Importance of Pancreatic Enzyme Replacement Therapy after Surgery of Cancer of the Esophagus or the Esophagogastric Junction.

After surgical treatment of cancer of the esophagus or the esophagogastric junction we observed steatorrhea, which is so far seldom reported. We analyzed all patients treated in our rehabilitation clinic between 2011 and 2014 and focused on the impact of surgery on digestion of fat. Reported steatorrhea was anamnestic, no pancreatic function test was made. Here we show the results from 51 patients. Twenty-three (45%) of the patients reported steatorrhea. Assuming decreased pancreatic function pancreatic enzyme replacement therapy (PERT) was started or modified during the rehabilitation stay (in the following called STEA+). These patients were compared with the patients without steatorrhea and without PERT (STEA-). Maximum weight loss between surgery and rehabilitation start was 18 kg in STEA+ patient and 15.3 kg in STEA- patients. STEA+ patients gained more weight under PERT during the rehabilitation phase (3 wk) than STEA- patients without PERT (+1.0 kg vs. -0.3 kg, P = 0.032). We report for the first time, that patients after cancer related esophageal surgery show anamnestic signs of exocrine pancreas insufficiency and need PERT to gain body weight.

Characteristics and management of diaphragm involvement in patients with primary advanced-stage ovarian, fallopian tube, or peritoneal cancer.

OBJECTIVES: The aim of this study was to determine the frequency of diaphragm involvement (DI) in cases of International Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV primary epithelial ovarian, fallopian tube, or peritoneal cancer; the frequency of use of different surgical techniques in managing diaphragm implants; and the procedure-associated morbidity. METHODS: A retrospective analysis of consecutive patients undergoing primary surgery by a single surgical team between January 2005 and June 2007 was accomplished. Patients with tumors of low malignant potential and nonepithelial histologic diagnosis and those who received neoadjuvant chemotherapy were excluded. RESULTS: Thirty-three patients met the inclusion criteria. Diaphragm involvement was found in 91% of the cases. Whereas the left hemidiaphragm is never involved alone, the right side is significantly affected more extensively (P = 0.002) and frequently (alone, 20%; both sides, 80%). The frequency of use of procedures varies considerably in the literature, whereas full-thickness diaphragm resection (DR) had to be performed in 53% of our patients with DI. Diaphragm resection at the left hemidiaphragm and bilateral DRs are very rare in primary cases. A specific histopathologic examination of the DR preparation is desirable. A simple 4-tiered classification of the infiltration depth is proposed. The most frequent complication is serothorax, but a generous indication for intraoperative chest tube placement is solely recommended in cases of DR. CONCLUSIONS: Surgical effort in achieving an optimum cytoreduction could be evaluated more precisely with parameters of DI and diaphragm-related treatment procedures. The usual quality criteria for ovarian cancer surgery, such as residual tumor state and morbidity, are more marked by subjectivity and inconsistent definitions.

Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy?

Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so-called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5-cm-large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.

Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production upon second recurrence.

We present a 54-yr-old woman with ectopic corticotropin syndrome caused by a neuroendocrine tumor of the pancreas. At initial presentation, the patient suffered from diarrhea, heartburn, and nonspecific abdominal pain. There was no evidence of Cushing's syndrome. A neuroendocrine tumor in the head of the pancreas with metastases into peripancreatic lymph nodes was diagnosed and completely resected. Fourteen months later, abdominal computed tomography and scintigraphy with (111)In-labeled octreotide suggested relapse of the tumor. The patient again had no evidence of Cushing's syndrome. A second in toto tumor resection was performed. Another 8 months later, the patient developed forgetfulness, depressive episodes, muscle weakness, new-onset hypertension, hypokalemia, plethora, diabetes mellitus, polyuria, and weight loss. Endocrine testing suggested a source of ectopic ACTH production. An octreotide scan showed an intense uptake ventromedial of the left kidney, an area that showed a mass lateral of the superior mesenteric artery on abdominal magnetic resonance imaging. A complete pancreatectomy with splenectomy and left-sided adrenalectomy were performed. At this second relapse, this neuroendocrine tumor clinically had changed its hormonal profile. Immunohistochemically, in contrast to primary tumor and first relapse, we found strong immunostaining for ACTH in tumor cells of the second relapse and a MIB-1 index greater than 20%. To our knowledge, this is the first report describing a pancreatic neuroendocrine tumor that started to secrete ACTH de novo at the time of the second relapse after two former complete tumor resections. This case underscores the pluripotency of neuroendocrine tumor cells and the importance of keeping in mind a possible shift in hormone production during tumor evolution and progression.

Effects of portal vein arterialization on regeneration and morphology in liver transplantation: investigations using the rat model.

BACKGROUND: Portal vein arterialization (PVA) has been proposed as a technical variant in liver transplantation in the case of non-recanalizable thrombosis. The present study investigates the effects of the arterialized portal vein on the function, morphology, and regenerative behavior of the liver. METHODS: Different PVA techniques, including orthotopic liver transplantation, were used in a rat model. Portal blood flow was measured using a ultrasonic flowmeter. The regeneration capacity was determined on the basis of the increase of liver weight and the proliferating cell nuclear antigen index. The amount of hydroxyproline and the transcript levels of procollagen I were measured to determine the degree of fibrosis. The extracellular matrix was visualized with Picro-Sirius staining. RESULTS: The measurements obtained with an ultrasonic probe revealed a significant increase in portal blood flow after PVA. The regeneration capacity in the groups after PVA with no flow reduction was comparable to that of the control. Liver transplantation and PVA with no flow reduction was followed by a significant increase (four- to sixfold) in the amount of hydroxyproline and the level of the mRNA for procollagen I. In the Picro-Sirius staining, periportal and perivascular fibrosis with incipient formation of septa was seen. After reduction of the portal blood flow, these effects were significantly less pronounced. CONCLUSIONS: These operative techniques represent an excellent small animal model for studying the mechanism of liver regeneration and the genesis of fibrosis in liver and vessel tissue. The presenting findings indicate that the negative effects of "overarterialization" may be largely avoided by reducing portal blood flow. This implies that permanent PVA in clinical liver transplantation should be performed only in conjunction with a down-regulation of portal flow.

Percutaneous intragastric catheter (PIC) for administration of an unpalatable substance to large animals.

We studied an easy and reliable technique for administration of an unpalatable substance to large animals. There were three groups of pigs: group I (n = 6) received 1 g ethanol/kg body weight per day orally with water for 24 days, group II (n = 6) received 2 g ethanol/kg orally with water for 24 days and 4 g ethanol/kg via percutaneous intragastric catheter (PIC) for the next 24 days, group III (n = 6) received 6 g ethanol/kg via PIC for 72 days. The catheter was placed after insufflation of the stomach using an orogastric tube. PIC was successfully placed in each pig. No complications occurred during placement. The total amount of the administrated dose was assimilated each time. PIC is a safe, effective, well tolerated, and precise method of administering ethanol that is inexpensive and easy to perform. Ethanol administration via PIC is a convenient and effective mean of exposing animals to high levels of alcohol on a long-term basis.

Iatrogenic tracheobronchial ruptures - treatment and outcomes.

In the present paper we discuss the indication and follow-up of 42 patients with iatrogenic tracheobrochial ruptures. Thirty-five patients were treated by operation and 7 patients were treated conservatively. In the operated patients, four developed an insufficiency of the tracheal closure and the rupture related mortality was 2.8%. A significant effect on suture dehiscence was seen for mediastinitis (P<0.005) prior to operation, prior resection of the esophagus (P<0.001), and a long delay between injury and diagnosis (P=0.004). In the conservatively treated group the rupture related mortality was 29%. In conclusion to our results we suggest a surgical procedure whenever a tracheobronchial rupture is diagnosed and the patient's constitution allows the surgical procedure or anesthesia.

Does the inactivation of leukocytes in blood transfusions during and following liver transplantation by gamma-irradiation have an impact on rejection and infection rate?

BACKGROUND: Leukocytes transmitted in blood products exert a variety of immunological side-effects. Experience with bone marrow transplant recipients has shown that these can be induced even by very few cells. In liver transplant recipients, who usually receive large amounts of blood products, the effects of transfused leukocytes with regards to the rates of rejection and infection have not yet been investigated. MATERIAL/METHODS: Twenty liver transplant recipients were prospectively randomized to receive blood products (red blood cells, thrombocytes, fresh frozen plasma) through a leukocyte depletion filter, either irradiated with 40 Gy or not irradiated (10 patients, respectively). During the observation period of 90 days, the incidences of infections and rejections were analyzed. In addition, liver function tests, markers of infection (C reactive protein, lipopolysaccharide binding protein), and subpopulations of lymphocytes (total cell count, CD4/CD8 ratio, CD8CD45RO) were determined. RESULTS: Only one episode of mild rejection occurred (irradiated group). Rates of persistent graft dysfunction and severe infections were similar in both groups. The same applied to liver function tests, parameters of infection, and subpopulations of lymphocytes. CONCLUSIONS: These preliminary results suggest that irradiation of already leukocyte-depleted blood products may not be necessary and beneficial in liver transplant recipients.

Arterialisation of the portal vein as a model for the induction of hepatic fibrosis: description of microsurgical models in the rat.

Within the framework of liver transplantation, arterialisation of the portal vein in the case of non-recanalisable thrombosis has been reactivated. However, one of the consequences of this vascular reconstruction is the development of hepatic fibrosis. Clinical experience has shown that the development of fibrosis can be avoided by reducing portal inflow. We present, as a model for the induction of hepatic fibrosis, techniques of PVA, including transplantation. For PVA, several different techniques were used: the first with reduction of the portal inflow over a stent inserted in the right renal artery (PVA-B), the second with unrestricted flow using an aortic-portal segment (PVA-APS). The third technique was orthotopic liver transplantation with unrestricted portal arterialisation (OLTx-APS). Portal blood flow was measured with an ultrasonic flow probe. To determine the degree of hepatic fibrosis the amount of hydroxyproline was measured. Quantification of relative transcript levels of procollagen I was effected with real-time PCR using the TaqMan technology on a lightcycler instrument. The extracellular matrix was visualised with picro-sirius staining. Measurements with the ultrasonic probe showed a significant increase in flow rates, both with reduced (PVA-B) and unrestricted inflow (PVA-APS; OLTx-APS). The lowest survival rate (58%) was found in the group with unrestricted portal inflow. The reason for this was a high rate of thrombosis in the in the portal vascular tree (4 out of 12). In the OLTx-APS group four animals died within the first 3 postoperative days (69%), as a result of protracted postoperative shock. The overall survival rate was the highest (85%) in the group undergoing PVA with reduction of the portal inflow. PVA with unrestricted inflow was followed by a significant increase in extracellular collagen, which showed a clear correlation with the increase in the amount of hydroxyproline, the level of the mRNA for procollagen I and picro-sirius staining. With the operative PVA techniques presented herein, different arterial flow rates in the portal vein can be investigated. In our opinion these techniques represent an excellent animal model for studying the genesis of fibrosis and antifibrotic substances. By regulating the blood flow in the arterialised portal vein hepatic fibrosis can be reduced or even avoided. After a brief period of learning the microsurgical techniques, the surgeon can limit clamping times and achieve good results with these techniques.

Anti-CD20 monoclonal antibody treatment of Epstein-Barr virus-induced intrahepatic lymphoproliferative disorder following liver transplantation.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLDs) are a common cause of death in transplant patients. Their incidence following liver transplantation is reported to be between 0.5% and 4%. Despite various therapeutic approaches, there is still no consensus on a treatment strategy. The treatment of transplant recipients with monoclonal antibodies directed against B-cell antigens is a new, therapeutic approach with which, however, little clinical experience has so far been gained. Two patients developed intrahepatic PTLD 7 and 15 months, respectively, after transplantation. In one case, this was diagnosed as polymorphic PTLD, in the other as monomorphic, monoclonal PTLD. After having their immunosuppression terminated, 4 weeks after establishment of the diagnosis, both patients were treated with anti-CD20 antibodies (rituximab) at a dose of 375 mg/m(2) on days 1, 8, 15 and 22. Treatment with rituximab was tolerated well by both patients. One of the patients in whom cholestasis parameters remained high underwent re-transplantation. In one of the cases, the histological work-up confirmed necrosis of 90% of the tumour cells, and complete remission in the other. Both patients died of secondary complications 10 weeks and 10 months, respectively, after the diagnosis of PTLD. We can conclude that treatment of PTLD with Rituximab led to remission in both of our patients. Nevertheless, progression of cholestasis persisted, and both patients ultimately died of complications unrelated to PTLD.

Impact of changing immunosuppressive monotherapy from Cyclosporin A to Tacrolimus in long-term, stable liver transplant recipients.

A number of studies have reported a lower atherogenic lipid profile in liver transplant recipients under tacrolimus (FK506) than in those under cyclosporine A (CyA) immunosuppression. This has mainly been attributed to the steroid-saving effect of FK506. However, the effects of converting CyA to FK506 monotherapy on lipid metabolism have not been specifically investigated. In 20 patients with stable graft function, immunosuppressive monotherapy was switched from CyA to FK506 because of CyA-related side-effects (hypertension, nephrotoxicity, hypercholesterolaemia). Serum lipid levels were measured before and 3, 6 and 12 months after conversion. In 5 patients, a modification of immunosuppression became necessary during the study period (4 were reconverted to CyA, 1 to glucocorticoids). In the remaining 15 patients on FK506 monotherapy, 12 months after conversion, a slight decrease in mean serum cholesterol, a slight increase in LDL, but a significant decrease in mean serum HDL were observed, resulting in a significant increase in Chol/HDL and LDL/HDL ratios. Conversion of immunosuppressive monotherapy from CyA to FK506 had no beneficial effect on the atherogenic lipid profile in this selected study population of long-term liver transplant survivors.

Prognosis of a large cohort of patients with hepatocellular carcinoma in a single European centre.

BACKGROUND/AIM: Only a few follow up data are available for patients with hepatocellular carcinoma (HCC) in Europe and the USA. Therefore, we analysed all HCC patients admitted to our hospital between 1988 and 1999. METHODS: We documented aetiology, stage (HCC: Okuda and UICC classifications, liver cirrhosis: Child-Pugh score), and diagnostic and therapeutic measures of 281 consecutive HCC patients. Survival time was calculated as a function of staging and therapy. RESULTS: Cirrhosis was diagnosed in all patients. Seventy-two patients underwent liver resection, 28 liver transplantation, 31 transarterial chemoembolization and 14 percutaneous ethanol injection. One hundred and thirty-six patients received no treatment. The Okuda and the Child-Pugh classification predicted a significant decrease of median survival time, whereas the UICC classification was less powerful. CONCLUSIONS: HCC occurred only in patients with liver cirrhosis. Survival time correlated with therapy (or no therapy) and with the Child-Pugh Score. In European patients the Okuda classification is superior to the UICC classification and should be compared to novel classification systems.

Portal vein arterialisation as a technical option in liver transplantation: impact on function, regeneration, and morphology of the liver following hemihepatectomy in pigs.

BACKGROUND: Arterialisation of the portal vein has been propagated as a technical variant in liver transplantation. However, the consequences of this unphysiological vascular supply are insufficiently known. METHODS: Twenty-seven healthy pigs were subjected to a left hemihepatectomy and divided into three groups. The first group received complete arterialisation of the portal vein (PVA). In the second group hepatic artery blood flow was also interrupted by dividing the artery (PVA/DHA). Nine animals served as controls (Group C). RESULTS: Early mortality in the PVA/DHA group (6/9) was significantly increased in comparison with the PVA (2/9) and control (2/9) groups (P < 0.05). In the surviving animals, arterialisation (PVA and PVA/DHA) led to significantly faster hepatic regeneration in comparison with control animals, with comparable liver function and with liver size increasing to 278% and 293% vs 134% (P = 0.002) after 3 weeks, in liver ... weeks. This was accompanied by enhanced hepatic expression of the proliferation markers MIB-1 (22.4% and 16.7% vs 5.9%, P = 0.002) and PCNA (86% and 68% vs 66%, P = 0.002) one week postoperation. At the same time, the number of apoptotic hepatocytes increased from 1.6% to 2.5% and 2.3% (P = 0.002). No significant difference was found in the collagen content of the liver after 3 weeks. CONCLUSIONS: Arterialisation of the portal vein promotes early and enhanced hepatic regeneration without impairing liver function. This technique may therefore be useful in split-graft liver transplantation, where this aspect would be of particular importance.

Outcome of patients with pre-existing portal vein thrombosis undergoing arterialization of the portal vein during liver transplantation.

Arterialization of the portal vein is being propagated as a technical possibility in liver transplant recipients with pre-existing portal vein thrombosis. In our own small series, portal vein arterialization (PVA) was carried out in four patients undergoing orthotopic liver transplantation. In three of these cases, the portal vein was anastomosed to the aorta via an interposed iliac artery, and in one case, directly to the hepatic artery. After PVA, all transplants showed regular initial function. Two patients died postoperatively after 19 and 50 days, of intra-abdominal haemorrhage and liver necrosis with thrombosis of the portal vein, respectively. A further patient had previously developed fibrosis of the liver, which led to the death of the patient 11 months after PVA. In the remaining patient, chronic rejection requiring re-transplantation developed 24 months after PVA had been performed. These unfavourable results prompt the conclusion that PVA cannot be recommended as a standard clinical procedure.