ABSTRACT
PURPOSE: In locally advanced rectal cancer tumor-negative margins often cannot be obtained by surgery alone. Nevertheless only patients with complete tumor resection can be cured. Due to the poor prognosis of patients with R1/R2 resection the "Deutsche Krebsgesellschaft" recommends concurrent preoperative radiochemotherapy for patients with locally advanced rectal cancer. PATIENTS AND METHODS: Between May 1997 and November 1999 22 patients were treated with preoperative radiochemotherapy. A total dose of 45 Gy with a small-volume boost of 5.4 Gy was delivered in conventional fractionation (single dose 1.8 Gy). On days 1 to 5 and 29 to 33 patients received concurrently 5-fluorouracil (5-FU) as continuous infusion of 1,000 mg/m2. If there was any sign of cardiac toxicity chemotherapy was changed to 5-FU/folinic acid or ralitrexed. RESULTS: Surgery following radiochemotherapy was performed in 19/22 patients. Resections with negative margins were achieved in 16/19 (84%) patients. Sphincter-conserving surgery was possible in 9/19 (47%) patients. A downstaging of at least 1 T category was found in 12/19 (63%) patients. With a median follow-up of 16 months no locoregional recurrences occurred in patients who underwent surgery. Two-year disease-free survival of resected patients is 62%, 2-year overall survival is 89%, of the whole population 76%. CONCLUSION: Preoperative radiochemotherapy followed by surgery is able to achieve clear resection margins in more than 70% of patients with locally advanced rectal cancer and may improve the rate of sphincter-conserving surgery.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Fluorouracil/therapeutic use , Rectal Neoplasms/drug therapy , Rectal Neoplasms/radiotherapy , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Combined Modality Therapy , Disease-Free Survival , Dose Fractionation, Radiation , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasm Staging , Radiotherapy Dosage , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Survival Rate , Time FactorsABSTRACT
A major reason for the failure of clinical islet transplantations may be a limited islet mass. The aim of this study was to determine the critical islet mass necessary for normalization of glucose metabolism in a porcine model. Diabetes was induced by total pancreatectomy. The splenic lobe of the pancreas was intraductally distended with UW-solution containing 2.67-3.33 mg/ml collagenase, and the distended pancreas was digested in a continuous digestion filtration device. The islets were purified on a isoosmotic Ficoll-sodium-diatrizoate gradient. The survival period of the diabetic recipients in group 2 and 3 receiving, respectively, a low (2.14+/-0.39 microL/kg body weight) and a high (4.99+/-0.83 microL/kg body weight) islet mass was significantly prolonged compared to that of diabetic recipients in group 1 receiving no islet transplantation. However, the survival period of the recipients in group 2 was not significantly different to that in group 3. Three recipients of an islet mass of >5 microl/kg body weight became normoglycemic (fasting blood glucose <100 mg/dl) for more than two months. Furthermore, the glucose and insulin release reactions to the glucose challenge were comparable to that before pancreatectomy. Contrarily, another five diabetic recipients of an islet mass of <4 microL/kg body weight became a fasting blood glucose level of <200 mg/dl. The glucose and insulin release reactions to the glucose challenge were improved only, but not normalized compared to that before pancreatectomy. The data presented in this study demonstrate that metabolic normalization in pancreatectomized diabetic minipigs can be established by autotransplantation of an islet mass of >5 microl/kg body weight.
Subject(s)
Diabetes Mellitus, Type 1/surgery , Graft Survival , Islets of Langerhans Transplantation , Islets of Langerhans/cytology , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/metabolism , Female , Glucose Tolerance Test , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Pancreatectomy , Swine , Swine, Miniature , Transplantation, AutologousABSTRACT
BACKGROUND: Because of its anatomical and physiological similarities to humans, the pig appears to be a suitable large animal model for preclinical studies of islet transplantation. The aim of this study was to investigate islet auto- and allotransplantation in a pig model with diabetes induced by total pancreatectomy. METHODS: Porcine islets were isolated by a continuous digestion-filtration device at 32 degrees C and purified by a discontinuous iso-osmolar Ficoll-sodium-diatrizoate gradient on a Cobe 2991. The purified islets were autografted into the liver or the renal subcapsular space. The liver appears to be a more suitable site for the islet grafts than the renal subcapsular space, and the minimal amount of islets for reversal of diabetes is >5 microl/kg of body weight. RESULTS: Persistent normoglycemia (fasting blood glucose level: 72.4+/-44.38 mg/dl) with a normal insulin secretion response to glucose stimulation was successfully achieved in five of six diabetic pigs by implanting a sufficient islet mass into the liver. Triple-drug immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone did not prevent porcine islet allografts from experiencing early failure. However, the addition of 15-deoxyspergualin to the triple-drug immunosuppressive regimen significantly prolonged the function of the islet allografts. When antithymocyte globulin was added to the above-mentioned immunosuppressive drug regimen, the normoglycemic period was prolonged to more than 1 month (fasting blood glucose level: 75.4+/-17 mg/dl). CONCLUSION: We conclude that autotransplantation with a sufficient islet mass can induce normoglycemia with a normal insulin secretion response to glucose stimulation in pancreatectomized diabetic pigs and that allotransplantation can be successfully achieved when 15-deoxyspergualin and antithymocyte globulin are combined with the triple-drug immunosuppression described above. However, this immunosuppressive protocol results in a high rate of infectious complications.
Subject(s)
Diabetes Mellitus, Experimental/therapy , Islets of Langerhans Transplantation , Animals , Blood Glucose/analysis , Female , Graft Survival , Immunosuppressive Agents/pharmacology , Pancreatectomy , Swine , Swine, Miniature , Transplantation, Autologous , Transplantation, HomologousSubject(s)
Diabetes Mellitus, Type 1/surgery , Graft Survival/physiology , Immunosuppressive Agents/pharmacology , Islets of Langerhans Transplantation/physiology , Animals , Antilymphocyte Serum/therapeutic use , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Graft Survival/drug effects , Guanidines/pharmacology , Islets of Langerhans Transplantation/immunology , Pancreatectomy , Swine , Transplantation, HomologousSubject(s)
Diabetes Mellitus, Type 1/surgery , Glucose Tolerance Test , Islets of Langerhans Transplantation/physiology , Animals , Blood Glucose/metabolism , C-Peptide/blood , Diabetes Mellitus, Type 1/blood , Female , Insulin/blood , Islets of Langerhans Transplantation/methods , Pancreatectomy , Swine , Transplantation, Autologous/physiology , Transplantation, Homologous/physiologySubject(s)
Diabetes Mellitus, Type 1/therapy , Graft Survival , Islets of Langerhans Transplantation/physiology , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Drug Therapy, Combination , Female , Glucose Tolerance Test , Immunosuppressive Agents/therapeutic use , Insulin/blood , Insulin/metabolism , Insulin Secretion , Islets of Langerhans Transplantation/immunology , Pancreatectomy , Swine , Transplantation, HomologousABSTRACT
Successful transplantation of encapsulated islets (bioartificial pancreas) would circumvent problems of islet availability and rejection in the treatment of insulin-dependent diabetes with biological organ replacement. Alginates are widely used as a hydrogel matrix or membrane for immunoprotected transplantation. A major problem in the use of diffusion-based devices is the biocompatibility of the material used. The foreign body reaction after implantation of empty microcapsules into different compartments in rats, dogs and pigs is evaluated in this article. However, biocompatibility of the bioartificial pancreas has three different aspects: reaction of the entrapped islet to the encapsulation technique and material; reaction of the recipient against the incorporated device ( = foreign body reaction); and finally the reaction of the recipient against the encapsulated islet ( = immunology of bioartificial pancreas). It is obvious from different experiments that even if foreign body reactions (reactions against material) are almost abolished the recipient may react against material released from the encapsulated islet. In conclusion, transplantation of encapsulated islets induces various morphological reactions (i.e. inflammation and fibrosis) as a result of a variety of donor and recipient related factors. Therefore, the use of an adequate animal model that reflects the human situation is essential for progress in the development of a bioartificial pancreas.
Subject(s)
Biocompatible Materials/standards , Foreign-Body Reaction/prevention & control , Islets of Langerhans Transplantation , Islets of Langerhans/immunology , Alginates/adverse effects , Animals , Artificial Organs , Cell Survival/immunology , Diabetes Mellitus, Type 1/therapy , Dogs , Foreign-Body Reaction/immunology , Humans , Islets of Langerhans/cytology , Islets of Langerhans/physiology , Islets of Langerhans Transplantation/immunology , Microspheres , Rats , SwineSubject(s)
Antigens, Differentiation/analysis , Islets of Langerhans Transplantation/immunology , Animals , Azathioprine/therapeutic use , Cyclosporine/therapeutic use , Flow Cytometry , Immunosuppression Therapy , Lymphocytes/immunology , Monitoring, Immunologic , Pancreatectomy , Prednisolone/therapeutic use , Splenectomy , Swine , Transplantation, HomologousSubject(s)
Cyclosporine/pharmacology , Lymphoid Tissue/immunology , T-Lymphocytes/immunology , Animals , Antigens, Differentiation, T-Lymphocyte/immunology , Bone Marrow/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Flow Cytometry , Lymph Nodes/immunology , Spleen/immunology , Swine , T-Lymphocyte Subsets/immunology , T-Lymphocytes/drug effects , Thymus Gland/immunologyABSTRACT
Direct puncture of the small bowel under endoscopic guidance (direct EPJ) is possible in patients whose stomach has been removed or whose small bowel cannot be punctured by other methods. From January 1990 to June 1992 a total of 39 patients underwent successful direct EPJ at our institution. The indications were malnutrition after partial or total gastrectomy (n = 19), insufficient anastomosis or a stenosis after esophageal resection and esophagojejunostomy (n = 13), esophageal perforation (n = 3), fistulas (n = 2), or severe trauma (n = 2). The tubes were inserted at the bedside under local anesthesia using the string pull-through technique. The procedure was attempted in five other patients but it was technically impossible to insert the tubes in these patients. Postoperative enteral feeding was possible in all 39 patients whose direct EPJ was successful. Complications included tube dysfunction due to plugging and fracture in five patients, pressure-induced enteric ulcers in two, and local infections in three patients. The ulcers and infections were managed conservatively. We conclude that direct EPJ is a safe, effective alternative to surgical catheter-jejunostomy.
Subject(s)
Enteral Nutrition , Jejunostomy/methods , Laparoscopy/methods , Nutrition Disorders/surgery , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Endoscopy, Gastrointestinal , Humans , Middle Aged , Nutrition Disorders/etiology , Nutrition Disorders/therapy , Postoperative Complications , SkinSubject(s)
Diabetes Mellitus, Type 1/surgery , Islets of Langerhans Transplantation/methods , Adult , Blood Glucose/metabolism , C-Peptide/blood , Diabetes Mellitus, Type 1/blood , Diabetic Nephropathies/surgery , Female , Follow-Up Studies , Humans , Islets of Langerhans Transplantation/immunology , Islets of Langerhans Transplantation/physiology , Kidney Failure, Chronic/surgery , Kidney Transplantation , Parenteral Nutrition, Total , Prednisolone/therapeutic use , Time Factors , Transplantation, HomologousSubject(s)
Diabetes Mellitus, Experimental/surgery , Islets of Langerhans Transplantation/methods , Transplantation, Heterotopic/methods , Animals , Blood Glucose/metabolism , Cell Separation , Centrifugation, Density Gradient , Diabetes Mellitus, Experimental/blood , Glucose Tolerance Test , Islets of Langerhans/cytology , Islets of Langerhans Transplantation/physiology , Kidney , Portal Vein , Swine , Transplantation, Autologous , Transplantation, Heterotopic/physiologySubject(s)
Islets of Langerhans Transplantation/methods , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/surgery , Female , Islets of Langerhans Transplantation/physiology , Kidney , Male , Pancreatectomy , Portal Vein , Swine , Time Factors , Transplantation, Autologous , Transplantation, Heterotopic , Transplantation, HomologousSubject(s)
Graft Survival/immunology , Islets of Langerhans Transplantation/immunology , Macrophages/physiology , Transplantation, Heterotopic/methods , Animals , Blood Glucose/metabolism , Carrageenan/pharmacology , Graft Survival/drug effects , Guanidines/pharmacology , Immunosuppressive Agents/pharmacology , Portal Vein , SwineSubject(s)
Azathioprine/therapeutic use , Cyclosporine/therapeutic use , Islets of Langerhans Transplantation/immunology , Prednisolone/therapeutic use , Animals , Blood Glucose/metabolism , Drug Therapy, Combination , Immunosuppression Therapy/methods , Islets of Langerhans Transplantation/pathology , Islets of Langerhans Transplantation/physiology , Liver/pathology , Pancreatectomy , Swine , Transplantation, Heterotopic/immunology , Transplantation, Heterotopic/pathology , Transplantation, Heterotopic/physiology , Transplantation, Homologous/immunology , Transplantation, Homologous/pathology , Transplantation, Homologous/physiologySubject(s)
Islets of Langerhans Transplantation , Islets of Langerhans , Pancreas , Animals , Blood Glucose/metabolism , C-Peptide/metabolism , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/cytology , Islets of Langerhans Transplantation/physiology , Pancreatectomy , Swine , Tolbutamide/pharmacology , Transplantation, AutologousABSTRACT
In 66 patients with renal transplants 246 sonographic examinations were performed. The patients were divided into two groups based on their immunosuppressive protocol. Group I was treated with Cyclosporin A (CsA) and group II with azathioprin. A compensatory hypertrophy with a volume increase of 20% could be seen in nearly all grafts. During acute tubular necrosis only minimal sonographic changes could be found. In each group 16 patients developed an acute rejection episode. Sonographic signs of acute rejection were: (1) a hypoechoic enlargement of the renal pyramides; (2) an increase in cortical echogenicity; (3) an increase in graft volume greater than compensatory hypertrophy; (4) an indistinct parenchyma-pelvic border; (5) dilation of the pelvis with a parenchyma-pelvic index greater than 2.3:1 (in group II cases). Chronic rejection is characterized by graft shrinkage. No specific signs were evident. The increasing use of CsA diminishes the value of sonography in follow-up of acute rejection after kidney transplantation. Nevertheless, it is of great value for follow-up examination concerning other complications.