Long-term results after surgical treatment of nonparasitic hepatic cysts.

BACKGROUND: Studies evaluating surgical success in patients with benign liver cysts focus on cyst recurrence. The aim of this study was to evaluate the efficacy of surgical treatment with regard to clinical complaints. MATERIALS AND METHODS: Between 1995 and 2007, 99 patients (M:F 1:7.25) with symptomatic, benign, nonparasitic liver cysts (77 simple liver cysts [SLCs], 22 polycystic liver disease [PCLD]) underwent surgical treatment (77% laparoscopic surgery, 23% open surgery). Perioperative parameters (including morbidity) were evaluated. Moreover, a questionnaire was completed by 65 patients monitoring subjective complaints focusing on abdominal pain, vegetative symptoms, and dyspnea pre- and postoperatively (mean follow-up 76 months). RESULTS: Severe complications occurred in 7 patients. Abdominal pain, vegetative symptoms, and dyspnea were significantly improved in SLC patients. In PCLD patients abdominal pain and dyspnea were significantly decreased, whereas vegetative symptoms were unaffected by surgery. The symptom recurrence rate for SLC patients was significantly lower compared with PCLD patients (41% vs 66.6%). CONCLUSION: Indications for surgical treatment of PCLD should be well considered and limited to a selected group of patients.

[Diagnosis and multimodal therapy for hepatocellular carcinoma]. / Diagnose und multimodale Therapie des hepatozellulären Karzinoms.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in the world. The majority of HCCs develops on the basis of a chronic liver disease. This often complicates diagnosis and therapy. Non-invasive diagnostic criteria are based on dynamic imaging techniques and the serum level of AFP (alpha-fetoprotein). When evaluating HCC patients for therapy, besides tumor burden and localisation, the therapeutic evaluation must also consider the general condition of the patient and his/her liver function. For this purpose, the BCLC algorithm of the Barcelona Clinic for Liver Disease has proven helpful. Only one-third of the patients can be cured by resection, transplantation or local tumour ablation. In locally advanced cases transarterial procedures including transarterial chemoembolisation and radioembolisation are applied. HCC is a chemo-resistant tumour and chemotherapy is not accepted as standard of care in HCC. Sorafenib is the first systemic treatment with proven efficacy approved for the treatment of advanced and metastatic HCC. Interdisciplinary management of HCC patients is essential in order to provide every patient with the optimal therapy at his specific stage of disease.

[Acute abdomen: clinical background and demands on imaging]. / Akutes Abdomen: Klinische Begriffsbestimmung und Anforderungen an die Bildgebung.

The term "acute abdomen" does not describe a specific disease entity but is more a critical clinical state which incorporates very heterogeneous clinical presentations. The prognosis of any disease depends on the time frame from the onset of symptoms to the initiation of a specific therapy. For this reason there are special expectations by clinicians regarding the diagnostic assessment provided by radiology which is expected to deliver an immediate diagnosis supporting further therapeutic decisions. Along with the patient's clinical history, physical examination and blood tests, radiological diagnostics are essential for enabling a specific treatment. From a surgical point of view the radiologist is expected to help in differentiating between cases with indications for emergency surgery and cases eligible for elective surgery or conservative treatment.

The dark side of the moon: impact of moon phases on long-term survival, mortality and morbidity of surgery for lung cancer.

OBJECTIVE: Superstition is common and causes discomfiture or fear, especially in patients who have to undergo surgery for cancer. One superstition is, that moon phases influence surgical outcome. This study was performed to analyse lunar impact on the outcome following lung cancer surgery. METHODS: 2411 patients underwent pulmonary resection for lung cancer in the past 30 years at our institution. Intra- and postoperative complications as well as long-term follow-up data were entered in our lung-cancer database. Factors influencing mortality, morbidity and survival were analyzed. RESULTS: Rate of intra-operative complications as well as rate of post-operative morbidity and mortality was not significantly affected by moon phases. Furthermore, there was no significant impact of the lunar cycle on long-term survival. CONCLUSION: In this study there was no evidence that outcome of surgery for lung cancer is affected by the moon. These results may help the physician to quiet the mind of patients who are somewhat afraid of wrong timing of surgery with respect to the moon phases. However, patients who strongly believe in the impact of moon phase should be taken seriously and correct timing of operations should be conceded to them as long as key-date scheduling doesn't constrict evidence based treatment regimens.

Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling.

Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU+Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU+PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.

[Interdisciplinary diagnosis of and therapy for cholangiocarcinoma]. / Interdisziplinäre Diagnostik und Therapie von Gallengangskarzinomen.

The diagnosis of and therapy for cholangiocarcinomas still remains an interdisciplinary challenge. For diagnostic and therapeutic purposes intra- and extrahepatic cholangiocarcinomas need to be distinguished. Multiple imaging tools such as sonography, multidetector computer tomography, magnetic resonance tomography as well as endoscopic ultrasound and endoscopic retrograde cholangiography for the diagnosis and localisation of these tumours are available. To date, surgical resection is the only curative treatment. At the time of diagnosis, most of the tumours are advanced. Therefore, only a small percentage of patients are suitable for curative surgery. Infiltration of the portal vein no longer constitutes a contraindication for surgery. Liver transplantation is not a reasonable option for intrahepatic cholangiocarcinomas but may be of advantage for perihilar Klatskin tumours. Severe cholangitis is the main cause of death of patients with obstructive cholangiocarcinomas. Drainage of the biliary tree system or surgery with construction of a biliary-digestive anastomosis is often necessary. If possible, a photodynamic therapy (PDT) should be performed in addition to biliary drainage. PDT has been shown to facilitate biliary drainage and to improve survival. The value of radiologist-assisted interventional procedures as well as percutaneous ablation and radiochemotherapy is not well established. In addition, so far, there is no standardised chemotherapy in a palliative situation established but there is some evidence for a benefit of gemcitabine-based chemotherapy. For the best care and treatment of patients with cholangiocarcinomas an interdisciplinary approach is required and to achieve progress in the therapy patients should be included in prospective clinical trials to test new approaches.

The University of Munich lung cancer group database: design, profile of cohort and outcome analysis.

OBJECTIVE: Changes in therapeutic concepts can only be justified by a significant improvement of outcome parameters. Furthermore, detailed statistics of complications are needed to guarantee high quality of treatment. This study describes the new University of Munich Lung Cancer Group Database. METHODS: The MLCG-Database contains all patients who underwent surgery for lung cancer at the Department of Surgery, University of Munich Medical Centre since 1978. Data were database recorded on the patient's ward, or directly imported from other departments performing medical examinations on the patient. Data could be entered online at the time of surgery in the operating room. Relevant information from the Munich Tumour Registry was imported via encrypted data communication. Both epidemiological background and influence of preoperative risk factors on morbidity and mortality as well as on long-term survival were analysed. RESULTS: Median follow-up time was 45 months (1-295 months). Overall 5- and 10-year survival was 36% and 28% respectively. Preoperative risk factors were arterial hypertension in 43% of patients, COPD in 34%, abuse of nicotine in 26% and therapy with corticosteroids in 25%. Surgical procedure consist of lobectomy or bilobectomy in 69%, pneumonectomy in 16% and lesser resections in 15%. Intra- and postoperative complications occurred in 1.4% and 32% of patients, respectively. CONCLUSIONS: This paper provides an overview of our MLCG-Database, which allows performing statistics for outcome analysis and quality management reports as well as medical assessment on a huge collection of patient data on a day-to-day basis. In addition, impact analysis of risk factors on postoperative morbidity and mortality as well as investigation of long-term survival underlines results reported internationally.

[A method for reassessment of cost-intensive cases in visceral surgery. Results of project by the German Society for Visceral Surgery]. / Methode zur Abbildung kostenintensiver Fälle in der Viszeralchirurgie. Ergebnisse des DRG-Projekts der Deutschen Gesellschaft für Viszeralchirurgie.

Since the introduction of diagnosis-related groups (DRGs) many surgical departments report inappropriate reimbursement for complex cases and a shift in costly cases. To evaluate this situation, the German Society for Visceral Surgery inaugurated the present cost calculation project. In three university hospitals for 50 cases each, we depicted possible cost separators and utilized the complete cost calculation data (so-called Paragraph 21 data set) to test these separators. We identified "admission from another hospital", "severe surgically relevant concomitant disease", and "reoperation during the same hospital admission". The last was considered the economically most significant and medically most valid factor and was submitted as a possible modification to the german DRG system. The proposed cost separator "reoperation during the same hospital admission" was introduced into the DRG system after validation and leads to better allocation of reimbursements to complex and costly cases.

The janus face of immunosuppression - de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich.

After decades of successful organ transplantation clinicians continue to be troubled by the increasing incidence of cancers under maintenance immunosuppression. In this study, we examined rates of malignancies in 2419 renal transplant recipients transplanted in our institution between 1978 and 2005. In renal transplant recipients the cumulative incidence of cancer after 25 years was 49.3% for all tumors and 39.7% excluding non-melanoma skin cancers, compared with 21% for a normal sex- and age-matched population. The most frequent tumors observed were non-melanoma skin cancers (20.5%), kidney cancers (12.0%), and cancers of the pharynx, larynx, or oral cavity (8.2%). The general increase of cancer risk was 4.3-fold. Independent risk factors for the development of a tumor were male gender, older recipient age, the presence of preformed antibodies before transplantation, and the time on immunosuppression. Interestingly, the use of IL-2-receptor antagonists significantly reduced the tumor risk of transplant recipients. The tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mammalian target of rapamycin (mTOR) inhibitor-based immunosuppressive protocols showed a clear tendency for lower malignancy rates. De novo malignancies following renal transplantation represent a serious problem endangering the prognosis of otherwise successfully transplanted patients. Future studies will have to address whether optimized immunosuppressive regimens including mTOR-inhibitors are capable of reducing the incidence or preventing the development of posttransplant malignancies.

Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis.

Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigeltrade mark lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.

FTY720 inhibits tumor growth and angiogenesis.

De novo malignancies and recurrence of tumors are some of the biggest threats to allograft recipients subjected to chronic immunosuppression. FTY720, a synthetic myriocin analogue, is an immunosuppressant that induces apoptosis of activated lymphocytes and prevents infiltration of lymphocytes into allografts, thereby prolonging allograft survival in a dose-dependent manner. Additionally, FTY720 was shown to prevent tumor growth and metastasis. Therefore, we examined the effect of FTY720 on angiogenesis in a HUVEC spheroid model. To substantiate our in vitro findings the effect of FTY720 was also tested in C57/B16 mice subcutaneously injected with Lewis Lung Carcinoma (LLC1) cells. After establishment of a palpable tumor the animals were treated daily with either saline or 1, 5, or 10 mg/kg FTY720. Subsequently, the tumor size was measured, periodically. In our experiments FTY720 showed a strong antiangiogenic effect, overcoming the stimulating effect of VEGF (20 ng/mL) even at subnanomolar concentrations. In vivo, FTY720 showed a dose-dependent inhibition of subcutaneous tumors, and the tumor size of animals treated with 10 mg/kg FTY720 was less than half of the size of tumors in control animals. In conclusion, FTY-720 demonstrated a strong antiangiogenic effect in vitro and a substantial antitumor effect in vivo. Presumably, the stabilizing effect of surrounding pericytes limits the effect of FTY720 in our mouse model. Therefore, a combination of FTY720 with an mTOR inhibitor might be the most favorable immunosuppressive drug combination for allograft recipients at risk for tumor development.

[Consensus-recommendations for sirolimus in liver transplantation]. / Konsensusempfehlung zum Einsatz von Sirolimus in der Lebertransplantation.

Sirolimus is an m-TOR inhibitor without renal side effects and potentially protects against the development of malignancy. Due to a higher incidence of complications in two trials and an official warning in the drug information, the use of Sirolimus in liver transplantation is limited. The participants of this consensus meeting had to analyse and evaluate the literature with respect to the potential role of Sirolimus in liver transplantation. This consensus statement follows the scheme normally employed for the presentation of guidelines including the grading of evidence (1a-5) and the extent of recommendation (A-C). Moreover, the consensus included the experience of the authors with respect to the handling of Sirolimus after liver transplantation.

[Problems with the follow-up and aftercare of transplanted patients exemplified by kidney transplantation]. / Transplantationspatienten brauchen kompetente Nachsorge. Welche Hürden Ihr Patient jetzt nehmen muss.

The large number of post-transplantation patients overwhelm the capacity of most transplantation centers (TC) to provide aftercare, with the result that close cooperation has been established between transplantation centers and ambulatory centers. Surveillance of immunosuppression, but also the treatment of concomitant cardiovascular diseases and the elevated tumorigenesis rate in transplanted patients, presuppose a high degree of readiness to undergo further education on a permanent basis. Furthermore, patient compliance is a factor of decisive importance for ensuring optimal care by the general physician. In close cooperation with the TC, the latter bears a considerable burden of responsibility for the lifelong aftercare of such patients.

Cyclosporine: 20 years of experience at the University of Munich.

The history of solid organ transplantation is, from an immunotherapeutic standpoint, divided in the era before and after the introduction of cyclosporine to the clinic. The introduction of cyclosporine to the clinic in 1978 is looked upon as a turning point in transplantation. The immediate success of the new drug was based on the reduction of early graft rejection and the substantial improvement of 1-year graft survival. With growing experience in the use of this new compound, together with the ability to measure drug levels in serum, allograft rejection and organ survival could be improved even further. Because of the clinical results, cyclosporine became the gold standard in immunosuppressive therapy after organ transplantation. Even after 20 years, as more and more new immunosuppressants emerge, the clinical evaluation of a new drug is frequently compared versus a cyclosporine-based regimen. Today, cyclosporine is probably one of the best investigated drugs in the field of organ transplantation. Beside the undoubted benefits of cyclosporine, experimental and clinical studies have also revealed some unwanted effects, such as nephrotoxicity and an increased risk in development of malignant tumors. Here, we review the experience at our institution with transplant recipients receiving cyclosporine as the main immunosuppressant over the past 20 years.

Acute pneumatosis cystoides intestinalis following allogeneic transplantation -- the surgeon's dilemma.

Pneumatosis cystoides intestinalis (PCI) is still a poorly understood phenomenon, currently considered to result from primary mucosal insult from varying causes. We report a case of severe PCI in a patient with chronic GVHD after bone marrow transplantation (BMT) performed to treat secondary AML. Post BMT, the patient suffered acute intestinal and cutaneous GVHD, eventually developing intestinal and biopsy-proven cutaneous chronic GVHD, which necessitated continuous steroid therapy. Chronic pancreatitis associated with GVHD was diagnosed by explorative surgery in February 2000 on the basis of increasing epigastric discomfort, tumour marker (CA 125) increase and the CT finding of a suspicious mass in the pancreas. Readmission occurred in April 2000 for rapid onset of inferior abdominal pain with distinct peritoneal signs. Relaparotomy, deemed necessary on the grounds of both clinical and radiological findings, revealed marked PCI of the ascending and transverse colon and attached mesentery in an otherwise intact gastrointestinal tract. Post-operative reconvalescence was uneventful, with no clinical or radiological recurrence of PCI in the following 10 months. In the context of a review of the relevant literature, this case report illustrates the complex underlying pathophysiology, and difficulty in making a differential diagnosis and treating PCI.

Immunologic considerations for therapeutic strategies utilizing allogeneic hepatocytes: hepatocyte-expressed membrane-bound major histocompatibility complex class I antigen sensitizes while soluble antigen suppresses the immune response in rats.

Understanding the immunologic effects of hepatocytes is critical because of the potential to use these cells for bioartificial livers, as a vehicle for gene transfer, and as a means to induce donor-specific immunosuppression in organ transplantation. However, this understanding is complicated by the fact that hepatocytes express membrane-bound and soluble forms of major histocompatibility complex (MHC) class I antigen, each with the potential to induce different immune responses. In the present study we first determined the immunologic effect of normal donor-derived hepatocytes in a rat heart transplant model. We then used ex vivo hepatocyte gene transfer to examine the immunologic effects of different forms of hepatocyte-expressed MHC class I antigen. Results showed that intrasplenic injection of purified, donor-strain-specific hepatocytes into recipients primes alloimmunity, as evidenced by acceleration of heart allograft rejection. Interestingly, injection of autologous hepatocytes transfected ex vivo with DNA encoding only membrane-bound donor MHC class I antigen (RT1.A(a)) also accelerated allograft rejection. However, hepatocytes transfected to express only secreted donor MHC antigen prolonged transplant survival. Limiting-dilution analysis of lymphocytes from animals treated with hepatocytes producing only secreted alloantigen showed an antigen-specific reduction in cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) precursors. Further analysis of CTL populations by flow cytometry revealed a relatively high percentage of nonviable cells, implying that soluble antigen promotes allospecific CTL death. In summary, this study suggests that hepatocyte-expressed MHC class I molecules have opposing immunologic effects, with the membrane-bound antigen inducing immunologic sensitization, and the soluble antigen promoting donor-specific immunosuppression.