Biomedical subjects

Ernst Klar

Publications and source records attributed to Ernst Klar.

At least 37 records · Page 2Linked to original sources

PubMed2004

Neoadjuvant radiochemotherapy in locally advanced gastric carcinoma.

BACKGROUND AND PURPOSE: Gastric carcinoma is characterized by a high rate of local recurrences and distant metastases and is often not resectable due to locally advanced stage. The aim of this study was to examine feasibility and effectiveness of neoadjuvant radiochemotherapy (RCT) for locally advanced, primarily nonresectable gastric carcinoma and to achieve curative resection. PATIENTS AND METHODS: 21 patients with locally advanced gastric cancer located in cardia (n = 17) and corpus (n = 4; seven cT3; 14 cT4; 18 cN+; all cM0) with a median age of 61 years were scheduled to receive neoadjuvant RCT. Therapy consisted of a conventionally fractionated, conformal radiotherapy using the shrinking-field technique (1.8 Gy to 45 Gy + 5.4 Gy) and chemotherapy using cisplatin (20 mg/m(2), d1-5, 29-33), 5-fluorouracil (5-FU; 800 mg/m(2), d1-5, 29-33) or paclitaxel (135 mg/m(2), d1, 29). 4-6 weeks after completion of RCT, surgery was performed whenever feasible. RESULTS: Hematologic toxicity was moderate with grade 3 leukopenia in 10/21 patients and grade 3 thrombopenia in 5/21 (CTC). Nonhematologic toxicities consisted of 5/21 cases of fever as well as one fungal sepsis. Following RCT, tumors were classified resectable in 16/21 patients (76%); 12/21 patients (58%) were operated on, 11/12 achieved clear margins (R0). Response was as follows: complete remission (CR) 3/21 (14%), partial remission 13/21 (62%), no change 3/21 (14%), systemic progressive disease (PD) 2/21 (10%). The median survival and the 2-year survival rates were 18 months and 42%, respectively, for the patients following R0 resections as compared to 10 months and 0% for the remaining patients (p = 0.035). Local control (4 years) for patients following R0 resection was 89%. CONCLUSION: Neoadjuvant RCT is feasible and locally highly effective but must be further investigated involving a higher number of patients.

Adult↗

PubMed2004

C1-inhibitor reduces hepatic leukocyte-endothelial interaction and the expression of VCAM-1 in LPS-induced sepsis in the rat.

INTRODUCTION: Increased leukocyte-endothelial interaction (LEI) leading to hepatic microperfusion disorders is proposed as major contributor for hepatic failure during sepsis. Recently it has been demonstrated that complement inhibition by C1-inhibitor (C1-INH) is an effective treatment against microcirculatory disturbances in various diseases. The purpose of this study was to investigate the influence of C1-INH on microcirculation and LEI in the liver in a rat model of sepsis. MATERIALS AND METHODS: Rats received lipopolysaccharides (LPS) from Escherichia coli intravenously. Controls received Ringer solution only. Ninety minutes after LPS infusion some animals were treated with C1-INH intravenously (LPS + C1-INH). Others (LPS + SC) and controls (Ringer + SC) received sodium chloride (SC). Hepatic LEI and mean erythrocyte velocity (MEV) were quantified by intravital microscopy (IVM) 90 min after LPS or Ringer infusion (0) and 30, 60, 90 and 120 min following treatment. VCAM-1 m-RNA in hepatic tissue, C3a, TNF-alpha and hepatic enzyme liberation in blood was analysed. RESULTS: Leukocyte sticking to the endothelial wall in postsinusoidal venules was significantly reduced in the LPS + C1-INH vs. the LPS + SC group 30, 60, 90 and 120 min after treatment. VCAM-1 m-RNA expression in the hepatic tissue was markedly and C3a levels in plasma were significantly reduced in the LPS + C1-INH vs. the LPS + SC group. No differences in TNF-alpha levels were detected between these two groups. MEV was improved in the LPS + C1-INH vs. the LPS + SC group. CONCLUSIONS: Our results indicate that even upon delayed treatment hepatic adhesion molecule expression and LEI can be reduced by C1-INH. The multifunctional regulator may reduce hepatic microcirculatory disturbances during sepsis under clinical conditions.

Animals↗

PubMed2004

Effects of heparin in experimental models of acute pancreatitis and post-ERCP pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a complication of diagnostic or therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In a recent clinical trial, a decreased rate of post-ERCP pancreatitis was shown after prophylactic heparin treatment. The aim of this study was to evaluate the effects of prophylactic heparin application in various experimental models of AP and pancreatic duct obstruction and to assess the underlying mechanisms. METHODS: In various experimental models, pancreatic injury of graded severity was induced in Wistar rats: (1) mild pancreatitis by IV cerulein infusion over 6 hours; (2) severe pancreatitis by infusion of glycodeoxycholic acid into the pancreatic duct plus IV cerulein application over 6 hours. The clinical ERCP situation was imitated in groups (3) obstruction of the pancreatic duct and (4) infusion of contrast medium into the pancreatic duct plus obstruction. In every group the animals received either no heparin (n=six per group) or continuous IV heparin (n=six per group) starting before pancreatic injury. Histologic changes, amylase, and lipase in plasma were evaluated 12 hours after induction of pancreatic injury. Additional animals were treated to investigate pancreatic microcirculation by intravital microscopy (n=six per group). RESULTS: In groups 1, 3, and 4 (mild AP/duct obstruction/duct obstruction plus contrast medium), IV heparin-treated animals showed reduced edema, inflammation, and peak amylase values compared with the corresponding non-heparin-treated animals (P<.05). Moreover, mean erythrocyte velocity was significantly higher and leukocyte-endothelium interaction was reduced in these groups after prophylactic administration of heparin. In contrast, group 2 (severe AP) did not show any difference between control animals and animals that received heparin as assessed by histology and intravital microscopy. CONCLUSIONS: Prophylactic systemic application of heparin provides a protective effect in mild AP and in experimental post-ERCP pancreatitis. The mechanism of the protective effects of heparin seems to be the reduction of leukocyte-endothelium interaction and the normalization of pancreatic microcirculation.

Acute Disease↗

PubMed2003

Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation.

Kupffer cell depletion by gadolinium chloride (GdCl(3)) in rat livers has previously been proven to minimize hepatic ischemia/reperfusion injury after experimental liver transplantation (LTX). In the current study, we evaluated the effects of donor pretreatment with GdCl(3) on hepatic ischemia/reperfusion injury, macro- and microcirculation, and endotoxin clearance of the liver in a porcine model of experimental LTX. Two groups of 12 pigs were treated either with intravenous NaCl (0.9%; control) or GdCl(3) (20 mg/kg). Twenty-four hours after pretreatment, hepatic macrocirculation was quantified by Doppler flowmetry and liver parenchymous microcirculation by implanted thermodiffusion electrodes. The liver grafts were transplanted after 4-6 h of cold ischemia in University of Wisconsin (UW) solution. At 1 and 24 h after LTX, the perfusion values were re-evaluated and histology, biochemical (aspartate aminotransferase, AST) and functional parameters (partial thromboplastin time, prothrombin time, and bilirubin) were analyzed. Furthermore, endotoxin clearance of the liver was evaluated at all time points. In GdCl(3)-treated animals 80% of the Kupffer cells were destroyed, and 24 h after LTX ischemia/reperfusion injury in treated grafts was significantly lower in comparison to controls, as shown by histology, AST levels (741+/-490 U/l in controls vs 379+/-159 U/l in treated grafts, P<0.05), survival (67% vs 92%), and enhanced macro- (total transhepatic blood flow [THBF]=112+/-22 ml/min per 100 g in controls vs 157+/-45 ml/min per 100 g in treated grafts, P<or=0.05) and microcirculation (thermodiffusion [TD]=73+/-9 ml/min per 100 g in controls vs 90+/-16 ml/min per 100 g in treated grafts, P<or=0.05). Despite destruction of the macrophage system in the liver, the transhepatic endotoxin gradient of treated livers was enhanced before and 1 h after transplantation (58% in controls vs 85% in treated grafts, P<0.05). Destruction of Kupffer cells of donors by pretreatment with GdCl(3) in pigs is effective in preventing liver graft dys- and nonfunction after LTX. Pretreatment with GdCl(3) does not diminish but increase hepatic endotoxin clearance.

Animals↗

PubMed2003

Radiation-induced leukocyte adhesion to endothelium in normal pancreas and in pancreatic carcinoma of the rat.

High-dose radiation is known to induce an inflammatory reaction in normal and malignant tissue including leukocyte infiltration. The influence of radiation on leukocyte-endothelium interaction in tumor tissue, which precedes leukocyte migration, has not yet been investigated to our knowledge. In our study, intravital microscopy was used to compare the radiogenic effects on leukocyte-endothelium interaction and leukocyte migration in healthy and malignant pancreatic tissue in vivo. An established model of ductlike pancreatic cancer (DSL6A) of syngeneic Lewis rats was utilized. Irradiation with 15 Gy increased the high-affinity leukocyte-endothelium interaction both in normal and malignant tissue. The low-affinity leukocyte-endothelium interaction was not significantly altered. Radiation-induced tumor cell death 12 days after radiation was significantly higher in tumors with moderate and severe leukocyte infiltration compared to low leukocyte infiltration. Thus, radiation-induced leukocyte infiltration in pancreatic carcinoma correlates with the extent of tumor cell death.

Animals↗

PubMed2003

Assessment of renal graft function by perioperative monitoring of cortical microcirculation in kidney transplantation.

BACKGROUND: We evaluated the significance of perioperative cortical microperfusion for graft function and long-term prognosis after renal allotransplantation. Thermodiffusion technology was clinically applied for the first time, after previous validation for perfusion monitoring of the renal cortex in pigs. METHODS: A thermodiffusion probe was inserted into the renal cortex in 30 transplant recipients after graft reperfusion. Real-time measurements were recorded until the end of the operation. In 14 patients perfusion was measured daily until postoperative day 7. Microcirculation was correlated to serum creatinine level, scintigraphic findings, and long-term outcome. RESULTS: In primary graft function, intraoperative perfusion was 85+/-7 mL/100 g per min compared with significantly lower values in cases with subsequent graft dysfunction. The best discrimination was defined for a level of 70 mL/100 g per min with a positive predictive value of 88% for detection of good graft function and 86% for nonfunction. Intraoperative perfusion was significantly different in patients with normal grafts, delayed function, and graft loss. Postoperatively, lower perfusion was found in acute tubular necrosis; a significant correlation could be noted between microcirculation and perfusion index measured by nuclear scanning (r=0.78, P<0.01). Living-related grafts were characterized by higher intraoperative perfusion and superior graft quality. CONCLUSION: Thermodiffusion could be clinically applicable for the perioperative monitoring of renal graft perfusion. Intraoperative reduction of cortical microcirculation has a high predictive value with respect to detection of delayed renal function. Postoperatively, impaired renal microperfusion is associated with acute tubular necrosis. Living-related donor grafts show less microcirculatory alteration than cadaveric kidneys.

Adolescent↗

PubMed2003

Detection of hematogenic and lymphogenic tumor cell dissemination in patients with medullary thyroid carcinoma by cytokeratin 20 and preprogastrin-releasing peptide RT-PCR.

Despite an extensive surgical approach only 50% of the patients with medullary thyroid carcinoma (MTC) are biochemically cured. The failure to cure a larger number of patients is a result of the early dissemination of MTC. The present study evaluates two RT-PCR based assays for the detection of disseminated tumor cells in blood, bone marrow and lymph node samples of patients with MTC. Frozen tissue and blood samples of 19 patients with MTC and 61 cervical lymph nodes of these patients were obtained intraoperatively during thyroidectomy and lymphadenectomy. Preoperative bone marrow samples were obtained from 8 patients with MTC. An expression of CK20 and preproGRP was found in all MTC tissue samples. Using CK20-PCR, disseminated MTC cells were detected in 67% of the cervical lymph nodes of patients with MTC, compared to 72% involved lymph nodes, detected by preproGRP-PCR. In 16 of 61 nodes (26%) each PCR-system detected disseminated tumor cells in histologically tumor-free lymph nodes. Disseminated tumor cells were detected with CK20-PCR and preproGRP in 5 of 18 (28%) preoperative blood samples, each. The detection of a hematogenic tumor cell dissemination by preproGRP correlated significantly with the tumor stages (p = 0.019). Circulating MTC cells were found in 3 of 8 bone marrow samples with CK20-PCR, compared to 1 of 8 samples with preproGRP-PCR. Both PCR assays are highly sensitive to detect disseminated MTC cells in blood, bone marrow and lymph node samples. Our results of disseminated MTC cells in 26% of histologically tumor-free cervical lymph nodes and in 28% of the blood samples of patients with MTC might therefore explain the low biochemical cure rates.

Adult↗

PubMed2003

Detection and prognostic relevance of cytokeratin 20 in differentiated and anaplastic thyroid carcinomas by RT-PCR.

BACKGROUND: Metastatic disease in epithelial cancer results from tumor cell dissemination. We investigated an expression of cytokeratin 20 (CK20) by reverse transcriptase-polymerase chain reaction (RT-PCR) in differentiated (DTC) and anaplastic thyroid carcinomas (ATC) and correlated the results with TNM categories and the clinical follow-up. METHODS: Tissue and blood samples of 32 patients with papillary (PTC), 17 patients with follicular (FTC), and 7 patients with ATC were obtained during operation and subjected to CK20 RT-PCR. RESULTS: An expression of CK20 transcripts was detected in 47% of the tissue samples of PTC, 71% of the FTC, and 14% of the ATC. Patients with CK20-positive FTC had a significantly better outcome than patients with CK20-negative FTCs (P=.0016). Disseminated tumor cells were found in 9 of 22 (41%) blood samples of patients with CK20-positive carcinomas. The detection of CK20 transcripts in peripheral blood correlated with tumor categories. Four of 8 (50%) patients with DTC and circulating tumor cells developed local or distant recurrence compared with 3 of 13 (23%) patients with CK20-positive carcinomas and CK20-negative blood samples. CONCLUSION: Our results suggest that CK20 might be a suitable differentiation marker in thyroid carcinomas. In patients with CK20-positive tumors, those with CK20-positive blood samples had a poorer prognosis. We suggest that patients with thyroid cancer with positive CK20 blood samples should be evaluated for further adjuvant therapies after surgery.

Adenocarcinoma, Follicular↗

PubMed2003

Primary human hepatocytes--a valuable tool for investigation of apoptosis and hepatitis B virus infection.

BACKGROUND/AIMS: Apoptosis is a key event in the pathophysiology of many liver diseases. Primary human hepatocytes (PHH) provide a useful model to study physiological and pathophysiological processes in the liver. Our aim was to optimize PHH cultures to allow studies on induction of apoptosis and of hepatitis B virus (HBV) infection. METHODS: PHH were isolated from human liver tissue by two-step collagenase perfusion. PHH and hepatoma cells were treated with different apoptosis-inducing agents in parallel. PHH cultures were infected with wild type HBV and transduced with HBV genomes using adenoviral vectors. RESULTS: PHH were successfully isolated from 40 different tissue samples with high viability and purity. Perfusion time and seeding density turned out to be critical parameters for optimal cell yield and culture conditions, respectively. Serum addition to the medium reduced viability of PHH. PHH allowed reproducible studies of CD95-dependent and -independent apoptosis. Sensitivity towards CD95-mediated apoptosis was markedly higher than in hepatoma cells. PHH could efficiently be infected with HBV, but infection did neither induce apoptosis nor prevent CD95-induced cell death. CONCLUSIONS: Our data show that PHH provide an excellent tool for the investigation of apoptosis induced by agents like death receptor-ligands and hepatotropic viruses.

Apoptosis↗

PubMed2003

Different radiogenic effects on microcirculation in healthy pancreas and in pancreatic carcinoma of the rat.

OBJECTIVE: To compare the radiogenic effects on microcirculation in healthy and malignant pancreatic tissue. SUMMARY BACKGROUND DATA: Vascular injury is an important effect of radiotherapy, which has been suggested for antiangiogenic tumor therapy. METHODS: An established model of duct-like pancreatic cancer (DSL6A) was used. Investigation was performed in 12 healthy and 24 tumor-bearing Lewis rats. The tumors were locally irradiated with 15 Gy in 12 animals 4 weeks after intraperitoneal inoculation. Additionally, local radiation of the normal pancreas was performed in six healthy animals. Intravital microscopy of tumor and normal pancreatic microcirculation was performed 5 days after radiation. Relevant parameters were erythrocyte velocity and functional vessel density. Tumor apoptosis and the fraction of vital tumor cells were estimated histologically 5 and 12 days after radiation. RESULTS: Local radiation with 15 Gy caused a pronounced impairment of blood flow and functional capillary density in the normal pancreas 5 days after radiation, while the tumor blood flow was not significantly changed. A significant reduction in the fraction of vital tumor cells and a significant increase in tumor apoptosis were observed 12 days after radiation. CONCLUSIONS: Local radiation impairs blood flow in healthy pancreas but not in pancreatic cancer tissue. Tumor cell death is the leading consequence of radiation injury in malignant pancreatic tissue without affecting the vascular system of the tumor. The authors conclude that external beam radiation does not appear to be a useful adjunct for a vascular-targeted therapy in pancreatic carcinoma but causes distinct hypoperfusion in the healthy pancreas.

Animals↗

PubMed2003

Oxygen radicals promote ICAM-1 expression and microcirculatory disturbances in experimental acute pancreatitis.

BACKGROUND/AIMS: The course of pancreatitis is paralleled by a drastic reduction in organ perfusion and increased ICAM-1-mediated leukocyte-endothelial interaction. We aimed to evaluate the effect of oxygen radicals on ICAM-1 expression and the microcirculation in severe acute pancreatitis using the oxygen radical scavenger dimethylsulfoxide (DMSO). MATERIALS AND METHODS: Severe pancreatitis was induced in rats (n = 32) who were randomly assigned to one of two groups: either 4 ml/kg 50% DMSO/saline (v/v) started 3 h after induction of pancreatitis or 4 ml/kg saline (control). Microcirculation was evaluated by intermittent intravital microscopy. Serum amylase and lipase, histomorphometric changes, immunohistochemistry for ICAM-1 expression and 24-hour survival were investigated. RESULTS: Leukocyte adherence was significantly reduced (4.4 +/- 0.47 vs. 5.58 +/- 0.69 sticker/100 micro m, p < 0.05), and mean capillary (0.96 +/- 0.06 vs. 0.45 +/- 0.13 mm/s; p < 0.01) and venous erythrocyte velocity (1.16 +/- 0.12 vs. 0.58 +/- 0.16 mm/s, p < 0.01) were significantly increased by DMSO treatment. Microcirculatory disturbances were paralleled by an increase in endothelial ICAM-1 expression, whereas DMSO reduced ICAM-1 expression. CONCLUSION: DMSO improves pancreatic microcirculation and reduces ICAM-1 expression and subsequent leukocyte adhesion, suggesting an important role of oxygen free radicals in the pathway of endothelial ICAM-1 expression and microcirculatory disturbances in acute pancreatitis.

Acute Disease↗

PubMed2002

Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication.

In a transgenic mouse model of multistep carcinogenesis, highly angiogenic insulinomas contain an irregular vascular network and develop an intrinsic resistance to leukocyte infiltration and effector function. Even persistently high levels of activated tumor-specific T lymphocytes fail to eradicate the tumors. In contrast, we show that irradiation before adoptive transfer results in complete macroscopic tumor regression. Thus, effective tumor therapy requires a proinflammatory microenvironment that permits T cells to extravasate and to destroy the tumor. Early after initiation of the irradiation/adoptive transfer therapy, the capillary network reacquires an almost normal appearance, a likely consequence of strong induction of the chemokines monokine induced by IFN-gamma (Mig) and IFN-inducible protein 10 (IP10). This remodeling of the vasculature in a proinflammatory environment may directly affect lymphocyte extravasation and effector function. Therefore, irradiation/adoptive transfer therapy combines antigen-driven tumor cell eradication with anti-angiogenic effects on tumor endothelium, a powerful synergy that has not been previously appreciated.

Animals↗

PubMed2002

Transformation of the microvascular system during multistage tumorigenesis.

Simian virus SV40 large T Antigen expression in the islets of Langerhans of transgenic mice results in beta-cell hyperproliferation, onset of new blood vessel formation and the development of highly vascularized solid tumors. Angiogenesis in the RIPTag mouse model, as well as in human cancer, is a hallmark of multistage tumorigenesis and precedes the development of solid tumors. In our study, intravital microscopy was used to monitor changes in the blood vessel phenotype, microcirculation and leukocyte adhesion during the progression from normal islets to angiogenic islets and solid tumors. In RIP1-Tag5 mice, an aberrant microangioarchitecture becomes apparent in early stages during spontaneous tumor development. Notably, the transition from normal to angiogenic islets is characterized by an increase in vessel diameter rather than vessel numbers. Thus, dilatation of existing vessels precedes vessel sprouting. Once initiated, neovascularization in angiogenic islets results in loss of vessel hierarchy and differentiation. Solid insulinomas display a higher vessel density and even more dramatic vessel heterogeneity as revealed by local "hot spots" of neovascularization and irregular vessel diameters. Strikingly, profound changes in the microangioarchitecture are already observed in early angiogenic islets suggesting that key features of the angiogenic vasculature are established prior to the expansion of tumor mass. Moreover, adhesion of leukocytes was found to be dramatically decreased in both angiogenic islets and solid tumors and correlates with morphological alterations of the vasculature. Thus, vessel transformation and reduced leukocyte-endothelium interactions are not exclusively features of solid tumors but represent early events during tumorigenesis.

Animals↗

PubMed2002

Pancreatic capillary blood flow in an improved model of necrotizing pancreatitis in the rat.

INTRODUCTION: The development of acute pancreatitis is characterized by profound changes in pancreatic microcirculation. Using in vivo microscopy with fluorescent-labeled erythrocytes as tracers we studied changes in pancreatic microcirculation in an improved rat model of necrotizing pancreatitis (NP) in comparison to edematous pancreatitis (EP) and healthy controls. METHODS: Twenty-one male Wistar rats had their pancreatae exteriorized in a temperature-controlled immersion chamber followed by intravenous administration of fluorescent-labeled autologous erythrocytes. EP was induced by intraductal saline and intravenous caerulein (5 microg/kg/h) for 6 h (n = 7) and NP by controlled intraductal infusion of glycodeoxycholic acid (10 mmol/L) followed by intravenous caerulein (n = 7). Control animals received intraductal and intravenous saline (n = 7). The determination of pancreatic microcirculation was performed before as well as 1, 3, and 6 h after intraductal infusion by correlating the number of passing labeled erythrocytes/capillary/min with their concentration per microliter of arterial blood. RESULTS: Pancreatic capillary flow in control animals remained constant over the 6-h observation period. Pancreatic capillary flow in the EP group rapidly increased to 188% of baseline after 3 h and remained significantly elevated throughout the experiments (P = 0.0001). In contrast, pancreatic capillary flow decreased significantly in the group suffering NP with values 46.7% of baseline after 6 h (P = 0.0001). Complete capillary stasis developed in 38% of investigated capillaries in the NP group compared to 0-1% in both other groups (P = 0.0001). CONCLUSION: Pancreatic microcirculation in mild edematous pancreatitis is significantly increased while the evolution of necrotizing pancreatitis in the model studied herein is characterized by a dramatic reduction in pancreatic capillary flow in conjunction with areas of capillary stasis. These results underline the pathophysiologic relevance of the model and of therapeutic measures aimed at an improvement of pancreatic microcirculation in clinical necrotizing pancreatitis.

Animals↗

PubMed2002

Primary colorectal carcinomas and their intrapulmonary metastases: clinical, glyco-, immuno- and lectin histochemical, nuclear and syntactic structure analysis with emphasis on correlation with period of occurrence of metastases and survival.

BACKGROUND: The aim of the study was to correlate clinical factors (disease-free interval/survival) with growth pattern in terms of structural entropy of patients with primary colorectal carcinomas and secondary lung lesions. METHODS: Proliferation and apoptosis markers as well as determinants involved in information transfer by protein-carbohydrate interactions were monitored. The clinical history, surgical and histopathological reports, tumor load, survival of the patients with a maximum follow-up of 14 years, and sections of paraffin blocks of 60 colorectal carcinoma specimens and their pulmonary metastases were examined. Measurements of the staining intensities after processing sections of primary and secondary carcinomas with the marker panel and calculations of syntactic structure and stereological parameters were performed. RESULTS: The majority of primary tumors (80%, 49/60) were surgically treated at advanced tumor stages (pT3/pT4), with detectable lymph node involvement (34/60). Lung metastases were resected after a median disease-free interval of 30.5 months, an average of 3.0 metastases adding up to a mean intrapulmonary tumor load of 9.98 ccm. The median survival was calculated to be 82 months after resection of the colon/rectal carcinomas and 40 months after that of intrapulmonary metastases. It was correlated with certain structural and vascular features such as vascular circumference. The proliferation index and several textural features were strongly associated with vascularization in primary and secondary tumors. CONCLUSIONS: Despite intra- and interindividual variations, vascularization properties and features such as bcl-2 positivity and CEA- and galectin-3-associated structural entropy in primary tumors or metastases are described as independent prognostic features. Absence of lymph node involvement or limited tumor stages of colon/rectal carcinomas should not exclude patients from thorough postsurgical scrutiny to detect lung metastases.

Antigens, Differentiation↗

PubMed2002

Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with azathioprine-containing triple therapy in liver transplant recipients.

Acute graft rejection remains a major problem among additional sequelae in liver transplant recipients. Basiliximab, a chimeric monoclonal antibody with high affinity for the CD25 chain of the interleukin-2 receptor, has significantly reduced the incidence of acute rejection episodes in renal transplant recipients. This single-arm, open-label, multicenter study investigated the efficacy and tolerability of basiliximab immunoprophylaxis in adult patients undergoing first elective liver transplantation. One hundred one patients (70 hepatitis C virus [HCV]-negative patients, 31 HCV-positive patients) were administered basiliximab, 20 mg, by intravenous bolus injection the day of transplantation (day 0) and day 4. In addition, all patients were administered triple immunosuppressive therapy with cyclosporine, steroids, and azathioprine. The efficacy of basiliximab was assessed by conventional parameters, and tolerability was assessed by the incidence of adverse events, infections, and laboratory test result abnormalities. At 6 months, the incidence of first acute biopsy-confirmed rejection episodes was 22.8%. Rejections were more frequent in the HCV-positive (29.0%) than HCV-negative subgroup (20.0%; P =.441). No rejection episode was graded histologically as severe, and no patient required antibody therapy for the management of acute rejection. Ten patients (9.9%) required treatment with tacrolimus for acute rejection episodes. Patient and graft survival rates at 12 months were 90.1% and 88.1%, respectively. Basiliximab caused no injection-site reactions, anaphylaxis, or cytokine release syndrome. Five malignancies were reported at 12 months: of these, three malignancies predated transplantation surgery. Compared with earlier studies, the addition of basiliximab immunoprophylaxis to triple immunosuppressive therapy provides increased efficacy in reducing the incidence of acute rejection episodes, with no clinically significant increase in adverse events.

Adult↗

PubMed2002

RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple endocrine neoplasia type 2A syndrome?

BACKGROUND: In patients with multiple endocrine neoplasia type 2A syndrome, prophylactic thyroidectomy is generally recommended at the age of 5 to 6 years. Whether this recommendation is justified for exon 13 mutations is unknown. METHODS: We analyzed the clinical data from 40 patients harboring RET codon 790/791 mutations (exon 13) who had been treated in 4 specialized centers. RESULTS: Mean age was 35.2 +/- 21.6 years (range, 5.1-69.0 years). Thirteen patients were index patients (mean age, 57.7 +/- 11.3 years), 27 patients were screening patients (mean age, 24.4 +/- 16.5 years). In the index group, pT-category was: T0, n = 2; T1, n = 6; T2, n = 2; T3, n = 1; and T4, n = 2. Lymph node metastases were found in 5 patients and distant metastases in 1 patient. Postoperatively, 69% of index patients were biochemically cured. In the screening group, pT-category was: T0, n = 19; T1, n = 7; and T2, n = 1. Lymph node metastases were found in 2 patients. Postoperatively, 93% of screening patients were biochemically cured. The youngest patient with medullary thyroid carcinoma was 13.8 years, the youngest patient with lymph node metastases was 46.4 years. CONCLUSIONS: Patients with RET codon 790/791 mutations seemed to have a less aggressive clinical course compared with patients with classic multiple endocrine neoplasia type 2A syndrome. Still, index patients had a lower biochemic cure rate in comparison with screening patients. Timely total thyroidectomy including lymph node dissection is warranted.

Adolescent↗

PubMed2002

Ischemic preconditioning by brief extremity ischemia before flap ischemia in a rat model.

Ischemic preconditioning is a protective endogenous mechanism to reduce ischemia/reperfusion injury and is defined as a brief period of ischemia the authors term "preclamping." This is followed by tissue reperfusion and is believed to increase the ischemic tolerance. The objective of this study was to determine whether acute remote ischemic preconditioning, which has been reported to be successful for other organs, such as the heart, kidney, intestine, and liver, will also result in an enhancement of survival in flaps, and whether remote ischemic preconditioning is as effective as preclamping. Forty male Wistar rats were divided into four experimental groups. An extended epigastric adipocutaneous flap (6 x 10 cm) was raised, based on the left superficial epigastric artery and vein. In the control group, a 3-hour flap ischemia was induced. In the preclamping group, a brief ischemia of 10 minutes was induced by clamping the flap pedicle, followed by 30 minutes of reperfusion. Ischemia of the right hind limb was induced in the femoral ischemia group by clamping the femoral artery and vein for 10 minutes after flap elevation. The limb was then reperfused for 30 minutes. Thereafter, flap ischemia was induced as in the control group. A similar protocol was used in the tourniquet group. A tourniquet was used to induce hind-limb ischemia. The experiment was then performed as in the femoral ischemia group. Mean flap necrosis area was assessed for all groups on the fifth postoperative day using planimetry software. Average flap necrosis area was 68.2 +/- 18.1 percent in the control group, 11 +/- 8.38 percent in the preclamping group, 12.5 +/- 5.83 percent in the femoral ischemia group, and 24 +/- 11.75 percent in the tourniquet group. All preconditioned animals demonstrated a significantly lower area of flap necrosis than the control group (p < 0.001, one-way analysis of variance, post hoc Tukey's test). The data show that ischemic preconditioning and enhancement of flap survival can be achieved not only by preclamping of the flap pedicle but also by induction of an ischemia/reperfusion event in a body area distant from the flap before harvest. These findings indicate that remote ischemic preconditioning is a systemic phenomenon, leading to an enhancement of flap survival. The exact mechanism is not yet completely understood. The data suggest that remote ischemic preconditioning could be performed simultaneously with flap harvest in the clinical setting, resulting in an improved flap survival without prolongation of the operation. This may decrease the rate of partial flap loss or fat necrosis, especially in high-risk groups such as smokers, those with irradiated tissues, and obese patients.

Animals↗