor receptor 2 (VEGFR2) will affect tumor growth and angiogenesis of HCC.Materials and methodsHuman HCC cell lines, endothelial cells (EC), and vascular smooth muscle cells (VSMC) were used. For blocking Raf kinase and VEGFR2, the small molecule inhibitor NVP-AAL881 (Novartis, USA) was used. Activation of signaling intermediates was assessed by Western blotting, and changes in cell motility were evaluated in migration assays. Effects of NVP-AAL881 on HCC growth were determined in a subcutaneous tumor model.ResultsNVP-AAL881 disrupted activation of ERK and STAT3 in HCC cells and reduced cancer cell motility. In addition, the migration of ECs and VSMC was also significantly impaired. In ECs, HCC-conditioned media-induced activation of STAT3 was diminished by NVP-AAL881 treatment. In vivo, NVP-AAL881 significantly reduced tumor growth, CD31-vessel area, and numbers of BrdU-positive proliferating tumor cells.ConclusionsCombined inhibition of Raf and VEGFR2 disrupts oncogenic signaling and efficiently reduces tumor growth and vascularization of HCC. Hence, this strategy could prove valuable for therapy of HCC.