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Biomedical subjects

B Nordlinger

Publications and source records attributed to B Nordlinger.

At least 37 records · Page 2Linked to original sources
PubMed2001

Survival and functions of encapsulated porcine hepatocytes after allotransplantation or xenotransplantation without immunosuppression.

BACKGROUND: This study evaluated the survival and functions of encapsulated porcine hepatocytes after intraperitoneal allotransplantation and xenotransplantation without immunosuppression. METHODS: Isolated porcine hepatocytes were encapsulated in AN 69 polymer capsules (45.10(6)/capsule) and transplanted intraperitoneally in 12 rats and 12 pigs. Fifteen, 30, and 60 days after transplantation, capsules were removed and the viability and morphology of explanted hepatocytes were examined under light and electronic microscopy. The potential to produce albumin was assessed by evaluating the level of albumin messenger RNA, using semiquantitative reverse transcription-polymerase chain reaction. 6beta-Hydroxylase activity was measured by high-performance liquid chromatography. In addition, cytochrome P450 3A proteins were detected by Western blot only in allogeneic hepatocytes. RESULTS: Similar results were observed after allotransplantation and xenotransplantation. Histologic studies showed that hepatocytes were well-preserved and arranged in cords for up to 30 days. The expression of porcine albumin gene was maintained up to 15 days. 6beta-Hydroxylase activity was 2.5-fold lower at day 15 than in freshly encapsulated hepatocytes, which were not transplanted. In allogeneic hepatocytes, the expression of CYP 3A protein was detected up to 60 days after transplantation. CONCLUSIONS: Encapsulated porcine hepatocytes remain viable and functional for at least 15 days after allotransplantation and xenotransplantation without immunosuppression. The demonstration of maintained hepatic functions in transplanted porcine hepatocytes up to 15 days is a first step toward application in the treatment of acute liver failure.

Albumins↗
PubMed2001

[The internal bioartifical liver].

A possible alternative to liver transplantation is the internal bioartificial liver (IBAL) consisting in the transplantation of isolated encapsulated hepatocytes. The goal of IBAL is to allow an auxiliary liver until native liver regeneration. The hepatocytes could be allogeneic or xenogeneic (animal origin). Large animal source of liver cells should allow immediate isolation of fresh hepatocytes when IBAL is required. The peritoneal cavity is probably the site of implantation of IBAL. In the future, IBAL could be envisioned as the treatment of metabolic deficiencies or acute and chronic liver failure. It could ensure a therapeutic bridge until transplantation.

Animals↗
PubMed2001

The European Organization for Research and Treatment of Cancer Gastrointestinal Group Trials: surgery and liver surgery in Europe.

The aim of the Gastrointestinal Tract Cancer Cooperative Group is to develop protocols concerning the different aspects of gastro-intestinal tract malignancies, diagnosis, biology and treatment. All projects involving surgery are discussed first in the Surgery Committee. A multidisciplinary approach has always been one of the major principles of the group. This article provides an overview of the recent and present activities of the GI group of the EORTC in relation to surgery.

Catheter Ablation↗
PubMed2001

Semiautomatic macroencapsulation of fresh or cryopreserved porcine hepatocytes maintain their ability for treatment of acute liver failure.

We have previously demonstrated that fresh or cryopreserved xenogeneic hepatocytes manually macroencapsulated in AN69 polymer and transplanted intraperitoneally in rats were able to improve the survival rate after 95% hepatectomy without immunosuppression. In addition, we developed a semiautomatic device where porcine hepatocytes were coextruded with AN69 hydrogel in order to macroencapsulate large amounts of cells. The purpose of the present study was to 1) test whether transplanted porcine hepatocytes macroencapsulated in this device remained functional as evaluated by their ability to prevent death from acute liver failure, and 2) compare the efficiency of cryopreserved or freshly isolated hepatocytes. Fresh or cryopreserved porcine hepatocytes were macroencapsulated in the semiautomatic device by coextrusion in AN69 polymer in 2-m minitubes containing 6 x 10(7) cells. Acute liver failure was induced in rats by two-step 95% hepatectomy. At the time of completion of liver resection, rats were either not transplanted with minitubes (control group I, n = 13), or were implanted with two minitubes containing culture medium (control group II, n = 11), hepatocytes killed by heat treatment (control group III, n = 10), coextruded fresh hepatocytes (group IV, n = 11), or coextruded cryopreserved hepatocytes (group V, n = 11), without immunosuppression. The survival rate at day 7 was between 0% and 31% in the three control groups. By contrast, coextruded fresh hepatocytes significantly improved the survival rate (group IV, 82%) as did cryopreserved cells (group V, 91% survival). In surviving rats, minitubes were explanted after 20 days; either fresh or cryopreserved hepatocytes appeared morphologically viable and their ultrastructure was preserved. Their detoxification capacities evaluated by the activity of the cyt P450 CYP3A4 were partly maintained. In conclusion, porcine hepatocytes macroencapsulated by coextrusion using a semiautomatic device and transplanted without immunosuppression were able to prevent death from acute liver failure in rats. Cryopreserved cells were as efficient as fresh hepatocytes.

Animals↗
PubMed2000

Transplanted cryopreserved encapsulated porcine hepatocytes are as effective as fresh hepatocytes in preventing death from acute liver failure in rats.

BACKGROUND: An implantable bioartificial liver (BAL) using xenogeneic isolated hepatocytes may be an alternative method to orthotopic liver transplantation for treatment of acute liver failure. The purpose of this study was to demonstrate that not only fresh but also cryopreserved porcine hepatocytes could be used in a BAL to prevent death after the onset of acute liver failure in rats. METHODS: Acute liver failure was induced by two-stage 95% hepatectomy. At the time of completion of liver resection, 100 rats were assigned to undergo or not undergo transplantation into the peritoneum of 4 meters of hollow fibers filled with 60 million either fresh or cryopreserved porcine hepatocytes, or syngeneic hepatocytes, or culture medium, or of 60 million nonencapsulated cryopreserved porcine hepatocytes without immunosuppressive therapy. Survival rates at 7 days were compared between the different groups. RESULTS: In the control groups of hepatectomized animals not receiving encapsulated hepatocytes, 69-79% of the rats died from acute liver failure. The mortality rate was reduced to 15% (2 of 13) in rats receiving fresh porcine hepatocytes (P<0.01), 25% (4 of 16) in rats transplanted with either cryopreserved or syngeneic hepatocytes (P<0.05). Survival rates were maintained when hollow fibers were explanted > or =4 days after hepatectomy. In surviving rats, the weight of the remnant native liver increased with time and returned to the initial weight after 1 month. CONCLUSIONS: The implantable BAL using xenogeneic porcine hepatocytes was able in preventing death from acute liver failure without immunosuppressive therapy. Encapsulated cryopreserved hepatocytes were as effective as fresh hepatocytes.

Animals↗
PubMed2000

A reversible model of acute hepatic failure by temporary hepatic ischemia in the pig.

BACKGROUND: To evaluate new therapies for human fulminant hepatic failure, a suitable large animal model is needed. The purpose of this study was to develop a reversible surgical model of acute hepatic liver failure by transient ischemia in pigs. MATERIALS AND METHODS: Under general anesthesia, an end-to-side portacaval shunt was performed in 17 pigs and tape was laid around the hepatoduodenal ligament. Two days after construction of the functional portacaval shunt, 13 ambulant pigs underwent transient total liver ischemia by tightening of the tape around the hepatoduodenal ligament for 5.5 h. During ischemia, 10% glucose was continuously infused intravenously to prevent hypoglycemia. RESULTS: Ten animals (77%) died with hepatic coma after a mean duration of 22.5 +/- 1.9 h. The 3 remaining animals survived more than 5 days and were sacrificed. In dying animals, encephalopathy was observed 14 +/- 1.7 h after the onset of ischemia. During ischemia, similar progressive decrease of fibrinogen, platelets, prothrombin time, and factors V and VII activities was observed in dying and surviving animals. Just before death, mean prothrombin and factors V and VII activities were respectively 22 +/- 2, 21 +/- 4.4, and 24 +/- 5%. At 22 h, plasma ammonia and lactate levels were respectively 705 +/- 93 micromol/L and 10.5 +/- 0.4 mmol/L in dying animals and 249 +/- 75 micromol/L and 2.9 +/- 0.1 mmol/L in surviving animals (P < 0.01). Estimation of the percentage liver cells necrosed was 74 +/- 4.7% in the survivors and 86 +/- 5.5% in animals who died of hepatic coma (NS). CONCLUSIONS: This model is reproducible and reversible and should allow the quantitative evaluation of new technologies, such as bioartificial liver, for the support of hepatic failure in humans.

Acute Disease↗
PubMed2000

Semiautomatic macroencapsulation of large numbers of porcine hepatocytes by coextrusion with a solution of AN69 polymer.

We have previously demonstrated that allogenic and xenogenic hepatocytes macroencapsulated manually in AN-69 polymer and transplanted intra-peritoneally in rats remained viable for several weeks. However, this manual technique is inadequate to encapsulate several billions of hepatocytes which would be required to correct hepatic failure in big animals or humans. In the present study, we developed an original semiautomatic device in which isolated pig hepatocytes and the polymer solution containing 6% poly(acrylonitrile-sodium methallylsulfonate), 91% dimethylsulfoxide and 3% 0.9% NaCl solution were coextruded through a double-lumen spinneret. The extruded minitube (inner diameter: 1.8 mm, wall thickness: 0.07-0.1 mm) containing the encapsulated hepatocytes fell and coiled up in a 0.9% NaCl solution at 4 degrees C and was cut down in 4 m units containing about 120 million hepatocytes. This process allowed to encapsulate 50 million hepatocytes by minute with a preserved immediate cell viability (92 +/- 5%). To test prolonged cell viability after coextrusion, the minitubes were implanted intraperitoneally in rats. Three and seven days after implantation, they were explanted and analyzed. Cells were viable and well-preserved. Therefore, the semiautomatic device appears able to efficiently macroencapsulate in a limited time several billions of porcine hepatocytes which remain viable after transplantation in xenogenic conditions.

Acrylic Resins↗
PubMed2000

Regional chemotherapy in the treatment of advanced pancreatic cancer--is it relevant?

The treatment of pancreatic cancer is still problematic for physicians. Only 15% of patients present with resectable tumours, and systemic chemotherapy is of limited effectiveness. In order to achieve higher local drug concentrations in the tumour without causing the side-effects of a comparable level of systemic treatment, regional chemotherapy has been introduced as an alternative treatment. Several techniques have been developed over recent years, these include: celiac axis infusion (CAI), CAI with microspheres or haemofiltration, aortic stop flow (ASF) and isolated hypoxic perfusion (IHP). Whilst several authors have reported improved response rates and a prolongation of median survival time, these results have not been confirmed by others. In addition, the incidence of side-effects and the rate of technical complications have been reported to be high during regional chemotherapy. Except for a single trial containing 14 patients, no randomised trial comparing systemic and regional chemotherapy has been conducted. For these reasons, none of the reported treatment regimens can be considered to be standard treatment and in order to evaluate, if regional chemotherapy is indeed superior to systemic chemotherapy, randomised trials must be conducted.

Antineoplastic Agents↗
PubMed2000

Suppression of humoral immunization against encapsulated xenogeneic hepatocytes and prolongation of their function by 2-week cyclosporine treatment in the rat.

BACKGROUND: Xenogeneic liver transplantation may induce immune reactions not only against the grafted liver but also against the proteins that it synthesizes. We investigated whether 2-week cyclosporine treatment could suppress immunization and improve graft function in a xenogeneic hepatocyte transplantation model. METHODS: Free or encapsulated human hepatoma cells (HepG2) were cocultured for 28 days with splenocytes from Lewis rats or implanted for 60 days into the peritoneum of Lewis rats. RESULTS: Anti-HepG2 and antialbumin antibodies were detected in the supernatants of rat splenocytes that were cocultured with HepG2 cells and in the serum of rats that had undergone transplantation with HepG2 cells. Cyclosporine suppressed this antibody production both in vitro and in vivo. Human alpha-GST blood levels, which reflect hepatocyte injury, were low in cyclosporine-treated animals but high when encapsulated HepG2 cells were transplanted without cyclosporine therapy. Western blots revealed human albumin from day 3 to day 60 in the serum of rats treated with cyclosporine, but not after day 30 in untreated rats. CONCLUSIONS: Xenogeneic hepatocytes induce a humoral response that impairs their viability and function. A 2-week course of cyclosporine suppresses this immune response and improves graft function for up to 60 days.

Animals↗
PubMed2000

Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: A multicenter phase III trial.

OBJECTIVE: To evaluate the results of a prospective multicenter randomized study of adjuvant intraperitoneal 5-fluorouracil (5-FU) administered during 6 days shortly after resection of stages II and III colon cancers. SUMMARY BACKGROUND DATA: Systemic adjuvant chemotherapy improves the survival of patients with stage III colon cancer receiving treatment for 6 months. Intraperitoneal chemotherapy theoretically combines peritoneal and hepatic effects. METHODS: After resection, 267 patients were randomized into two groups. Patients in group 1 (n = 133) underwent resection followed by intraperitoneal administration of 5-FU (0.6 g/m2/day) for 6 days (day 4 to day 10). These patients also received intravenous 5-FU (1 g) during surgery. Patients in group 2 underwent resection alone (n = 134). RESULTS: In group 1, 103 patients received the total dose, 18 received a partial dose as a result of technical or tolerance problems, and 12 did not receive the chemotherapy. Rates of surgical death and complications were similar in both groups. Tolerance to treatment was excellent or fair in 97% of the patients and poor in 3%. After a median follow-up of 58 months, 5-year overall survival rates were 74% in group 1 and 69% in group 2; disease-free survival rates were 68% and 62%, respectively. Survival curves were superimposed until 3 years after treatment and began diverging thereafter. Among patients receiving the full treatment, the 5-year disease-free survival rate was improved in the treatment group in patients with stage II cancers but was unchanged in patients with stage III cancers. CONCLUSIONS: Chemotherapy with intraperitoneal 5-FU administered during a short period after surgery was well tolerated but was not sufficient to reduce the risk of death significantly. However, it reduced the risk of recurrence in stage II cancers. These results suggest that it should be associated with systemic chemotherapy to reduce both local and distant recurrences.

Adenocarcinoma↗
PubMed2000

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Adenocarcinoma↗
PubMed1999

[Established data and practical recommendations concerning pre- and postoperative chemotherapy of rectal cancer].

Adjuvant chemotherapy appears to be active in stage II-III rectal cancers; the NSAPB R01 trial demonstrated a survival advantage for patients receiving chemotherapy using the MOF protocol and 3 meta-analyses are in favor of the efficacy of adjuvant chemotherapy in rectal cancer. Three randomized trials have also demonstrated that combinations of radiation and chemotherapy are superior to surgery alone or adjuvant radiotherapy and demonstrated the major role of systemic chemotherapy combined with radiotherapy. However this efficacy of adjuvant chemotherapy alone or combined with radiation therapy is still debated and specific trials must be conducted to test the value of chemotherapy using more active regimens than those previously tested and taking into account the quality of surgery and radiotherapy; such trials are in progress, especially the trial conducted by the EORTC and the FFCD. The efficacy of neoadjuvant chemotherapy has never been clearly demonstrated, although a combination of radiotherapy and chemotherapy as first-line treatment for locally advanced rectal cancer and in the case of synchronous metastasis seems to facilitate surgical resection. It is a reasonable and tolerable approach with manageable toxicity which gives substantial results in 2/3 of patients. This strategy also allows better selection of patients likely to benefit from surgical resection of their primary tumor and in some cases of their synchronous metastases. However, the efficacy of perioperative treatments should not decrease the quality of the surgical resection and especially mesorectal excision as well as the need for high quality pathological examination which must be very thorough with analysis of a sufficient number of lymph nodes. The efficacy of combined treatment in advanced rectal cancers is a major argument in favor of the multidisciplinary coordination required for optimal treatment of patients with rectal cancer.

Antineoplastic Agents↗
PubMed1998

[Mixed corticomedullary tumor].

BACKGROUND: Pheochromocytoma and primary hyperaldosteronism rarely occur simultaneously. Few cases have been reported in the literature. CASE REPORT: A patient explored for hypertension was found to have hypokalemia related to primary hyperaldosteronism. Pathology examination of the ablated adrenal showed a co-existing pheochromocytoma suspected at history taking although urine catecholamines were normal. DISCUSSION: Different pathogenic hypothesis have been proposed. Such dual tumors could be a simple coincidence, occur in a particular genetic setting, be related to direct contact between cortical and medullary tissue leading to reactional cortical hyperplasia, pheochromocytoma produced factors stimulating aldosterone synthesis, or factor X, a substance produced by cortical adenomas and favoring growth of the pheochromocytoma.

Adrenal Gland Neoplasms↗