ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo investigate whether liver regeneration is an angiogenesis-associated phenomenon.Summary Background DataAngiogenesis is predominantly known for its pivotal role in tumor growth. However, angiogenesis could also play a role in physiologic processes involving tissue repair, such as liver regeneration.MethodsMice subjected to 70% partial hepatectomy were treated with human angiostatin (100 mg/kg body weight). Regeneration-induced hepatic angiogenesis was determined by assessing intrahepatic microvascular density using CD31 staining of frozen liver sections. Liver regeneration was evaluated by assessing wet liver weights and BrdU incorporation in DNA at regular intervals after partial hepatectomy. Possible direct effects of angiostatin on hepatocytes were studied by assessment of liver enzymes (ASAT, ALAT, bilirubin, lactate dehydrogenase), MTT assay (cytotoxicity), aminophenol production (metabolic function), and TUNEL (apoptosis).ResultsIn a regenerating liver, microvascular density increased by 38%. Angiostatin significantly inhibited this response by 60%. In addition, angiostatin inhibited liver regeneration by 50.4% and 24.9% on postoperative days 7 and 14, respectively. In control mice liver weights regained normalcy in 8 days, whereas those in angiostatin-treated mice normalized after 21 days. In angiostatin-treated mice, the maximal BrdU incorporation was decreased and delayed. Direct adverse effects of angiostatin on cultured and in vivo hepatocytes were not observed. Angiostatin neither induced necrosis on hematoxylin and eosin staining nor affected serum levels of liver enzymes.ConclusionsLiver regeneration is accompanied by intrahepatic angiogenesis. Antiangiogenic treatment using angiostatin inhibits both phenomena. The authors conclude that liver regeneration is, at least in part, an angiogenesis-dependent phenomenon.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo determine the patient factors affecting patient outcome of first liver retransplantation at a single center to help in the decision process for retransplantation.Summary Background DataGiven the critical organ shortage, one of the most controversial questions is whether hepatic retransplantation, the only chance of survival for patients with a failing first organ, should be offered liberally despite its greater cost, worse survival, and the inevitable denial of access to primary transplantation to other patients due to the depletion of an already-limited organ supply. The authors’ experience of 139 consecutive retransplantations was reviewed to evaluate the results of retransplantation and to identify the factors that could improve the results.MethodsFrom 1986 to 2000, 1,038 patients underwent only one liver transplant and 139 patients underwent a first retransplant at the authors’ center (first retransplantation rate = 12%). Multivariate analysis was performed to identify variables, excluding intraoperative and donor variables, associated with graft and patient long-term survival following first retransplantation. Lengths of hospital and intensive care unit stay and hospital charges incurred during the transplantation admissions were compared for retransplanted patients and primary-transplant patients.ResultsOne-year, 5-year, and 10-year graft and patient survival rates following retransplantation were 54.0%, 42.5%, 36.8% and 61.2%, 53.7%, and 50.1%, respectively. These percentages were significantly less than those following a single hepatic transplantation at the authors’ center during the same period (82.3%, 72.1%, and 66.9%, respectively). On multivariate analysis, three patient variables were significantly associated with a poorer patient outcome: urgency of retransplantation (excluding primary nonfunction), age, and creatinine. Primary nonfunction as an indication for retransplantation, total bilirubin, and factor II level were associated with a better prognosis. The final model was highly predictive of survival: according to the combination of the factors affecting outcome, 5-year patient survival rates varied from 15% to 83%. Retransplant patients had significantly longer hospital and intensive care unit stays and accumulated significantly higher total hospital charges than those receiving only one transplant.ConclusionsThese data confirm the utility of retransplantation in the elective situation. In the emergency setting, retransplantation should be used with discretion, and it should be avoided in subgroups of patients with little chance of success.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.Summary Background DataPreviously the authors have shown highly effective therapy with PRRT of SSR-positive tumors. This treatment is SSR-mediated; successful treatment is seen only in SSR-positive tumors, with no effect in SSR-negative tumors. As many tumors lack this receptor, the idea arose to transfect SSR-negative tumor cells with an SSR gene to apply PRRT on these SSR-transfected tumor cells.MethodsCC531 colon carcinoma cells (SSR-negative) were transfected in vitro with an SSR (subtype 2) gene (CC2B). Liver metastases were produced after intraportal injection of these tumor cells in rats. On day 7, animals were treated with 185 or 370 MBq [177Lu-DOTA0, Tyr3]octreotate. After 21 days rats were killed and liver metastases were counted.ResultsTreatment with 370 MBq [177Lu-DOTA0, Tyr3]octreotate showed a significant antitumor response in rats with CC2B liver metastases (SSR-positive) in comparison with controls. No significant antitumor effect was seen in PRRT-treated rats with CC531 liver metastases (SSR-negative). Also, a dose-dependent tumor response was seen in rats with CC2B liver metastases treated with 185 MBq [177Lu-DOTA0, Tyr3]octreotate compared with controls. In addition, rats with mixed liver metastases treated with 185 MBq [177Lu-DOTA0, Tyr3]octreotate had significantly fewer metastases compared with controls.ConclusionsThe authors showed an impressive antitumor effect of SSR (subtype 2)-transfected colon carcinoma cells with PRRT in a rat liver metastasis model. Moreover, rats with mixed liver metastases had significantly fewer liver metastases compared with control rats, which may be due to a radiologic bystander effect of [177Lu-DOTA0, Tyr3]octreotate. This phenomenon is beneficial in the concept of in vivo gene therapy.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate the prevalence of mutations in the CDKN2A gene encoding p16INK4aand p14ARFin familial pancreatic cancer (FPC).Summary Background DataThe genetic basis of FPC is still widely unknown. Recently, it has been shown that germline mutations in the p16INK4atumor suppressor gene can predispose to pancreatic cancer. The presence of p14ARFgermline mutations has yet not been determined in this setting.MethodsEighteen families with at least two first-degree relatives with histologically confirmed pancreatic cancer and five families with at least one patient with pancreatic cancer and another first-degree relative with malignant melanoma of the German National Case Collection for Familial Pancreatic Cancer were analyzed for CDKN2A germline mutations including p16INK4aand p14ARFby direct DNA sequencing. All participating family members were genetically counseled and evaluated by a three-generation pedigree.ResultsNone of 18 FPC families without malignant melanoma revealed p16INK4amutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16INK4agermline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14ARFgermline mutations.ConclusionsCDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer–melanoma syndrome associated with CDKN2A germline mutations affecting p16INK4a. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16INK4amutations to identify high-risk family members who should be enrolled in a clinical screening program.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate whether the vascular endothelial growth factor (VEGF) pathway can be used as a target for effective treatment of pancreatic cancer.Summary Background DataVEGF and its receptors (VEGF-RI and -RII) are the predominant regulators of tumor neoangiogenesis, a key element for tumor growth and progression. However, VEGF receptor expression has been thought to be limited to endothelial cells, limiting the possibility of targeting it for therapy of pancreatic cancer.MethodsProtein localization and mRNA were studied in pancreatic cancer specimens, normal pancreas, human pancreatic cancer cell lines, and an endothelial cell line. Cell proliferation was determined by [3H] thymidine uptake. Both VEGF receptors were genetically eliminated by antisense technology. The same approach was used in a murine model of pancreatic cancer in a therapeutic approach.ResultsVEGF-RI mRNA and VEGF-RII mRNA were expressed in 17 and 15 of 24 pancreatic cancer samples, respectively. VEGF receptors were found not only in blood vessels but also in pancreatic cancer cells. VEGF-RII expression correlated with poor tumor differentiation and was associated with poorer survival, while VEGF-RI expression did not correlate. VEGF treatment led to extensive growth stimulation in six of seven pancreatic cancer cell lines, which was completely inhibited by antisense treatment against VEGF-RII. Liposome-mediated gene transfer in nude mice with pancreatic tumors markedly reduced local tumor growth and decreased metastatic tumor spread.ConclusionsThe VEGF/VEGF-RII pathway regulates angiogenesis and local tumor growth and spread in pancreatic cancer. Genetic targeting of VEGF-RII blocks local growth and metastatic spread of pancreatic cancer cells in vivo and therefore offers a potential new therapeutic option for patients with this disease.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo assess the outcome of laparoscopic Heller myotomy for achalasia using a specific quality of life (QoL) instrument for gastrointestinal disorders.Summary Background DataCurrent therapies for achalasia do not restore normal esophageal motility but aim at palliating dysphagia. However, many other symptoms may persist that cannot be assessed objectively by currently available symptom scores. Although generic QoL instruments have shown improvement in QoL after myotomy, disease-specific QoL instruments may be more responsive to change and therefore more reliable for comparing outcomes of therapeutic options for achalasia.MethodsThe Gastrointestinal Quality of Life Index (GIQLI) was studied before and after laparoscopic Heller myotomy associated with posterior partial fundoplication.ResultsStarting in January 1991, 73 consecutive patients were operated on laparoscopically for various clinical stages of achalasia. Since 1996, 40 patients completed a GIQLI questionnaire both preoperatively and after a minimum postoperative follow-up of 1 year. Median preoperative GIQLI score was 84 (range 34–129) out of a theoretical maximum score of 144. At a median follow-up of 31 months (range 12–54), the score had significantly improved to 119 (range 77–143), close to the range for the normal French population. Not only items assessing gastrointestinal symptoms but also the domains of physical, social, and emotional function were significantly improved. The most marked improvements were achieved in patients with the lowest preoperative scores.ConclusionsThe GIQLI allows us to objectify the impact of achalasia symptoms on health-related QoL. At medium-term follow-up, laparoscopic Heller myotomy, performed either as primary treatment or after endoscopic dilation, significantly improves most health-related QoL aspects. Short of randomized comparisons between the different therapeutic options available for achalasia, reported series could be made more comparable if validated QoL instruments specific for gastrointestinal disorders were used routinely for outcome evaluation.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveThe primary endpoint was to compare the impact of laparoscopic and open colorectal surgery on 30-day postoperative morbidity. Lymphocyte proliferation to mitogens and gut oxygen tension were surrogate endpoints.Summary Background DataEvidence-based proof of the effect of laparoscopic colorectal surgery on immunometabolic response and clinically relevant outcome variables is scanty. Further randomized trials are desirable before proposing laparoscopy as a superior technique.MethodsTwo hundred sixty-nine patients with colorectal disease were randomly assigned to laparoscopic (n = 136) or open (n = 133) colorectal resection. Four trained members of the surgical staff who were not involved in the study registered postoperative complications. Lymphocyte proliferation toCandida albicansand phytohemagglutinin was evaluated before and 3 and 15 days after surgery. Operative gut oxygen tension was monitored continuously by a polarographic microprobe.ResultsIn the laparoscopic group the conversion rate was 5.1%. The overall morbidity rate was 20.6% in the laparoscopic group and 38.3% in the open group. Postoperative infections occurred in 15 of the 136 patients in the laparoscopic group and 31 of the 133 patients in the open group. The mean length of hospital stay was 10.4 ± 2.9 days in the laparoscopic group and 12.5 ± 4.1 days in the open group. On postoperative day 3, lymphocyte proliferation was impaired in both groups. Fifteen days after surgery, the proliferation index returned to baseline values only in the laparoscopic group. Intraoperative gut oxygen tension was higher in the laparoscopic than in the open group.ConclusionsLaparoscopic colorectal surgery resulted in a significant reduction of 30-day postoperative morbidity. Lymphocyte proliferation and gut oxygen tension were better preserved in the laparoscopic group than in the open group.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo evaluate the clinical relevance of real-time quantitative polymerase chain reaction (qPCR) detection of CEA and CK20 transcripts, as potentially related to tumor cell dissemination, in blood and peritoneal lavage from patients undergoing surgery for colorectal cancer.Summary Background DataDissemination of single colorectal cancer cells in the peritoneal cavity, as well as in tumor drainage and peripheral blood vessels, might play a role in the metastasis process, thus affecting the clinical course. However, this phenomenon needs further elucidation.MethodsIn a prospective study the authors evaluated the potential of qPCR in the detection of CEA and/or CK20 transcripts in the peritoneal lavage fluid and in the peripheral and mesenteric venous blood of 39 patients undergoing curative resection for colorectal cancer. Peritoneal lavage and peripheral blood was sampled before and after tumor resection; mesenteric venous blood was sampled from the major tumor-draining vein immediately before clamping. After RNA extraction and reverse transcription, qPCR was performed using specific cDNA primers and probes for CEA and CK20. The dichotomous results from the qPCR were used as a predictor along with other covariates in Cox proportional hazard regression models of long-term outcome (disease-free survival and overall survival).ResultsOf 39 patients, 11 were positive. The median follow-up at analysis was 31 months for all patients. The dichotomous qPCR covariate was significant, withP= .001 and .0035 for disease-free survival and overall survival, respectively, in the proportional hazard regression models with only qPCR. In seven patients, disseminated colorectal cancer cells were found in the peritoneal lavage fluid but not in blood specimens; five of these patients (71%) had recurrence.ConclusionsThese data suggest that detection of mRNA coding for CEA and/or CK20 using qPCR has potential clinical utility as a prognostic marker and should be evaluated in larger clinical studies. Identification of patients at high risk for metastatic disease after curative resection of colorectal cancer might be improved by analyzing peritoneal lavage specimens in addition to blood samples. This is based on the observation that in more than half of qPCR-positive patients, disseminated colorectal cancer cells were detected in peritoneal lavage specimens but not in blood samples, and that 71% of them had recurrence.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo study the adhesive mechanisms underlying ischemia/reperfusion (I/R)-induced leukocyte–endothelium interactions in the colon.Summary Background DataLeukocyte recruitment is a key feature in I/R-induced tissue injury, but the mechanisms regulating leukocyte rolling and adhesion in the colon are not known. The authors recently developed a new model to study the molecular mechanisms of I/R-provoked leukocyte–endothelium interactions in the colon microcirculation using inverted intravital fluorescence microscopy.MethodsThe superior mesenteric artery was occluded for 30 minutes and leukocyte responses were analyzed after 120 minutes of reperfusion in colonic venules in mice. The adhesive mechanisms underlying I/R-induced leukocyte rolling and adhesion were investigated using monoclonal antibodies against L-, E- and P-selectin, and CD11a gene-targeted mice were used to examine the role of lymphocyte function antigen-1 (LFA-1, CD11a/CD18).ResultsReperfusion provoked a clear-cut increase in leukocyte rolling and adhesion in colonic venules compared to negative controls. Both P- and E-selectin mRNA were expressed in the colon after this I/R insult. Pretreatment with an anti-P-selectin antibody reduced leukocyte rolling and adhesion by 88% and 85%, respectively, whereas antibodies against L- and E-selectin had no effect. Moreover, I/R-induced leukocyte adhesion in LFA-1-deficient mice was reduced by more than 95%.ConclusionsThis study provides evidence that leukocyte rolling is exclusively and nonredundantly mediated by P-selectin and that firm adhesion is supported by LFA-1 in I/R-induced leukocyte recruitment in the colon. Taken together, both P-selectin and LFA-1 may be important targets to control pathologic inflammation in I/R-induced tissue injury in the colon.

ISSN:0003-4932    

出版商:OVID    

年代:2002

数据来源: OVID