We have reviewed results of therapy in 740 patients with grades II-IV acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. At the beginning of therapy, 597 patients (81%) had rash, 369 (50%) had liver dysfunction and 396 (54%) had gut dysfunction. Initial treatment was with glucocorticoids (n = 531), cyclosporine (n = 170), antithymocyte globulin (ATG) (n = 156) or monoclonal antibody (n = 3) either singly (n = 633) or in combination (n = 107). Parameters of GVHD severity in each organ were recorded weekly, and evaluation of response was made using values at the initiation of secondary treatment or, for patients without such treatment, using values on day 29 of primary treatment or the last recorded value before death, whichever occurred first. Minimal criteria for improvement or progression were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement rates were 43% for skin disease, 35% for evaluable liver disease and 50% for evaluable gut disease. Overall complete or partial responses were seen in 44% of patients. Multivariate analyses were carried out to identify patient, disease or treatment factors associated with likelihood of overall improvement and likelihood of response in at least one organ. A similar analysis was also carried out to identify covariates associated with time to treatment failure (defined as initiation of secondary therapy or death not due to relapse of malignancy). In all three models, GVHD prophylaxis using cyclosporine combined with methotrexate was associated with favorable GVHD treatment outcome compared to prophylaxis with either agent alone, and treatment with glucocorticoids or cyclosporine was more successful than treatment with ATG. Other factors associated with unfavorable outcome in the model of time to treatment failure and also entered in one of the response models were recipient HLA disparity with the donor, presence of a liver complication other than GVHD, and early onset of GVHD. Results of this analysis indicate that glucocorticoids represent the best initial therapy available for treatment of acute GVHD, although much room for improvement remains.
Prior administration of BU and/or phenytoin significantly alters exposure to CY and HCY. Interpatient variability in HCY exposure at a given CY dose is substantial.
Summary:We examined the degree of hepatic iron overload in patients receiving marrow transplant for hematologic malignancy and evaluated a new method of morphometric analysis of marrow iron content as a means of estimating hepatic iron stores in these patients. The iron content of marrow and liver specimens from 10 consecutive patients who died between 50 and 100 days after transplant was determined by spectrophotometry. Their mean age was 34.9 years (range 10-59). The mean time to death from disease onset was 2.2 years (0.5-8.7). Patients had received 30.2 ± ± ± 17.4 units of red cells during the transplant period and 47.6 ± ± ± 25.9 red cell units from diagnosis to death. The median hepatic iron concentration (HIC) was 4307 g/g dry weight (range 1832-13120; normal 530-900) and the median hepatic iron index (HIC (mol/g dry weight/age (years)) was 3.85 (0.76-8.14). The median biochemical marrow iron content was 1999 g/g dry weight (range 932-3942). Morphometric analysis of the marrow iron content was performed on digital photomicrographs of a single Prussian blue-stained section of marrow. Strong correlations were demonstrated between morphometric marrow iron content and (1) biochemical marrow iron content (r = 0.8, P = 0.006) and (2) biochemical hepatic iron index (r = 0.82, P = 0.004). We conclude that marrow transplant recipients have a high liver iron content at 50-100 days post transplant with the hepatic iron index in the hereditary hemochromatosis range. Computerized morphometric marrow iron determination is a readily available means of estimating hepatic iron stores in these patients.
We studied the route of transport of long-chain fatty acids (LCFA) from the rat intestine. Lauric (12:0), myristic (14:0), palmitic (16:0), stearic (18:0), linoleic (18:2), and linolenic (18:3) acids were infused intraduodenally for 4 h as micellar solutions into unanesthetized thoracic duct-fistula rats. Proportionally more of each LCFA was transported by the portal vein at infusion rates of 0.3 mumol/h than at 15 mumol/h. Of the LCFA absorbed at low rates of infusion, 72% of lauric, 58% of myristic, 41% of palmitic, 28% of stearic, 58% of linoleic, and 68% of linolenic acid bypassed the lymphatic pathway. To test the inference that 58% of absorbed linoleate was transported by the portal vein, [14C]linoleic acid was infused at 0.3 or 15 mumol/h into unanesthetized rats equipped with both thoracic duct and portal venous fistulas. Portal venous blood (0.1 ml) was withdrawn every 30 min for 4 h. Proportionally more [14C]linoleate was recovered in portal blood at the low infusion rate. To examine the morphology of fat absorption, segments of rat jejunum in anesthetized rats were infused with micellar linoleic acid at 3 or 150 mumol/h. At 3-mumol/h infusion rate, an appearance identical to the fasting state was seen by electron microscopy. At 150 mumol/h, many larger chylomicron-sized particles appeared in absorptive cells, intercellular spaces, and lymphatics. We conclude that a substantial proportion of unsaturated LCFA is transported from rat intestine in portal venous blood.
We have reviewed results of secondary therapy in 427 patients with acute graft-versus-host disease (GVHD) who did not have a durable satisfactory response after primary treatment. At the beginning of secondary treatment, 320 patients (75%) had rash, 252 (59%) had liver dysfunction, and 228 (53%) had gut dysfunction. Secondary treatment was with glucocorticoids (n = 249), cyclosporine (n = 80), antithymocyte globulin (n = 114), or monoclonal antibody (n = 19) either singly (n = 390) or in combination (n = 37). Parameters of GVHD severity were recorded weekly, and responses were determined according to values at the initiation of tertiary treatment or, for patients without such treatment, using values on day 29 of secondary treatment or the last recorded values before death, whichever occurred first. Minimal criteria for improvement or deterioration were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement or resolution of GVHD in the respective organ was seen in 45% of patients with skin disease, 25% of patients with evaluable liver disease, and in 35% of patients with evaluable gut disease. Overall complete or partial responses were seen in 40% of patients. The highest complete response rate with secondary therapy (23%) was seen when GVHD recurred during the taper phase of primary glucocorticoid treatment and was managed by increasing the dose of glucocorticoids. Multivariate analyses were performed to identify patient, disease, or treatment factors associated with likelihood of complete response or overall improvement. A similar analysis was performed to identify covariates associated with time to treatment failure (defined as initiation of tertiary therapy or death not due to relapse of malignancy). Severe dysfunction in the skin, liver, and gut at the beginning of treatment was associated both with a decreased likelihood of complete response and an increased treatment failure rate. The times to treatment failure and the proportions of patients in various response categories were similar for primary and secondary treatment, suggesting that the potential efficacy of new immunosuppressive agents for treatment of acute GVHD can be assessed meaningfully in patients who have not responded adequately to initial therapy.
Summary:recognize the symptoms of pancreatitis in this population. However, marrow transplant patients may be predisposed to developing pancreatitis due to the high prevalence of Pancreatitis has been described as an infrequent complication of marrow transplantation. This study investibiliary sludge and sonographic biliary tract abnormalities, 2,3use of irradiation and cytotoxic drugs in the conditioning gated the prevalence of pancreatitis at autopsy in marrow transplant patients and determined risk factors for regimen, and treatment with medications that have been associated with pancreatitis such as corticosteroids and its development. We reviewed consecutive autopsy reports from 1991 to 1993. Medical records and laboracyclosporine. [4][5][6][7][8][9][10][11][12] Infectious etiologies of pancreatitis are also possible because of the profound immunosuppression tory reports were reviewed for analysis of clinical variables. Autopsy findings and clinical variables were corthat develops after transplant. There are reports in marrow transplant patients of disseminated cytomegalovirus, related with the autopsy diagnosis of pancreatitis. Pancreatitis was found in 51 of 184 (28%) patients at adenovirus, and varicella zoster virus infections involving the pancreas and mimicking attacks of idiopathic autopsy. Of those with pancreatitis, 35% had abdominal pain, 10% had measurements of serum pancreatic pancreatitis. 13-16To estimate the prevalence of pancreatitis at autopsy in enzymes, and 20% had abdominal imaging studies in the week prior to death. By univariable analysis, risk marrow transplant patients, we reviewed the histologic and gross findings from all patients autopsied at our center factors associated with development of pancreatitis included clinical grades 3 and 4 GVHD, GVHD at autobetween January 1991 and December 1993. Clinical, radiologic, and laboratory data were also reviewed to analyze psy, liver GVHD at autopsy, major infection at autopsy, and increasing days of survival. By multivariable analythe frequency of pre-mortem signs and symptoms in patients with pancreatitis. Gallbladder contents were sis, independent risk factors for its development included any GVHD at autopsy, increasing length of obtained at autopsy and analyzed chemically and microscopically for the presence of sludge, as previously survival after transplantation, and major infection at autopsy. We conclude that pancreatitis is a common but described. 17 To determine risk factors for its development, the frequency of clinical and therapeutic parameters in often subclinical complication of marrow transplantation. Its development may be associated with a high patients with pancreatitis was compared to those in patients without pancreatitis. prevalence of biliary sludge and prolonged treatment of GVHD with cyclosporine and prednisone.
We have reviewed results of therapy in 740 patients with grades II-IV acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. At the beginning of therapy, 597 patients (81%) had rash, 369 (50%) had liver dysfunction and 396 (54%) had gut dysfunction. Initial treatment was with glucocorticoids (n = 531), cyclosporine (n = 170), antithymocyte globulin (ATG) (n = 156) or monoclonal antibody (n = 3) either singly (n = 633) or in combination (n = 107). Parameters of GVHD severity in each organ were recorded weekly, and evaluation of response was made using values at the initiation of secondary treatment or, for patients without such treatment, using values on day 29 of primary treatment or the last recorded value before death, whichever occurred first. Minimal criteria for improvement or progression were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement rates were 43% for skin disease, 35% for evaluable liver disease and 50% for evaluable gut disease. Overall complete or partial responses were seen in 44% of patients. Multivariate analyses were carried out to identify patient, disease or treatment factors associated with likelihood of overall improvement and likelihood of response in at least one organ. A similar analysis was also carried out to identify covariates associated with time to treatment failure (defined as initiation of secondary therapy or death not due to relapse of malignancy). In all three models, GVHD prophylaxis using cyclosporine combined with methotrexate was associated with favorable GVHD treatment outcome compared to prophylaxis with either agent alone, and treatment with glucocorticoids or cyclosporine was more successful than treatment with ATG. Other factors associated with unfavorable outcome in the model of time to treatment failure and also entered in one of the response models were recipient HLA disparity with the donor, presence of a liver complication other than GVHD, and early onset of GVHD. Results of this analysis indicate that glucocorticoids represent the best initial therapy available for treatment of acute GVHD, although much room for improvement remains.
This study evaluated the effect of pentoxifylline (PTX) on the incidence of regimen-related toxicity in patients receiving allogeneic marrow transplants from related donors. All patients received a regimen of methotrexate and cyclosporine as prophylaxis against acute graft- versus-host disease (GVHD). Patients were randomized to receive PTX or a placebo for 70 days and the outcome was examined in a blinded fashion. Forty-four patients were evaluate in each study arm. PTX had no significant effect on engraftment, the incidence of GVHD, venocclusive disease of the liver, infection, the need for oxygen, posttransplant survival, or the duration of hospitalization. Patients receiving PTX were significantly more likely to develop major elevations of serum creatinine levels. PTX was poorly tolerated and induced significantly more vomiting than the placebo. PTX as administered in this randomized study was associated with significant toxicity and offered no benefit in reducing transplant-related morbidity or mortality.
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