[Surgical treatment of chronic pancreatitis: indications, timing, methods]. / Khirurgicheskoe lechenie khronicheskogo pankreatita: pokazaniya, sroki, metody.

The review is devoted to complex treatment of chronic pancreatitis considering modern data on pathogenesis of this disease. The authors analyze various aspects of endoscopic and surgical interventions in refractory pain syndrome and complications of chronic pancreatitis, as well as positive and negative aspects of each method. Various surgical interventions and indications are analyzed in detail. One of the important points was analysis of the period between disease onset and surgical treatment that affects quality of life in patients with chronic pancreatitis in mid- and long-term period.

[Interventions for pancreatitis]. / Interventionen bei der Pankreatitis.

Approximately 20% of patients with acute pancreatitis develop complications that require surgical or radiological intervention. Radiology plays a central role, not only for imaging (course of the disease, detection of superinfection and their related complications, and development of necrosis) but also for the treatment of vascular and nonvascular complications. In the treatment of severe or necrotizing pancreatitis, a multidisciplinary staged approach with minimally invasive therapies such as endoscopic or percutaneous drainage should be used. Applying a sufficient number of drains of sufficient size, strict irrigation therapy under computed tomographic (CT) control and repositioning of the drains can successfully treat pancreatic and peripancreatic necrosis often without the need for subsequent surgical debridement. Arterial complications affect 1-10% of all patients with pancreatitis, most of which are ruptured pseudoaneurysms, which represent the most dangerous bleeding complication of pancreatitis and can be treated with a high technical success rate through embolization and/or use of an endovascular stent-graft.

[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.

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.

Five-year follow-up after late conversion from calcineurin inhibitors to sirolimus in patients with chronic renal allograft dysfunction.

BACKGROUND: Chronic allograft nephropathy (CAN) is, among others, caused by nephrotoxic side effects of calcineurin inhibitors (CNI), which are to date still the mainstay of immunosuppressive therapy. Sirolimus (SIR), an immunosuppressive compound without effects on glomerular perfusion, has been used in CNI-sparing immunosuppressive protocols. We report the 5-year follow-up of a prospective, controlled conversion study from CNI to SIR in patients with moderately to severely impaired renal function. METHODS: Twelve renal transplant recipients with moderately to severely impaired renal function (estimated glomerular filtration rate of 17 to 35 mL/min according to the MDRD formula), enrolled in a prospective, controlled 1-year pilot study were followed for 5 years. RESULTS: Three renal grafts (25%) were lost during the 5-year follow-up. Graft loss was due to noncompliance in one patient and to CAN in the other two patients. These two patients returned to dialysis 43 and 59 months after conversion, corresponding to 86 and 75 months after transplantation, respectively. Six of nine patients had a stable or even better renal function compared to the baseline. The lipid profile increased initially, but then remained stable over time. CONCLUSION: Conversion of immunosuppressive therapy from CNI to SIR in patients with impaired renal function more than 1 year after transplantation is feasible and safe yielding improved renal function in the majority of patients, which was sustained at 5 years follow-up.

[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.

Conversion from calcineurin inhibitors to sirolimus in patients with chronic renal allograft dysfunction.

BACKGROUND: Chronic renal transplant dysfunction in part may be due to the nephrotoxic effects of calcineurin inhibitors, which are still the mainstay of immunosuppressive therapy. Sirolimus, a new immunosuppressive compound devoid of significant nephrotoxicity, might therefore exhibit beneficial effects when used in renal transplant recipients with graft dysfunction. METHODS: Twelve renal transplant recipients included in this study had all been receiving calcineurin inhibitors for more than 12 months, and were free of rejection for more than 12 months. However, they demonstrated moderate renal dysfunction with serum creatinine values ranging from 1.8 to 4.0 mg/dL (164 to 351 micromol/L). After reaching a sirolimus level of 10 to 20 ng/mL, calcineurin inhibitor therapy was withheld. RESULTS: One month after initiation of sirolimus therapy, all patients were off calcineurin inhibitors. The average daily sirolimus dosage was 5.8+/-3.4 mg. No acute rejection episode and no graft failure was observed. No patient required hemodialysis or admission to the hospital. Calculated creatinine clearance increased from 63.4+/-9.9 to 69.2+/-9.7 mL/min (P=.0368) and serum bicarbonate increased from 20.8+/-3.17 to 22.5+/-3.7 meq/L (P=.001). Serum cholesterol increased from 180+/-26.5 to 239+/-28.8 mg/dL (4.65+/-0.69 to 6.18+/-0.74 mmol/L, P<.001), triglycerides increased from 155+/-53 to 289+/-123 mg/dL (1.75+/-0.6 to 3.26+/-1.39 mmol/L) and low-density lipoprotein cholesterol increased from 99+/-32 to 131+/-25.1 mg/dL (2.56+/-0.83 to 3.39+/-0.65 mmol/L, P=.01). Arterial blood pressure remained well controlled (126+/-15.6/74+/-8.9 vs 134+/-16.8/83+/-9.7). CONCLUSION: Conversion from calcineurin inhibitor therapy to sirolimus in patients more than 1 year after transplantation with impaired organ function is feasible, safe, and associated with a trend toward improved renal function.

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.

Effective use of donor MHC class I gene therapy in organ transplantation: prevention of antibody-mediated hyperacute heart allograft rejection in highly sensitized rat recipients.

Immunologically sensitized recipients present one of the most critical problems in clinical organ transplantation today, since preformed antibodies rapidly destroy donor tissue expressing specific MHC class I antigens (Ag). Therefore, sensitized patients are either unable to receive a compatible organ, or experience a prolonged waiting period. In this study we examined the effectiveness of donor MHC class I gene therapy in preventing hyperacute rejection (HR) of rat heart allografts in passively sensitized recipients. Our gene therapy strategy to address this problem is based on the phenomenon that liver transplants, which resist antibody-mediated HR, produce soluble MHC class I Ag capable of neutralizing preformed antibodies and suppressing the immune response. To mimic this "liver effect," we used liposomes to transfect cultured recipient (Lewis-RT1.Al) hepatocytes with plasmid DNA encoding the soluble donor MHC class I Ag, RT1.Aa. Control or RT1.Aa-transfected hepatocytes were implanted intrasplenically into Lewis recipients 1 day prior to heterotopic ACI (RT1.Aa) heart transplantation and injection of 6 ml of anti-ACI hyperimmune serum (HIS). Results showed that nearly all recipients receiving ACI-specific HIS and control hepatocytes experienced HR, while none of the recipients receiving HIS and hepatocytes expressing soluble RT1.Aa developed HR. Furthermore, active immunosuppression by soluble RT1.Aa was evidenced by prolongation of allograft survival, compared with controls not receiving HIS. In summary, soluble donor-MHC class I Ag gene therapy can prevent antibody-mediated destruction associated with HR. Future development of a similar strategy in humans may significantly improve the results of clinical organ transplantation in immunologically sensitized recipients.

Secreted donor-MHC class I antigen prolongs liver allograft survival and inhibits recipient anti-donor cytotoxic T lymphocyte responses.

BACKGROUND: Liver transplants may be less susceptible to rejection and may protect other transplanted organs from rejection, because the liver produces large amounts of soluble MHC class I antigen. Most studies supporting this hypothesis have used in vitro models. Here we tested the application of this theory in vivo in a rat transplant model. METHODS: Primary cultured Lewis (RT1.A(l)) hepatocytes were transfected by lipofection with plasmids encoding allogeneic membrane-bound or secreted RT1.A(a). After portal vein injection of transfected hepatocytes into a Lewis rat, either an ACI (RT1.A(a)) liver transplant was performed or lymph nodes were removed for immunologic analysis. RESULTS: Rats injected with hepatocytes secreting alloantigen showed extended liver allograft survival and decreased cytotoxic T lymphocyte activity. Recipients injected with hepatocytes expressing membrane-bound alloantigen demonstrated accelerated graft rejection and showed cytotoxic T lymphocyte sensitization. CONCLUSIONS: Soluble donor-specific MHC class I molecules may have immunosuppressive effects that can be used to promote graft survival in an organ transplantation situation.

Split tolerance induced by immunotoxin in a rhesus kidney allograft model.

BACKGROUND: Renal allografts were performed in rhesus monkeys using FN18-CRM9, a potent immunotoxin capable of depleting T cells to less than 1% of baseline levels in blood and lymph nodes, as a preparative agent. We have recently reported that animals pretreated with FN18-CRM9 1 week before transplantation without further immunosuppression had prolonged graft survival time compared with control animals, and frequently became tolerant. METHODS: This report examines the alloimmune responses of recipient monkeys to the donor, including cytotoxic T lymphocyte precursor (CTLp) frequency, mixed lymphocyte response, and antidonor IgG response. RESULTS: CTLp frequencies declined significantly (P<0.01) after FN18-CRM9 treatment and renal transplantation. This decline in CTLp was initially nonspecific, as CTLp frequencies against third-party animals also declined (P<0.01). The decrease in CTLp was maintained in five of five animals tested 6 months after transplant. However, unresponsiveness was limited to the CTL arm of the immune response as antidonor IgG was detected in four of four animals tested, and the 5-day mixed lymphocyte response stimulation index and relative response were not significantly different before and after transplant. In long-term survivors (>150 days), an increase in anti-third-party CTLp was detected 1 month after grafting with third-party skin. No change was seen in the antidonor CTLp frequency after donor skin grafting, indicating that a specific defect in the antidonor CTL response had developed. CONCLUSIONS: These data suggest that FN18-CRM9 treatment of rhesus monkeys allows the development of specific down-regulation of antidonor CTL activity in renal allograft recipients.

Immunologic suppression mediated by genetically modified hepatocytes expressing secreted allo-MHC class I molecules.

Studies suggest that immunosuppression associated with liver transplantation may be related to the secretion of MHC class I antigen (Ag) by hepatocytes. To investigate this possibility, we developed a culture system whereby naive Lewis (RT1.A1) splenocytes were cocultured with autologous hepatocytes transfected with plasmids encoding either the membrane-bound or secreted allogeneic MHC class I Ag, RT1.Aa. Cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) limiting dilution assays were subsequently performed on preconditioned lymphocytes. Lymphocytes preconditioned with hepatocytes secreting RT1.Aa showed an alloantigen specific inhibition of CTL precursors (CTLp). In contrast, exposure of splenocytes to hepatocyte-expressed membrane-bound RT1.Aa resulted in Ag-specific CTLp priming. This CTLp priming effect by hepatocyte-expressed membrane-bound Ag could be effectively blocked when splenocytes were first preincubated with hepatocytes secreting RT1.Aa, before being exposed to hepatocytes expressing membrane-bound RT1.Aa. In contrast to CTLp, HTLp frequency, as determined by IL-2 production, was unaffected by either hepatocyte-expressed membrane-bound or secreted RT1.Aa. Further studies on splenocytes conditioned with hepatocytes expressing secreted allo-MHC Ag suggest the possibility of suppressor cell development. This was demonstrated by prolongation of ACI (RT1a) heart allograft survival in Lewis recipients following adoptive transfer of splenocytes that were preconditioned in vitro with hepatocytes secreting alloantigen.

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.

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.

[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.

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.