Successful conversion to rapamycin for calcineurin inhibitor-related neurotoxicity following liver transplantation.

INTRODUCTION: Neurotoxicity is a well-recognized side effect of calcineurin inhibitors. Rapamycin is considered to be significantly less neurotoxic than calcineurin inhibitors (CNIs). The aim of this study was to retrospectively analyze a group of post-liver transplant patients who had been converted to rapamycin because of CNI-related neurotoxicity. PATIENTS AND METHODS: Orthotopic liver transplantation (OLT) was performed in 56 consecutive patients between April 1, 2003, and August 15, 2004. Immunosuppression was administered with tacrolimus, mycophenolic acid, and corticosteroids. RESULTS: Seven patients were converted to rapamycin due to new-onset neurotoxicity or exacerbation of previous neurological symptoms secondary to CNI. None of the patients had toxic levels tacrolimus (>15 ng/mL) at the time of symptoms, which persisted despite reduction of CNI dose. The indications for conversion were: (1) peripheral neuropathy; (2) seizure; (3) metabolic encephalopathy; and (4) central pontine myelinolysis. All patients showed improvement or resolution of their neurological symptoms after conversion to rapamycin. Two patients died, the first due to a hypoxic event and the second due to central pontine myelinolysis with limited improvement and a family decision to withdraw care. There were no complications directly attributed to rapamycin. Specifically, there were no thrombotic events, wound complications, or biliary leaks. Three patients had a rejection episode that was successfully treated with pulse corticosteroids and low-dose tacrolimus (levels < 5 ng/mL). CONCLUSIONS: Rapamycin can be safely used in OLT recipients with severe neurological symptoms ascribed to or exacerbated by CNIs. Rapamycin monotherapy may be inadequate to control rejection early after transplantation. Rapamycin can be combined with low doses of CNI to prevent rejection.

Gastrointestinal stromal tumors (GIST).

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GIST) are the most frequent non-epithelial tumors of the alimentary tract. The interstitial cells of Cajal or more primitive progenitor mesenchymal cells are suggested as their cells of origin. GIST's occur throughout the gastrointestinal tract but are generally located in the stomach and the intestine. About 70% of GIST's are immunohistochemically positive for CD34 and more than 90% for c-kit protein (CD117). About two thirds of GIST's are malignant. The tumor size, mitotic rate, cellularity and nuclear pleomorphism are the most important parameters characterizing the biological behavior of tumors. The diagnostic procedures are similar to those of other gastrointestinal neoplasms but only a half of the patients will have correct preoperative histological diagnosis. GIST's can be cured only by surgery. The procedure of choice, if possible, is resection without extended lymphadenectomy. Radiation and chemotherapy are generally ineffective. METHODOLOGY: 22 patients were operated on for GISTs in our department between 1996 and 2003. RESULTS: All but one proved to be benign. The patients were all asymptomatic after the operation except the malignant case. In his case an irresectable local recurrence developed later. CONCLUSIONS: GIST is a rare neoplasm of the GI tract. The only possibility for treatment of GISTs is surgical removal.

A prospective cohort study of risk prediction in simultaneous pancreas and kidney transplantation.

INTRODUCTION: Current risk prediction scoring systems in pancreas transplantation are limited to organ factors and are specific to predicting graft outcome. They do not consider recipient factors or inform regarding recipient morbidity. The aim of this study was to assess the utility of commonly used general surgical risk prediction models (P-POSSUM [Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity], MODS [multiple organ dysfunction score], Charlson co-morbidity index, revised cardiac risk index, ASA [American Society of Anesthesiologists] grade and Waterlow score), and to correlate them with total length of hospital stay (LOS) and critical care unit (CCU) LOS, important surrogate markers of patient outcome. METHODS: All risk prediction scores were calculated prospectively for all simultaneous pancreas and kidney (SPK) transplant recipients from November 2011 to October 2013, and correlated with outcome measures. RESULTS: Overall, 57 SPK transplant recipients were analysed. The mean age was 42.0 years (standard deviation [SD]: 7.60 years), 27 (52%) were male and the mean body mass index was 25.43kg/m(2) (SD: 3.11kg/m(2)). The mean pancreas and kidney cold ischaemic times were 703 minutes (SD: 182 minutes) and 850 minutes (SD: 192 minutes) respectively. The median total LOS and mean CCU LOS was 17 days (range: 8-79 days) and 7 days (SD: 4.04 days) respectively. When correlated with risk prediction scores, Waterlow score was the only significant predictor of total LOS and CCU LOS (p<0.001 [Spearman's correlation] and p=0.001 [Pearson's correlation] respectively). CONCLUSIONS: Preoperative risk prediction plays an important part in planning perioperative care. To date, no validated risk prediction scoring system exists for SPK transplantation. This prospective study indicates that Waterlow score identifies high risk individuals and has value in the prediction of outcome following SPK transplantation.

Effect of different immunosuppressive agents on acute pancreatitis: a comparative study in an improved animal model.

BACKGROUND: Immunosuppressive drugs have been associated with the development and progression of acute pancreatitis after organ transplantation. Consequently, a reduction or a change in immunosuppressive therapy has been recommended once posttransplantation pancreatitis has been suspected. However, it is not known which of the available immunosuppressive agents is most harmful to the pancreas and which may be used safely in this situation. The objective of this study was to investigate the effect of different immunosuppressive drugs in various dosages on intrapancreatic protease activation, acinar cell necrosis, and mortality in an improved model of acute necrotizing pancreatitis in the rat. The rat model of acute necrotizing pancreatitis, like posttransplantation pancreatitis, is characterized by ischemia and microcirculatory disorders. METHOD: Acute pancreatitis was induced in rats by using a combination of low-dose controlled intraductal glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. Six hours thereafter, animals were randomized to intravenous therapy with 2, 10, or 50 mg/kg/day prednisolone (PRED); 3, 15, or 60 mg/kg/day cyclosporine A (CsA); 10 mg/kg/day azathioprine (AZA); 0.6 mg/kg/day orthoclone OKT3 (OKT3); or saline. After 36 hr, surviving animals were killed to determine acinar cell necrosis and trypsinogen activation peptides levels (TAP) in blood and ascites. RESULTS: Compared with saline-treated control rats, animals treated with 60 mg/kg/day CsA developed significantly more acinar cell necrosis and had increased amounts of TAP in ascites. Likewise, there was more extensive acinar cell necrosis in animals subjected to AZA therapy. However, this was not associated with incremental TAP. Animals treated with 3 or 15 mg/kg/day CsA, OKT3, or PRED showed no significant changes in these target parameters. Animals given 10 or 50 mg/kg/day PRED even had decreased hematocrit values and produced significantly less ascites than animals in the other groups. CONCLUSION: The present results suggest that AZA and high doses of CsA aggravate acute pancreatitis and should, therefore, be avoided once posttransplantation pancreatitis has been suspected, whereas lower doses of CsA, OKT3, and PRED may be used safely. PRED can even be used at higher doses as may be required when graft rejection is suspected.

RES function and liver microcirculation in the early stage of acute experimental pancreatitis.

BACKGROUND/AIMS: The reticuloendothelial system and in particular the Kupffer cells in the liver are important for eliminating antigens and toxic substances in many diseases including acute pancreatitis. Optimal Kupffer cell function is believed to depend on numerous factors including intact hepatic blood supply and microcirculation. The aim of the study was to evaluate whether hepatic microcirculation and Kupffer cell function are impaired in acute pancreatitis and whether enhancement of hepatic capillary blood flow leads to improved reticuloendothelial system function. METHODOLOGY: Acute pancreatitis was induced in rats by intraductal infusion of bile salt followed by i.v. cerulein hyperstimulation. Animals were randomized to receive either a selective endothelin-A receptor antagonist (ET-RA; LU-135252; 50 mg/kg) or saline. Sham-operated animals (intraductal and i.v. saline infusion) treated according to the same protocol served as controls. Liver phagocytic function was evaluated in 6 animals per group 6 and 24 hrs after acute pancreatitis induction and treatment using 99mTc-labeled Nanocoll and a scintillation camera technique. Another 6 animals of each group were used for intravital microscopic determination of hepatic capillary blood flow using fluorescein-labeled erythrocytes. RESULTS: Six hours after acute pancreatitis induction, hepatic capillary blood flow and nanocoll clearance were significantly decreased in saline-treated animals (compared to saline-treated healthy controls). Endothelin-A receptor antagonist significantly improved hepatic capillary blood flow and nanocoll clearance. This beneficial effect was no longer seen after 24 hrs when these parameters had spontaneously returned to values not significantly different from normal. CONCLUSIONS: Reticuloendothelial system function and hepatic capillary blood flow are impaired (only) in the early stage of this acute pancreatitis model. Endothelin-A receptor antagonist improves hepatic capillary blood flow at this stage. Enhancement of hepatic capillary blood flow is accompanied by normalization of nanocoll clearance, suggesting that hepatic microcirculation influences phagocytic Kupffer cell function early in acute pancreatitis.

[Multiple organ failure in experimental pancreatitis]. / Többszervi elégtelenség kísérletes pancreatitisben.

BACKGROUND: Multiple organ failure (MOF) is the most severe complication and the most frequent cause of death in acute necrotizing pancreatitis (ANP). OBJECTIVE: To evaluate the components and the time course of MOF in an experimental model of ANP. METHOD: Induction of ANP in rats by a standardised bile-salt infusion into the pancreatic duct and i.v. cerulein hyperstimulation. Six hours after AP-induction animals were randomised into 4 groups to receive (I) no therapy; (II.) 4 ml/kg/h Ringer lactate (R.L) i.v.; (III) 8 ml/kg/h RL i.v.; or (IV) 4 ml/kg/h RL plus an endothelin receptor antagonist. Animals were observed for 24 hours and vital parameters were investigated. RESULTS: After 6 hrs all animals presented with severe haemoconcentration (hematokcrit > 57%) and oliguria (< 0.5 ml/6 hrs). Until 12 hrs following AP-induction in animals without therapy increased hematocrit and oliguria was observed. Animals receiving fluid resuscitation had a significant drop in hematocrit and kept their blood gas values compensated. Between 12 and 24 hrs urine production significantly increased with fluid resuscitation and respiratory parameters stabilised except for animals treated with 8 ml/kg/h RL. These animals developed arterial hypoxia and hypercapnia. CONCLUSIONS: (1) In the early phase of ANP in our model renal failure developed. (2) Massive fluid resuscitation that is necessary to increase urine output may lead to respiratory distress. (3) Reduction of intravascular fluid loss by endothelin receptor blockade is associated with improved renal and respiratory function.

Successful management of a ruptured mycotic pseudoaneurysm following pancreas transplantation using bovine pericardial patch: a case report.

Arterial mycotic pseudoaneurysms are a rare complication of pancreas transplantation. Rupture results in catastrophic hemorrhage with a high risk of mortality. Definitive management is complicated by an extensive arterial defect within a contaminated surgical field. Synthetic vascular grafts often fail due to subsequent graft infection whereas primary repair often results in arterial stenosis. Arterial ligation may be required to prevent exsanguination. A 41-year-old man, type 1 diabetic with associated renal failure, underwent successful simultaneous pancreas and kidney transplantation. He presented, 9 months following transplantation, with life-threatening rectal bleeding secondary to a ruptured mycotic pseudoaneurysm. This was successfully managed with a bovine pericardial patch (BPP) repair of the arterial defect and enteric diversion following graft pancreatectomy. He remains well with no vascular insufficiency 18 months following the procedure. A ruptured mycotic pseudoaneurysm following transplantation carries a significant risk of mortality and represents a surgical challenge as conventional techniques using synthetic materials often fail due to the contaminated field. A BPP offers good handling characteristics, excellent hemostatic properties and a favorable profile of infection risk in comparison with synthetic grafts. This case highlights its use as a treatment for a post-transplantation ruptured mycotic pseudoaneurysm.

Outcomes of methicillin-resistant Staphylococcus aureus infection after kidney and/or pancreas transplantation.

BACKGROUND: The true extent of Methicillin-Resistant Staphylococcus aureus (MRSA) colonization and incidence of infection after solid organ transplantation in adults and children is not well-known. The aim of this study was to evaluate the incidence and the outcomes of MRSA infection following kidney and/or pancreas transplantation. MATERIAL AND METHODS: We reviewed the case notes of all patients who developed MRSA colonization and infection within the first year of transplantation between September 2002 and December 2009. The primary endpoint of this study was mortality. The secondary endpoints included morbidity, graft failure, and length of hospital stay. RESULTS: During the study period 1116 transplantations were performed. MRSA colonization was detected in 14 patients (1.25%) and infection occurred in 6 cases (0.53%) post-transplantation. Graft failure was not associated with MRSA colonization/infection in any of the cases. The mortality rate attributed to MRSA was 10% (n = 2). The overall median length of stay was 16 days (range, 6-243 days). CONCLUSIONS: Our study demonstrates that the prevalence of MRSA colonization and infection in our unit is low in spite of immunosuppression. The incidence of MRSA infection was higher among patients who underwent pancreas transplantation. Patients who had MRSA colonization and then developed infection had higher morbidity and mortality rates.

Outcomes of patients who develop symptomatic Clostridium difficile infection after solid organ transplantation.

Clostridium difficile-associated diarrhea is the most common cause of hospital-associated diarrhea in the UK. Infection can produce a spectrum of manifestations from mild diarrhea to toxic megacolon, colonic perforation, and death. The aim of this study was to evaluate the outcomes of patients who developed symptomatic Clostridium difficile infection (CDI) within the first year after solid organ transplantation. Between 2004 and 2007, we performed 682 transplantation: 433 from deceased-donor kidney, 143 live-donor kidney, 18 pancreas-only, and 88 simultaneous kidney and pancreas transplants. Within the first year of transplantation, 24 patients developed symptomatic CDI. No single risk factor or antimicrobial agent was associated with acquiring infection. Among this group, 2 patients developed toxic megacolon requiring subtotal colectomy and recovered. Although 5 patients who developed CDI died within the first year, CDI was not the primary cause of death. The overall mortality of patients who developed CDI within the first year of transplantation accounted for 0.7% of all transplanted patients. Increased awareness of CDI and barrier nursing can minimize the impact of CDI on the morbidity and mortality associated with transplantation. Patients should be informed of the risk of CDI during consenting for transplantation, because the 3.5% incidence is more common than that of graft loss due to thrombosis.

Isolated massive pleural effusion caused by pancreatico-pleural fistula.

BACKGROUND: Massive pleural effusions are uncommon but well-documented complications of chronic pancreatitis, usually caused by the development of a pancreaticopleural fistula. The mechanism of the fistula formation is thought to be rupture of the pancreatic duct or pseudocyst. MATERIAL AND METHODS: In the past 7 years we have treated 5 patients with massive pleural effusion of pancreatic origin in the Surgical Department of Semmelweis University Medical School. 4 patients were males; the average age was 52 years (range: 46-59 years). RESULTS: All 5 patients had a history of alcohol abuse and were admitted to the pulmonary department because of respiratory distress. Other symptoms such as abdominal pain, chest pain, or weight loss were not always present. The diagnosis was confirmed by a markedly elevated amylase level in the aspirated pleural fluid. Abdominal ultrasound, CT scan, and ERCP examinations were carried out in order to determine the cause of the pancreaticopleural fistula. Conservative (nonsurgical) treatment was effective within 3 weeks in only one case. The other 4 patients required surgical management. In 3 cases distal pancreatic resection with splenectomy and cholecystectomy was done. In one case cystojejunostomy was performed. All 5 patients have been cured with complete resolution of their pleural effusions. CONCLUSIONS: Patients with large pleural effusions may have underlying pancreatitis with a pancreaticopleural fistula. It is important to establish this diagnosis because treatment may require operative interventions.

Effect of fluid resuscitation with and without endothelin A receptor blockade on hemoconcentration and organ function in experimental pancreatitis.

BACKGROUND: Intravascular fluid loss contributes to pancreatitis-associated multiple organ dysfunction and is thus a major target for therapy in this life-threatening disease. AIM: To evaluate intravascular fluid loss and extravascular fluid sequestration together with cardiorespiratory and renal function in a well-established rat model of severe acute pancreatitis (AP) and to investigate the effect of fluid resuscitation with and without endothelin receptor A blockade on these parameters. METHOD: Induction of AP in rats by a standardized bile salt infusion into the pancreatic duct and intravenous cerulein hyperstimulation. Six hours after AP induction, animals were randomized into 4 groups to receive (1) no therapy; (2) 4 ml/kg/h Ringer's lactate (RL) i.v.; (3) 8 ml/kg/h RL i.v., or (4) 4 ml/kg/h RL plus an endothelin receptor antagonist. Target parameters measured before and after AP induction and during the 24-hour observation period included: mean arterial blood pressure, heart rate, hematocrit, arterial blood gases, urine production, ascites and pleural effusions. RESULTS: After 6 h, all animals presented with severe hemoconcentration (hematocrit >57%) and oliguria (<0.5 ml/6 h). Cardiorespiratory parameters were within the normal range. Up to 12 h after AP induction, animals without therapy had an increased hematocrit and oliguria and developed metabolic acidosis. Animals receiving fluid resuscitation had a significant drop in hematocrit and maintained compensated blood gas values. A significant increase in urine production was only observed in animals given 8 mg/kg/h RL. Between 12 and 24 h, urine production significantly increased with fluid resuscitation and respiratory parameters stabilized except for animals treated with 8 ml/kg/h RL which developed arterial hypoxia and hypercapnia. CONCLUSIONS: Intravascular fluid loss and extravascular fluid sequestration together with decreased urine production characterize the early phase of this model of severe AP. Massive fluid resuscitation necessary for increasing urine output may lead to respiratory distress. Reduction of intravascular fluid loss by endothelin receptor blockade is associated with improved renal and respiratory function.

[The treatment of gastric tumours in our practice: a five year survey]. / Ein 5-Jahres-Uberblick über unsere Behandlung des Magenkarzinoms.

Between the 1st of January, 1998 and the 31st of December, 2002 we treated 111 patients for gastric cancer in the 2nd Department of Surgery, Semmelweis University, Budapest, Hungary. The majority of patients belonged to the advanced stages of the disease. In 65% of the cases a partial or total gastrectomy was performed. We combined the operation with D2 lymph node dissection if a R0 resection was possible, in the other cases with D1 lymphadenectomy. Postoperative morbidity rate ranged to 15%, the mortality 5.4%. 74 patients could be followed, 41 are dead and 33 still alive. According to the follow up examination the median survival time is 20.4 months at the moment. We observed a significantly shorter survival time, if vascular or lymphoid vessel invasion was present in the histologic specimen. The study has not been finished and the follow up will be continued.