Unlocking the enigma: Combined percutaneous-transhepatic and endoscopic strategies for retrieval of severed Dormia basket in choledocholithiasis. A case report and literature review.

Choledocholithiasis, characterized by the presence of stones in the common bile duct, poses significant challenges in clinical management, particularly when the stones are massive. While endoscopic methods are often effective in stone removal, complications such as the impaction of foreign bodies like Dormia baskets can occur. These complications may necessitate alternative approaches, including surgical intervention, highlighting the importance of exploring innovative interventional techniques. We report on an 89-year-old patient presenting with massive choledocholithiasis, involving complete filling of the intra- and extrahepatic bile duct system with large stones up to a maximum of 2 cm. The patient underwent interventional removal of a Dormia basket (3.5Fr. Boston Scientific, USA) impacted in the common bile duct. This procedure proved challenging due to the metallic end marker of the basket perforating through the wall of the distal common bile duct, rendering it fixed. Given the complexity of the case, a parallel approach combining percutaneous transhepatic cholangiography and drainage with simultaneous endoscopy was employed to successfully extract the fixed Dormia basket. In cases of severe choledocholithiasis complicated by the impaction of foreign bodies such as Dormia baskets, innovative interventional strategies are crucial for successful management. Our case highlights the effectiveness of a parallel approach involving percutaneous transhepatic cholangiography and drainage alongside simultaneous endoscopy in safely removing the fixed foreign body from the common bile duct. This multidisciplinary approach not only offers a viable alternative to surgical intervention but also underscores the importance of collaboration between interventional radiologists and endoscopists in optimizing patient outcomes in complex biliary interventions.

Pancreaticobiliary Diseases with Severe Complications as a Rare Indication for Emergency Pancreaticoduodenectomy: A Single-Center Experience and Review of the Literature.

The pancreaticobiliary system is a complex and vulnerable anatomic region. Small changes can lead to severe complications. Pancreaticobiliary disorders leading to severe complications include malignancies, pancreatitis, duodenal ulcer, duodenal diverticula, vascular malformations, and iatrogenic or traumatic injuries. Different therapeutic strategies, such as conservative, interventional (e.g., embolization, stent graft applications, or biliary interventions), or surgical therapy, are available in early disease stages. Therapeutic options in patients with severe complications such as duodenal perforation, acute bleeding, or sepsis are limited. If less invasive procedures are exhausted, an emergency pancreaticoduodenectomy (EPD) can be the only option left. The aim of this study was to analyze a single-center experience of EPD performed for benign non-trauma indications and to review the literature concerning EPD. Between January 2015 and January 2022, 11 patients received EPD due to benign non-trauma indications at our institution. Data were analyzed regarding sex, age, indication, operative parameters, length of hospital stay, postoperative morbidity, and mortality. Furthermore, we performed a literature survey using the PubMed database and reviewed reported cases of EPD. Eleven EPD cases due to benign non-trauma indications were analyzed. Indications included peptic duodenal ulcer with penetration into the hepatopancreatic duct and the pancreas, duodenal ulcer with acute uncontrollable bleeding, and penetration into the pancreas, and a massive perforated duodenal diverticulum with peritonitis and sepsis. The mean operative time was 369 min, and the median length of hospital stay was 35.8 days. Postoperative complications occurred in 4 out of 11 patients (36.4%). Total 90-day postoperative mortality was 9.1% (1 patient). We reviewed 17 studies and 22 case reports revealing 269 cases of EPD. Only 20 cases of EPD performed for benign non-trauma indications are reported in the literature. EPD performed for benign non-trauma indications remains a rare event, with only 31 reported cases. The data analysis of all available cases from the literature revealed an increased postoperative mortality rate of 25.8%. If less invasive approaches are exhausted, EPD is still a life-saving procedure with acceptable results. Performed by surgeons with a high level of experience in hepatobiliary and pancreatic surgery, mortality rates below 10% can be achieved.

Successful heparin-perfusion therapy for complete thrombosis of the intra- and extrahepatic portal and mesenteric vein. A case report and literature review.

The initial treatment of acute and subacute portal vein thrombosis, which is the most common cause of portal vein occlusion, consists of intravenous anticoagulation with heparin, but there is still a huge uncertainty among physicians regarding the role of more invasive therapies. We report a 61-year-old male patient, who presented in our emergency room with a subacute complete thrombosis of the intra- and extrahepatic portal vein, mesenteric vein, with associated venous congestion of 20-30 cm length of the small intestine with a quick and complete remission of the portal vein thrombosis under sole i.v. heparin-perfusor therapy without any complications. Molecular genetic analysis found combined genetic mutations of the gene factor 2 (c.20210G>A, heterozygotic), SERPINE1 (-675 5G>4G, heterozygotic), and the MTHFR gene. Along with this interesting case, we also present the recent status of portal vein thrombosis and portal vein occlusion in the literature.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

BACKGROUND: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). METHODS: In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. RESULTS: Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). CONCLUSIONS: Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Quality of life in peritoneal carcinomatosis: a prospective study in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND/AIMS: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (HIPEC) can improve survival in selected patients with peritoneal carcinomatosis, but bear a significant risk of perioperative morbidity. The aim of this study was to prospectively evaluate the quality of life (QoL) following cytoreduction and HIPEC. METHODS: In this study including 40 patients (65% females) with different primary tumors, the EORTC QLQ-C30 questionnaire was applied prior to CS and HIPEC as well as 3, 9, and 18 months postoperatively. RESULTS: Global health status was not impaired significantly following HIPEC. Scales and symptom scores that deteriorated 3 months postoperatively (p < 0.05), that is, physical, role, and social functions as well as fatigue, pain, dyspnea, insomnia, and diarrhea, all returned to preoperative values within 9 months. CONCLUSIONS: Following cytoreductive surgery and HIPEC, QoL returns to preoperative levels within 9 months. Selected patients that are likely to benefit oncologically from HIPEC should not be denied this option for fear of reduced postoperative QoL.

Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients.

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long-term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long-term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow-up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post-transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus-based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus-based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.

Surgery for metastasis to the pancreas: is it safe and effective?

BACKGROUND: Pancreatic metastases are rare and only sparse data exists on treatment options. After recent advances in pancreatic surgery, metastasectomies have become promising treatment alternatives. METHODS: Twenty-six patients underwent pancreatic metastasectomy between 1991 and 2010 at our institution. Data was evaluated retrospectively. RESULTS: Renal cell carcinoma was the most common origin of pancreatic metastases (n = 16; 62%). Other primaries include gall bladder carcinoma, leiomyosarcoma, colon cancer (all n = 2), and others. The median time interval between primary tumor and pancreatic resection was 5.3 years [0-24]. Eleven pancreatic head resections (42%), fourteen distal pancreatectomies (54%), and one total pancreatectomy were performed (4%). The estimated 3- and 5-year survival rates were 73.2% and 52.3%, respectively. The estimated median overall survival was 63 months (CI: 37.8-88.1 months). There' was no perioperative death. The complication rate and relaparotomy rate was 31% and 19%, respectively. Patients suffering from synchronous metastases at the time of pancreatic surgery had a statistically significant shorter median overall survival time (11 months vs. 64 months). CONCLUSIONS: Despite the operative risk involved, we believe that pancreatic resection should be considered in selected patients with good performance status, stable disease and isolated pancreatic metastases.

ß-Catenin mutations in 2 nested stromal epithelial tumors of the liver--a neoplasia with defective mesenchymal-epithelial transition.

Nested stromal epithelial tumor of the liver is a rare neoplasm of early childhood and adolescence with a characteristic nested morphology of spindle and epithelioid cells. Histogenesis and pathogenesis of this neoplasm are, however, still unclear. Because the characteristic nested morphology with spindle mesenchymal and epithelioid cells is suggestive of altered mesenchymal-epithelial transition and ß-catenin mutations are rather common in other liver tumors such as hepatoblastomas, we investigated the ß-catenin gene in 2 nested stromal epithelial tumors of the liver and analyzed additional factors involved in mesenchymal-epithelial transition, such as E-cadherin, vimentin, c-Met, TWIST, SNAIL, and SLUG by molecular genetic and immunohistochemical methods. Mutation analysis of both cases revealed large deletions in exon 3 of the ß-catenin gene (155 and 228 base pairs), resulting in an accumulation of ß-catenin in the cytoplasm and nuclei of tumor cells, as evidenced by immunohistochemistry. The expression of the mesenchymal-epithelial transition factors SNAIL, SLUG, TWIST, c-Met, vimentin, and ß-catenin was generally increased, whereas E-cadherin was decreased. Morphological and immunohistochemical analysis, however, showed a variable expression pattern of various epithelial and mesenchymal markers both in the spindle and epithelioid cell compartments of the tumors, thus illustrating the transitional status of the tumor cells. In conclusion, our data clearly identify protein stabilizing mutations of the ß-catenin gene as a common feature of nested stromal epithelial tumors of the liver, similarly as in hepatoblastomas. Therefore, nested stromal epithelial tumors of the liver may be regarded as a variant of hepatoblastoma, despite differing from it in clinical and morphological aspects. The characteristic epithelioid-spindle morphology along with the incomplete epithelial differentiation proposes impaired mesenchymal-epithelial transition as a possible pathogenetic mechanism of this rare tumor. However, because only 2 cases were studied, this hypothesis awaits further validation.

Acute liver failure, rupture and hemorrhagic shock as primary manifestation of advanced metastatic disease.

BACKGROUND: Malignancies rarely cause of acute liver failure, the presence of which have to be ruled-out during transplant evaluation. Tumor-related liver ruptures sporadically occur and might further complicate patient management. CASE REPORT: We report the case of a previously healthy 56-year-old male with complaints of abdominal pain. Initially, levels of liver enzymes were elevated, however, comprehensive imaging examinations revealed no gross abnormalities. As acute liver failure developed, transplantation was evaluated. Sudden liver rupture and hemorrhage forced the performance of an emergency laparotomy. Hepatectomy was planned, until a donor organ was allocated. Intraoperatively, the liver unexpectedly revealed diffuse tumor infiltration. Without further therapeutical options, the patient died. Immunohistochemistry showed metastatic infiltration of a carcinoma of unknown primary. CONCLUSION: Even in previously healthy patients suffering from acute liver failure, exclusion of malignancies is mandatory before transplantation. As imaging might be misleading, a biopsy should be considered early in unresolved cases.

Arterial blood flow predicts graft survival in liver transplant patients.

Proper liver perfusion is essential for sufficient organ function after liver transplantation. The aim of this study was to determine the effects of portal and arterial blood flow on liver function and organ survival after liver transplantation. The arterial and portal venous blood flow was measured intraoperatively by transit time flow measurement after reperfusion for 290 consecutive liver transplants. The graft survival, hepatic cell damage (alanine aminotransferase and aspartate aminotransferase), and liver function (prothrombin ratio and bilirubin) were determined. Grafts were stratified into groups according to arterial blood flow measurements [<100 mL/minute for arterial blood flow group I (ART I), 100-240 mL/minute for ART II, and ≥ 240 mL/minute for ART III] and portal venous blood flow measurements (<1300 mL/minute for portal venous blood flow group I and ≥ 1300 mL/minute for portal venous blood flow group II). With multivariate analysis, the impact of blood flow on graft survival was determined, and potential confounders were considered. Decreased portal venous blood flow was associated with significantly less organ survival in univariate analysis but not in multivariate analysis. In contrast, the arterial blood flow was significantly correlated with organ survival after liver transplantation in univariate and multivariate analyses [hazard rate ratio = 2.5, confidence interval = 1.6-4.1, P < 0.001, median survival = 56.6 (ART I), 82.7 (ART II), or 100.7 months (ART III)]. Moreover, low arterial blood flow resulted in impaired postoperative organ function and higher rates of primary nonfunction. Biliary complications were not affected by blood flow. Other risk factors for graft failure that were identified by multivariate analysis included retransplantation, histidine tryptophan ketoglutarate solution versus University of Wisconsin solution, and donor treatment with epinephrine. Impaired arterial blood flow after reperfusion represents a significant predictor of primary graft nonfunction and is associated with impaired graft survival. Whether the intraoperative measurement of hepatic arterial flow is predictive of graft survival should be evaluated in a prospective trial.

Late reuse of liver allografts from brain-dead graft recipients: the Munich experience and a review of the literature.

The increasing donor organ shortage requires the consideration of any possible organ donor in order to meet the current demand. However, the growing number of long-term survivors of liver transplantation may create a situation in which former organ recipients may experience brain death with a functioning graft and therefore become organ donors themselves. Previous reports concerning this rare situation predominantly refer to the reuse of donor organs within the first 8 days after primary liver transplantation. So far, only a single case of late reuse of a donor liver has been published, with 2 additional cases mentioned in a summary of the United Network for Organ Sharing database. Here we report the case of a 43-year-old female donor who had received a liver graft for complications of Budd-Chiari syndrome 5 years before becoming an organ donor herself after cerebral infarction with consecutive brain death.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.

BACKGROUND: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. METHODS/DESIGN: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. DISCUSSION: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. TRIAL REGISTER: Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).

Atrial resection for lung cancer: morbidity, mortality, and long-term follow-up.

BACKGROUND: The purpose of this study was to examine our results of combined resection of the atrium and non-small-cell lung cancer using a concurrent and continuously updated database. METHODS: A total of 35 patients underwent extended pulmonary resection with partial resection of the atrium. The main focus of the study was to define subgroups of patients who can potentially benefit from surgery. RESULTS: Pneumonectomy was performed in 31 cases, and the other 4 patients underwent a lesser resection. Postoperative morbidity was 20%, and the mortality rate was 9%. The median intensive care unit stay was 2 days and the hospital stay 13 days. The survival rates were 80% at 1 year, 21% at 3 years, and 16% at 5 years. The median survival of patients with low-grade tumors (G1/2) was 27 months, contrasted by only 15 months' survival for patients with high-grade tumors (P = 0.026). Multivariate analysis indicated that completeness of resection had a significant impact on survival (P = 0.042). CONCLUSIONS: Combined resection of lung and atrium is a complex surgical procedure, but it can be performed with fair morbidity and mortality rates, even in patients with an increased number of preoperative risk factors. Patients suffering from low-grade tumors benefit significantly from radical surgery. Future studies must define whether a multimodal therapeutic approach that includes induction therapy can prolong patient survival.

Esophageal leiomyomatosis combined with intrathoracic stomach and gastric volvulus.

CASE REPORT: A 42-year-old female presented with long-standing symptoms suggestive of gastroesophageal reflux disease improved after proton pump inhibitor treatment. An upper endoscopy revealed an intrathoracic position of the stomach (type 4 hiatal hernia) with no mucosal abnormality. Barium swallow demonstrated gastric herniation with gastric volvulus without stenosis. A computed tomographic scan confirmed the intrathoracic location of the stomach associated with thickening and edema of the gastric wall due to gastric volvulus, but no evidence of malignancy. The patient was scheduled for laparoscopic gastric repositioning with anterior hemifundoplication. Due to the incidental intraoperative finding of a large distal esophageal tumor (frozen section: esophageal leiomyomatosis), the operation was converted to conventional distal esophagectomy and proximal gastrectomy with reconstruction using a Merendino procedure. Final histology revealed extensive circumferential leiomyomatosis of the distal esophagus with a diameter of 10 cm. Esophageal leiomyomatosis is an extremely rare pathological finding with <100 cases reported in the literature. CONCLUSION: Any surgeon performing laparoscopic fundoplication has to be ready to deal with such unexpected findings, ie, converting the procedure and doing reconstruction with minimal morbidity. The Merendino procedure is a well-established reconstructive surgical option in cases of tumor formation at the gastroesophageal region with fewer postoperative morbidities like reflux symptoms.

Effect of graft steatosis on liver function and organ survival after liver transplantation.

BACKGROUND: It was the aim to determine the effect of graft steatosis on intraoperative organ blood flow, postoperative liver function, and organ survival. METHODS: A total of 225 consecutive liver transplants were reviewed. Liver blood flow, hepatic function (AST, ALT, prothrombin time), and organ survival were determined. Donor liver grafts were categorized into 2 subgroups: mild (<30%) (n = 175) and moderate to severe (>/=30%) (n = 50) macrovesicular steatosis. RESULTS: Moderate to severe steatosis was associated with significantly increased AST and ALT levels and significantly diminished prothrombin time on the first and second postoperative day. By day 7 differences in liver function were no longer evident. Organ blood flow was not affected by steatosis. After adjustment for potential confounders, organ survival did not depend on the degree of donor steatosis (5-year-survival rates: 68% and 58% with steatosis <30%, or >/= 30%, respectively) (hazard ratio .754, confidence interval .458-1.242, P = .268). CONCLUSION: Steatotic livers can be transplanted safely with good results for long-term organ survival if other contraindications are absent.

Multifocal manifestation does not affect vascular invasion of hepatocellular carcinoma: implications for patient selection in liver transplantation.

BACKGROUND AND AIMS: Liver transplantation (OLT) for hepatocellular carcinoma (HCC) improves patient survival when tumor size and number are limited according to the Milan criteria. However, the impact of tumor size vs. the number of lesions for tumor recurrence after OLT is unclear. Microvascular invasion appears to be a significant risk factor for tumor recurrence. Therefore, it was the aim of this study to investigate tumor differentiation and microvascular invasion in relation to tumor number and size and their impact on survival after transplantation. PATIENTS AND METHODS: In 97 adult HCC patients who underwent OLT between June 1985 and December 2005 the incidence of microvascular invasion, tumor differentiation, and the number and size of tumor lesions were analyzed retrospectively. Their impact on survival was studied by multivariate analysis. RESULTS: Microvascular invasion was the only independent negative predictor of survival after OLT for HCC (p = 0.025). Tumor size > 5 cm was predictive for microvascular invasion (p = 0.007). In contrast, tumor number did not affect the incidence of microvascular invasion or cumulative survival. CONCLUSION: The size of the largest HCC lesion, but not the number of tumors, determined microvascular invasion, a predictor of the outcome following OLT for HCC. Thus, the number of HCC lesions should not be applied to patient selection prior to OLT. These data support the extension of the Milan criteria for the selection of HCC patients for OLT with regard to tumor number, but not tumor size.

Liver resection or combined chemoembolization and radiofrequency ablation improve survival in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: To evaluate the long-term outcome of surgical and non-surgical local treatments of patients with hepatocellular carcinoma (HCC). METHODS: We stratified a cohort of 278 HCC patients using six independent predictors of survival according to the Vienna survival model for HCC (VISUM-HCC). RESULTS: Prior to therapy, 224 HCC patients presented with VISUM stage 1 (median survival 18 months) while 29 patients were classified as VISUM stage 2 (median survival 4 months) and 25 patients as VISUM stage 3 (median survival 3 months). A highly significant (p < 0.001) improved survival time was observed in VISUM stage 1 patients treated with liver resection (n = 52; median survival 37 months) or chemoembolization (TACE) and subsequent radiofrequency ablation (RFA) (n = 44; median survival 45 months) as compared to patients receiving chemoembolization alone (n = 107; median survival 13 months) or patients treated by tamoxifen only (n = 21; median survival 6 months). Chemoembolization alone significantly (p < or = 0.004) improved survival time in VISUM stage 1-2 patients but not (p = 0.341) in VISUM stage 3 patients in comparison to those treated by tamoxifen. CONCLUSION: Both liver resection or combined chemoembolization and RFA improve markedly the survival of patients with HCC.

The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1-phosphate receptor 1.

FTY720, a sphingosine 1-phosphate (S1P) analog, acts as an immunosuppressant through trapping of T cells in secondary lymphoid tissues. FTY720 was also shown to prevent tumor growth and to inhibit vascular permeability. The MTT proliferation assay illustrated that endothelial cells are more susceptible to the anti-proliferative effect of FTY720 than Lewis lung carcinoma (LLC1) cells. In a spheroid angiogenesis model, FTY720 potently inhibited the sprouting activity of VEGF-A-stimulated endothelial cells even at concentrations that apparently had no anti-proliferative effect. Mechanistically, the anti-angiogenic effect of the general S1P receptor agonist FTY720 was mimicked by the specific S1P1 receptor agonist SEW2871. Moreover, the anti-angiogenic effect of FTY720 was abrogated in the presence of CXCR4-neutralizing antibodies. This indicates that the effect was at least in part mediated by the S1P1 receptor and involved transactivation of the CXCR4 chemokine receptor. Additionally, we could illustrate in a coculture spheroid model, employing endothelial and smooth muscle cells (SMCs), that the latter confer a strong protective effect regarding the action of FTY720 upon the endothelial cells. In a subcutaneous LLC1 tumor model, the anti-angiogenic capacity translated into a reduced tumor size in syngeneic C57BL/6 mice. Consistently, in the Matrigel plug in vivo assay, 10 mg/kg/d FTY720 resulted in a strong inhibition of angiogenesis as demonstrated by a reduced capillary density. Thus, in organ transplant patients, FTY720 may prove efficacious in preventing graft rejection as well as tumor development.

Biochemical monitoring of mTOR inhibitor-based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy.

BACKGROUND: Immunosuppressive therapy with the mammalian target of rapamycin (mTOR) inhibitors requires a fine balance between allograft maintenance and drug-related side effects. METHODS: In this study we examined the feasibility of monitoring TOR inhibitor-based immunosuppression by assessment of the phosphorylation status at the Thr(389) site of the p70S6 kinase in peripheral blood mononuclear cells (PBMCs). At total of 36 patients with renal transplants and 8 healthy controls were enrolled. RESULTS: We found that sirolimus treatment was associated with a pronounced inhibition of p70S6 kinase phosphorylation, as compared to healthy donors or otherwise immunosuppressed patients. In sirolimus-treated patients, phosphorylation of the p70S6 kinase was significantly inhibited when sirolimus trough levels were > 6 ng/mL. In contrast, for trough levels <6 ng/mL, the degree of inhibition of p70S6 kinase phosphorylation showed a high degree of interindividual variability. We recorded a total of five clinical relevant rejection episodes in this patient category. Intriguingly, rejecters uniformly maintained a high degree of phosphorylation independent of the sirolimus trough level whereas non-rejecters showed a significant inhibition of phosphorylation. CONCLUSION: Therefore, the phosphorylation status of the p70S6 kinase appears to provide more relevant information on the desired effect of sirolimus in target cells as compared to trough level measurements. Moreover, this assay provides an opportunity to safely titer down sirolimus levels to avoid overimmunosuppression and, on the other hand, to identify patients with insufficient TOR inhibitor therapy that are at risk for rejection.

mTOR inhibition and its effect on cancer in transplantation.

A considerable amount of data indicates that transplanted patients are at increased risk for de novo and recurrent cancer. Treatment of this population is difficult. It remains unclear if the immunosuppressive therapy should be continued, tapered or even stopped or if immunosuppressive drugs with antiproliferative properties have beneficial effects in this situation. In various models, mTOR-inhibitors were shown to have immunosuppressive and anti-tumor effects. Here, we have reviewed the current literature trying to clarify if mTOR-inhibition brings advantages for the transplanted patients suffering from tumors.