Neoadjuvant Down-Sizing of Hilar Cholangiocarcinoma with Photodynamic Therapy--Long-Term Outcome of a Phase II Pilot Study.

Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after complete resection (R0) recurrence can be as high as 70%. Photodynamic therapy (PDT) is an established palliative local tumor ablative treatment for non-resectable hilar CC. We report the long-term outcome of curative resection (R0) performed after neoadjuvant PDT for downsizing of tumor margins in seven patients (median age 59 years) with initially non-resectable hilar CC. Photofrin(®) was injected intravenously 24-48 h before laser light irradiation of the tumor stenoses and the adjacent bile duct segments. Major resective surgery was done with curative intention six weeks after PDT. All seven patients had been curatively (R0) resected and there were no undue early or late complications for the neoadjuvant PDT and surgery. Six of seven patients died from tumor recurrence at a median of 3.2 years after resection, the five-year survival rate was 43%. These results are comparable with published data for patients resected R0 without pre-treatment, indicating that neoadjuvant PDT is feasible and could improve overall survival of patients considered non-curatively resectable because of initial tumor extension in bile duct branches/segments--however, this concept needs to be validated in a larger trial.

Identifying tumor patients' depression.

PURPOSE: The aim of this study was to compare the precision of two different methods in detecting clinical depression in tumor patients: the use of a screening questionnaire versus the assessment by health care providers (nurses and doctors). METHODS: During their first days of inpatient cancer treatment, tumor patients were interviewed using the Structured Clinical Interview for DSM (SCID). Their physicians and nurses were asked to assess the mental health of the patients and their need for professional psychosocial support. Additionally, every patient completed the Hospital Anxiety and Depression Scale (HADS). RESULTS: Out of 329 patients, 28 were diagnosed with either a major or a minor depression according to the SCID. Physicians assessed 15 of the depressed patients as being depressed (sensitivity, 0.54; specificity, 0.38). Nurses identified 19 (sensitivity, 0.68; specificity, 0.45) and the HADS 27 (sensitivity, 0.96; specificity, 0.50) of the depressed patients. CONCLUSION: The HADS performed well in detecting depressed cancer patients in acute oncological care, whereas physicians and nurses often were unable to recognize depressed patients.

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).

Impact of daclizumab, low-dose cyclosporine, mycophenolate mofetil and steroids on renal function after kidney transplantation.

BACKGROUND: Early and long-term use of cyclosporine A (CsA) leads to increased risks of renal toxicity. We hypothesized that administration of daclizumab in combination with mycophenolate mofetil (MMF) allows a relevant reduction in the dose of CsA. METHODS: We carried out a 3-year, prospective, randomized, controlled clinical multi-centre trial in 156 patients. The patients were randomized to standard treatment (CsA, MMF, steroids) or to high-dose daclizumab (first dose: 2 mg/kg), in combination with low-dose CsA, MMF and steroids. We maintained the mean CsA levels of daclizumab patients at 57% of standard patients (132 versus 216 ng/ml) on Day 7 post-transplant, and 84% by 6 months. RESULTS: Primary outcome, creatinine clearance (with imputation of informative dropouts) at 12 months, was significantly better in daclizumab-treated (34 +/- 17) than standard patients (29 +/- 17; P = 0.028, two sided). Only 5 cases of BPAR were recorded in the daclizumab compared to 22 in the standard group (P = 0.0016). Daclizumab patients had 91% event-free survival after 1 year compared to 66% in standard patients (P = 0.00017). CONCLUSION: We demonstrate here that high-dose daclizumab in combination with lower CsA levels in adult renal transplant recipients is as or more effective than standard regimen (CsA, MMF, steroids) and may result in better outcomes at 12 months post-transplant with no increase in adverse reactions.

Serum peptidome profiling revealed platelet factor 4 as a potential discriminating Peptide associated with pancreatic cancer.

PURPOSE: Mass spectrometry-based serum peptidome profiling is a promising tool to identify novel disease-associated biomarkers, but is limited by preanalytic factors and the intricacies of complex data processing. Therefore, we investigated whether standardized sample protocols and new bioinformatic tools combined with external data validation improve the validity of peptidome profiling for the discovery of pancreatic cancer-associated serum markers. EXPERIMENTAL DESIGN: For the discovery study, two sets of sera from patients with pancreatic cancer (n = 40) and healthy controls (n = 40) were obtained from two different clinical centers. For external data validation, we collected an independent set of samples from patients (n = 20) and healthy controls (n = 20). Magnetic beads with different surface functionalities were used for peptidome fractionation followed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). Data evaluation was carried out by comparing two different bioinformatic strategies. Following proteome database search, the matching candidate peptide was verified by MALDI-TOF MS after specific antibody-based immunoaffinity chromatography and independently confirmed by an ELISA assay. RESULTS: Two significant peaks (m/z 3884; 5959) achieved a sensitivity of 86.3% and a specificity of 97.6% for the discrimination of patients and healthy controls in the external validation set. Adding peak m/z 3884 to conventional clinical tumor markers (CA 19-9 and CEA) improved sensitivity and specificity, as shown by receiver operator characteristics curve analysis (AUROC(combined) = 1.00). Mass spectrometry-based m/z 3884 peak identification and following immunologic quantitation revealed platelet factor 4 as the corresponding peptide. CONCLUSIONS: MALDI-TOF MS-based serum peptidome profiling allowed the discovery and validation of platelet factor 4 as a new discriminating marker in pancreatic cancer.

A new anchor electrode design for continuous neuromonitoring of the recurrent laryngeal nerve by vagal nerve stimulations.

PURPOSE: Intraoperative neuromonitoring has the limitation that the recurrent laryngeal nerve (RLN) is still at risk for damage between two stimulations with a handheld bipolar stimulation electrode. The purpose of this study was to establish the vagal anchor electrode for real-time monitoring of the RLN in surgical routine and to be alerted to imminent nerve failure by electromyography (EMG) signal analysis whereby the nerve damage becomes reversible. PATIENTS AND METHODS: This fully implantable electrode has been used in addition to a conventional handheld bipolar stimulation electrode during thyroid surgery on 45 consecutive patients (78 nerves at risk) stratified to low- and high-risk groups. The signal analysis was performed as real-time audio/video feedback by the use of a new multichannel EMG system. RESULTS: No complications were attributable to the use of the anchor electrode. The mean delay to place the anchor electrode was 1.45 min, whereas the mean stimulation time of the vagus nerve was 38 min. Stable and repeatable signals were evocable in all cases with one exception. No permanent RLN paralyses occurred in this study. CONCLUSIONS: The vagal anchor electrode is safe and easy to use. It allows continuous neuromonitoring without any threats. The new technique will provide more security, especially during preparation steps on the RLN that are difficult for the surgeon.

A single-center experience with liver transplantation for Wilson's disease.

Wilson's disease is an inherited disorder of copper metabolism, presenting with prominent hepatic and neurologic manifestations. There is an established place for liver transplantation in the presence of liver disease, while the indication for neurologic manifestations is debated. Between 1993 and 2005, 11 patients were liver transplanted for Wilson's disease at our institution. We retrospectively reviewed the medical records of the patients. The pathology of the explanted livers was analyzed. The patients were divided into three groups based on the evolution of the disease. Postoperative data gathered included patient and graft outcome, complications, neurologic status, and copper metabolism. Six males and five females were transplanted at a mean age of 29.7 yr (range 15-48 yr). Three patients had a fulminant presentation, two patients had decompensation of established disease, and six patients had chronic disease. Neurologic features were prominent in five patients. The pathologic analysis of the explanted graft showed cirrhosis in all patients. The five patients with fulminant and acute on chronic presentations also showed necrosis in the explant. The mean postoperative follow-up was 56.8 months (range 10-129 months). Two patients were re-transplanted. One patient died because of severe sepsis. Two patients with severe neurologic dysfunction showed significant remission of symptoms. Liver transplantation is a safe and effective treatment for both acute and chronic presentations of Wilson's disease. Acute presentation correlates with the presence of necrosis in the explanted liver. In our series, there was a relevant improvement of the neurologic features after transplantation.

Prognostic value of eicosanoid pathways in extrahepatic cholangiocarcinoma.

BACKGROUND: Chronic inflammation of the bile duct is linked to an increased risk for the development of cholangiocarcinoma. Arachidonic acid and linoleic acid oxidation through cyclooxygenase and lipoxygenase--two major pro-inflammatory pathways--have rarely been investigated in extrahepatic cholangiocarcinoma. MATERIALS AND METHODS: Paraffin-embedded specimens from 51 resected adenocarcinomas of the extrahepatic bile duct were immunostained for cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) to evaluate their intracellular distribution and prognostic value. RESULTS: Cholangiocarcinoma had significantly higher levels of 5-LOX and COX-2 expression compared with normal tissue (p = 0.015). High expression of nucleus-located 5-LOX was significantly associated with intensive staining for COX-2, (p = 0.023). Median disease-free survival (DFS) in patients with low expression of 5-LOX was significantly better than in patients with high expression of 5-LOX (log rank p = 0.046). DFS in patients with low COX-2 expression was also significantly better than DFS in patients with high COX-2 expression (log rank p = 0.0187). CONCLUSION: The present study demonstrates that 5-LOX and COX-2 protein expression was increased in cholangiocarcinoma suggesting that these two enzymes might be of prognostic value and offer a potential additional adjuvant therapeutic approach to this disease.

Unchanged high mortality rates from acute occlusive intestinal ischemia: six year review.

OBJECTIVE: Acute intestinal ischemia (AII) is an uncommon surgical emergency that has been increasing in incidence and remains a highly lethal condition with a difficult diagnosis. We undertook this study to evaluate our experience in treating this condition with a view to expand the cumulative information in the literature. MATERIALS AND METHODS: Between January 2000 and December 2006, 60 patients with AII caused by thrombotic vascular event underwent surgery at our surgical center. The patients' medical records including data covering demographic features, comorbid medical conditions, medical risk factors, clinical symptoms, history and physical examination findings, and biochemical and radiologic examinations were reviewed. Operative records, the American Society of Anesthesiology physical status classification (ASA-PS), postoperative complications, duration of hospital stay, and final outcome were also considered. RESULTS: Of the 60 patients with primary thrombotic vascular event, 20 patients had embolism and 19 patients arterial thrombosis. In 21 patients, mesenteric venous thrombosis was the etiology of AII. The median age was 73 years (range, 43-96). Higher ASA classification, age >70 years, late presentation, and high serum lactate levels were predictors of adverse outcome. The overall death rate was 60% (36/60), which was within the range of that observed in the published series. CONCLUSION: AII remains a highly lethal condition. Mortality rates remain as high as they did decades ago due in part to advanced presentation and advanced age with multiple associated conditions and risk factors, all of which are independent predictors of adverse outcome.

Colorectal cancer metastases affect the biochemical characteristics of the human liver beta-adrenoceptor-G-protein-adenylate cyclase system.

The sympathetic-catecholamine system is involved in the regulation of hepatic metabolic pathways mainly through cAMP-linked beta2-adrenoceptors (beta2-ARs) in humans and to a lesser extent through cAMP-independent mechanisms, but no information is available about the possible biochemical changes of beta2-ARs and their signalling pathways in human colorectal cancer (CRC) and colorectal cancer hepatic metastases (CRCHM). Changes in density and distribution of beta-ARs as well as in post-receptor signalling components were studied in membranes of human liver with CRCHM, and for comparison, in membranes of nonadjacent, non-metastatic human liver (NA-NM) obtained from 13 patients, using binding and competition binding studies. Studies were also carried out using normal and cancerous human colon tissues. In CRCHM, the density of beta-ARs (B(max)) was significantly reduced, compared to NA-NM liver tissues (40.09+/-2.83 vs. 23.09+/-3.24 fmol/mg protein; P<0.001). A similar decrease in the beta-AR density was observed in the colon with primary colorectal cancer compared to healthy colon (37.6+/-2.2 vs. 23.8+/-3.5 fmol/mg protein), whereas the affinity of ICYP binding to the receptor remained unaffected. Desensitized beta-ARs were uncoupled from stimulatory G-protein (G(S)), as total density of beta-adrenoceptors in the high affinity state was significantly reduced. Concomitantly, CRCHM elicited decrease in the catalytic adenylate cyclase (AC) activity (cAMP formation) in response to isoproterenol plus GTP or forskolin or NaF. In NA-NM and CRCHM liver, the inhibition-concentration curves of ICI 118.551 showed the presence of a homogeneous population of the beta2-AR subtypes. Neither the binding patterns nor the inhibition constant (K(i)) of ICI 118.551 were altered in CRCHM. In CRCHM, the hepatic beta-AR-G-protein(s)-AC signalling system was markedly impaired, thus, these changes may well influence beta-AR-mediated functions in both organs.

Complicated small-bowel diverticulosis: a case report and review of the literature.

While jejunoileal diverticula are rare and often asymptomatic, they may lead to chronic non-specific or acute symptoms. The large majority of complications present with an acute abdomen similar to appendicitis, cholecystitis or colonic diverticulitis but they also may appear with atypical symptoms. As a result, diagnosis of complicated jejunoileal diverticulosis can be quite difficult, and may solely depend on the result of surgical exploration. In the absence of contra-indications, diagnostic laparoscopy has the benefit of thorough examination of the abdominal contents and helps to reach an absolute diagnosis. Surgical resection of the involved small-bowel segment with primary anastomosis is the preferred treatment in patients with symptomatic complicated jejunoileal diverticular disease. An atypical presentation of complicated jejunal diverticulitis in conjunction with sigmoid diverticulitis diagnosed with laparoscopy and treated with surgical resection is presented.

Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients.

AIM: To evaluate the diagnostic potential of cytokeratin-19 (CK-19) mRNA for the detection of disseminated tumor cells in blood, bone marrow and peritoneal lavage in patients with ductal adenocarcinoma of the pancreas. METHODS: Sixty-eight patients with pancreatic cancer (n = 37), chronic pancreatitis (n = 16), and non-pancreatic benign surgical diseases (n = 15, control group) were included in the study. Venous blood was taken preoperatively, intraoperatively and at postoperative d 1 and 10. Preoperative bone marrow aspirates and peritoneal lavage taken before mobilization of the tumor were analyzed. All samples were evaluated for disseminated tumor cells by CK-19-specific nested-PCR and quantitative fluorogenic RT-PCR. RESULTS: CK-19 mRNA expression was increased in 24 (64%) blood samples and 11 (30%) of the peritoneal lavage samples in the patients with pancreatic cancer. In 15 (40%) of the patients with pancreatic cancer, disseminated tumor cells were detected in venous blood and bone marrow and/or peritoneal lavage. In the peritoneal lavage, the detection rates were correlated with the tumor size and the tumor differentiation. CK-19 levels were increased in pT3/T4 and moderately/poorly differentiated tumors (G2/G3). Pancreatic cancer patients with at least one CK-19 mRNA-positive sample showed a trend towards shorter survival. Pancreatic cancer patients showed significantly increased detection rates of disseminated tumor cells in blood and peritoneal lavage compared to the controls and the patients with chronic pancreatitis. CONCLUSION: Disseminated tumor cells can be detected in patients with pancreatic ductal adenocarcinoma by CK-19 fluorogenic RT-PCR. In peritoneal lavage, detection rate is correlated with tumor stage and differentiation. In the clinical use, CK-19 is suitable for the distinction between malignant and benign pancreatic disease in combination with other tumor-specific markers.

Regenerative capacity differs between micro- and macrovesicular hepatic steatosis.

INTRODUCTION: Independent of etiology, the hepatic microvesicular steatosis has a worse prognosis compared with macrovesicular steatosis. Proliferation compensates for apoptosis and reflects regenerative mechanisms following liver injury. It is unknown whether these two types of fatty liver have differences in regenerative capacity and apoptosis, which could have an impact on their prognosis. METHODS: Two groups of pigs were studied for 72 days under a protein-deficient diet. One group received only protein-deficient diet (n=6), the other was treated in addition to the diet with 6g ethanol/kg/day by means of a percutaneous intragastric catheter (n=6). The rate of proliferating and apoptotic hepatocytes was determined, respectively, by proliferation cell nuclear antigen (PCNA) and ISEL/TUNEL staining for apoptosis in liver biopsies with similar steatosis grade in pigs with micro- or macrovesicular fatty liver. RESULTS: The ethanol-treated group developed microvesicular steatosis, the other group developed macrovesicular steatosis. Proliferation index was significantly increased in macrovesicular in comparison with microvesicular steatosis (p<0.05). Apoptosis rate was similar in both groups. CONCLUSIONS: Regeneration, but not apoptosis rate differs between micro- and macrovesicular steatosis. The reduced regenerative capacity in microvesicular steatosis may contribute to the worse prognosis of this subtype of fatty liver disease.

Intraoperative subcutaneous or intrasplenic vaccination with modified autologous tumor cells leads to enhanced survival in a mouse tumor model.

PURPOSE: We investigated the effect of intraoperative intrasplenic or subcutaneous vaccination with modified tumor cells on tumor progression in a mouse model. METHODS: Pre-established B16 melanomas on C57/Bl6 mice were surgically removed; mice were vaccinated intraoperatively with B16 cells transfected with an IL-12-encoding pRSC construct, the empty plasmid, or B16 frozen cells. Cells were given either intrasplenically or subcutaneously. Intrasplenic effects of vaccination were examined along with survival data. Mice without tumor recurrence underwent a second tumor implantation. RESULTS: Animals administered IL-12 pRSC cells showed significant alterations in the spleen, such as higher percentages of (activated) CD4+ and CD8+ T cells and tumor-specific CD4+ T cells among splenocytes. The tumor recurrence rate after resection ranged from 13 to 36%. Cases with recurrent tumors in particular benefited in all therapy groups, resulting in enhanced (tumor-free) survival, reduced tumor growth and lower metastasis rates. Following macroscopic complete tumor resection, the optimum outcome resulted from vaccination with IL-12 pRSC cells into the spleen and subcutaneously administered frozen cells. Survival times were enhanced in all therapy groups after tumor reimplantation, although results were not significant. CONCLUSIONS: Intraoperative whole-cell vaccination with autologous tumor cells yields promising data, and could be considered as a future option in adjuvant cancer therapy.

Attenuation of proinflammatory gene expression and microcirculatory disturbances by endothelin A receptor blockade after orthotopic liver transplantation in pigs.

BACKGROUND: Endothelin-1 (ET-1), a very potent mediator of vasoconstriction, leads to microcirculatory disturbances and release of proinflammatory cytokines under pathophysiologic conditions. Our aim was to evaluate the effect of a selective ET(A)-receptor antagonist (ET(A)-RA) on cold ischemia/reperfusion (I/R) injury in a pig model. METHODS: Twenty pigs revealed orthotopic liver transplantation. The animals were randomized into 2 groups: control pigs received isotonic saline; the treated group received the selective ET(A)-RA BSF 208075 at the beginning of reperfusion. On postoperative days 4 and 7, animals were re-laparotomized to obtain tissue specimens. Liver tissue samples were collected and quantitative mRNA expression for prepro-ET-1, ET(A) receptor, pro-IL-1beta, pro-IL-6, pro-TNF-alpha, and endothelial nitric oxide synthase was analyzed using the TaqMan system. Additionally, immunohistochemical analysis for ET-1 was performed. Hepatic microcirculation was evaluated by laser Doppler flow measurement and partial pressure of oxygen and carbon dioxide measurements with the Paratrend sensor. Postischemic liver damage was monitored by measurement of liver enzymes and by histologic analysis using a semiquantitative scoring classification. RESULTS: Treatment with the ET(A)-RA significantly reduced the severity of I/R injury evidenced by lower serum AST, ALT and GLDH. Analysis of partial pressure of oxygen and blood flow revealed a significant improvement of capillary perfusion and blood flow in the treated group and was associated with a relevant reduction of tissue injury. One hour after reperfusion, quantitative RT-PCR revealed significantly lower expression of prepro-ET-1, ET(A) receptor, endothelial nitric oxide synthase, pro-TNF-alpha, pro-IL-1beta and pro-IL-6 in the therapy group. Immunohistochemical analysis demonstrated significantly reduced ET-1 immunostaining after therapy. Histologic investigation suggested less tissue damage in treated animals. CONCLUSIONS: Treatment with the selective ET(A)-RA BSF 208075 has protective effects on microcirculation after liver transplantation. ET(A)-RA not only affects the expression of vasoactive genes, but also decreases gene expression of proinflammatory cytokines such as TNF-alpha, IL-1beta and IL-6.

Management and outcome in patients with Klatskin-mimicking lesions of the biliary tree.

The preoperative and even intraoperative differentiation between benign and malignant strictures at the hepatic hilum remains difficult. The aim of this study was to assess clinical, radiologic, intraoperative, and histopathologic findings; surgical treatment; and outcome of patients with Klatskin mimicking benign lesions. Of 49 consecutive patients who were operated on the initial preoperative radiologic diagnosis of hilar adenocarcinoma (Klatskin tumor), 7 (14%) had benign conditions after final histopathologic diagnosis. Pretreatment work-up, therapy, and outcome of these patients were analyzed. Based on preoperative clinical symptoms, imaging assessment, and CA19-9 values, all seven patients were classified as having malignant neoplasms. At laparotomy, the tumors of six patients were judged to be malignant. Five patients underwent hilar resection and concomitant liver resection, and two patients underwent hilar resection alone. There were no operative deaths. The definitive histopathologic examination showed severe cholangitis with extensive periductal fibrosis in all patients. After a median follow-up of 32 months, all patients are well. Clinical presentation and imaging assessment were similar for Klatskin tumors and benign fibrosing disease; therefore, an aggressive resectional approach is justified in any patient with suspicious obstruction of the liver hilum.

Particle-mediated cytokine gene therapy leads to antitumor and antimetastatic effects in mouse carcinoma models.

BACKGROUND: We investigated the effects of continuous cancer gene therapy including (antigen-presenting cell) (APC) engineering and local stimulation of the immune system. MATERIALS AND METHODS: Lewis lung carcinomas and B16 melanomas, intradermally established on C57/Bl6 mice, were shot using a gene gun every 4th day with a combination of plasmids. The first therapy group received plasmids coding the genes for interleukin (IL)-12 and IL-2. The second therapy group was treated with plasmids coding for B7.1 interferon-gamma (IFN-gamma)/IL-12 alternated by a plasmid coding IL-2. Control were mice without any therapy or treatment with the empty plasmid. RESULTS: Gene therapy led to reduced tumor sizes in the therapy groups of both models (significant for the Lewis lung carcinoma). We found an enhanced survival and reduced tumor growth rate in the therapy groups; however, the effects were not significant. IL- 12/IL-2 therapy was more effective, compared to B7.1/IFN-gamma/IL-12 and IL-2. Cytokine gene transfer let to a significantly lower metastasis rate in Lewis lung carcinoma. CONCLUSIONS: Continuous particle-mediated gene transfer is easy to handle and shows good results. Gene therapy combining the genes coding for IL-12 and IL-2 was superior to additional IFN-gamma/B7.1. APC engineering does not appear to be sufficient in these poorly antigenic tumors.

Liver resection and transplantation in the management of hepatocellular carcinoma: a review.

Hepatocellular carcinoma (HCC) accounts for more than 80% of all primary liver cancers and is one of the most common malignancies worldwide. Most patients with HCC also suffer from concomitant cirrhosis, which is the major clinical risk factor for hepatic cancer and results from alcoholism, infection with the hepatitis B or hepatitis C virus, and other causes. HCC is often diagnosed at an advanced stage, when established treatment options provide limited benefit. Effective treatment for HCC includes liver resection and liver transplantation. Under most clinical circumstances, those options provide a high rate of complete response and are thought to improve survival. Partial hepatectomy is the therapy of choice in patients with HCC and a noncirrhotic liver. Usually, liver transplantation is not indicated for such patients, although in individual cases, transplantation may be considered. For most cirrhotic patients who fulfill the Milan criteria, liver transplantation is the ultimate treatment option. Liver transplantation restores liver function and ensures the removal of all hepatic foci of tumor as well as tissue with a high oncogenic potential for early tumor recurrence. Because of the present lack of available organs, living-donor liver transplantation (LDLT) is an increasingly popular alternative. LDLT enables recipients to avoid a long pretransplantation waiting time and increases the number of livers available for transplantation. It is also the most effective approach to reducing the dropout rate. Strategies to reduce tumor growth in patients who are awaiting liver transplantation are important to ensure that those individuals continue to fulfill the Milan criteria for transplantation. For that purpose, using ablative techniques or chemoembolization to control local tumor growth is useful.

Caroli's disease: liver resection and liver transplantation. Experience in 33 patients.

BACKGROUND: The aim of this study was to review and discuss our observations on 33 patients who underwent surgical treatment for Caroli's disease (CD), focusing on diagnosis, current surgical management, and long-term outcome. METHODS: Between May 1993 and June 2004, 642 liver resections and 286 liver transplantations in 252 patients were performed in our department of surgery. Thirty-three patients were referred to our center for diagnostic and therapeutic management of CD. Prior surgical interventions for hepatobiliary disorders, current diagnostic and surgical procedures, procedure-specific complications, duration of hospital stay, duration of follow-up, outpatient information, and long-term outcome were reviewed. RESULTS: Fifteen male and 18 female patients were treated in this study. Initial symptoms and signs of the disease noted in our patients included right upper quadrant pain, fever, and jaundice. In 2 of the 33 patients, we noted clinical evidence of cirrhosis followed by histologic confirmation. One patient suffered from variceal bleeding. In 26 patients, diagnoses were established by a combined endoscopic retrograde cholangiopancreatography, ultrasonography, and computed tomographic studies. The disease was localized in 25 and diffuse in 8 patients. Liver resection was carried out in 29 patients. Partial hepatectomies were performed in 27 of these 29 at our institution. Two female patients with the diffuse disease underwent orthotopic liver transplantation. Thirteen of the 31 patients who underwent surgery at our institution had an uneventful postoperative course. Fourteen patients had minor postoperative complications and responded well to medical management. Four patients had major complications that required further surgical treatment. Two patients died of complications related to postoperative hemorrhage and sepsis. Two patients with intrahepatic cholangiocarcinoma died because of primary tumor progress. One patient with cholangiocarcinoma died 1 year after a successful left hepatectomy because of metastatic disease recurrence. The long-term results of the 26 surviving patients were assessed during a mean follow-up of 3.7 years (range, 1-11 years). All 26 patients remained free of biliary symptoms or complications. In 25 patients, surgery including liver transplantation was curative. CONCLUSIONS: Partial hepatectomy for localized CD is potentially curative. In patients with diffuse CD, liver transplantation provides gratifying long-term results.

Improvement of postischemic hepatic microcirculation after endothelinA receptor blockade--endothelin antagonism influences platelet-endothelium interactions.

Endothelin (ET) contributes to disturbances of hepatic microcirculation after ischemia/reperfusion (I/R) by causing vasoconstriction and enhancing leukocyte- and platelet-endothelium interactions. The aim of this study was to investigate a possible protective role of a selective endothelin(A) receptor antagonist (ET(A)-RA) in this setting. In a rat model, warm ischemia of the left lateral liver lobe was induced for 90 minutes under intraperitoneal anesthesia with xylazine and ketamine. Groups of rats consisted of sham-operated (SO, n=14), untreated ischemia (n=14), and treatment with BSF208075 (5 mg/kg body weight IV, n=14). The effect of the ET(A)-RA on I/R was assessed by in vivo microscopy 20 to 90 minutes after reperfusion; by measurement of local tissue Po(2), serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione S-transferase alpha levels, and by histologic investigation. In the untreated group, sinusoidal constriction to 69.4+/-6.7% of diameters of SO rats was observed, leading to a significant decrease in perfusion rate (74.3+/-2.1% of SO) and liver tissue Po(2) (43.5+/-3.2% of SO) (P < 0.05). In addition, we found an increased percentage of stagnant leukocytes (142.9+/-11.9%) and platelets (450.1+/-62.3%) in sinusoids and in postsinusoidal venules (P < 0.05). Hepatocellular damage (AST and ALT increase to 1330+/-157 U/L and 750+/-125 U/L respectively; previously, 27.1+/-3.5 U/L and 28.5+/-3.6 U/L) was detected 6 hours after reperfusion (P < 0.05). Administration of the ET(A)-RA before reperfusion significantly reduced I/R injury. Sinusoidal diameters were maintained (108.5+/-6.6%), and perfusion rate (93.1+/-1.8%) and tissue Po(2) (95.3+/-5.7%) were significantly increased (P < 0.05). According to reduced leukocyte-endothelium interactions after therapy, both platelet rolling and adhesion were significantly reduced (P < 0.05). The number of stagnant platelets in sinusoids was 199.5+/-12.3% of 50 (P < 0.05). After treatment, hepatocellular damage was decreased (AST and ALT levels after 6 hours of reperfusion: 513+/-106 U/L and 309+/-84 U/L, respectively; P < 0.05), and histologic changes were reduced in the long term. Our results provide evidence that the new therapeutic approach with an ET(A)-RA is effective in reducing hepatic I/R injury. In addition to reduced leukocyte-endothelium interactions, the number of stagnant and rolling platelets in sinusoids and venules was significantly reduced. The reduction in microcirculatory damages is responsible for better organ outcome.