Prognostic factors for radioimmunotherapy in patients with B-lymphocytic malignancies.

The Ann Arbor staging classification has proven less useful in nonHodgkin's lymphoma, because this malignancy is inherently a multifocal disorder. Since 1985, 57 adult patients with advanced B-lymphocytic malignancies that progressed despite standard therapy entered into one of three different therapy trials using radiolabeled Lym-1 antibody. Tumor regression in 31 (54%) of these patients fulfilled conventional requirements for an oncological response to the therapy. To define the role of radioimmunotherapy in B-lymphocytic malignancies better and to find opportunities for improving its therapeutic efficacy, the records of these patients were reviewed to assess the significance of various parameters as prognostic indicators. Twenty-one pretherapy characteristics were evaluated, including age at diagnosis, age at study entry, sex, Karnofsky performance status, prior chemotherapy and radiation therapy, interval since diagnosis, histology, constitutional B symptoms, extranodal malignancy (excluding marrow), bone marrow malignancy, tumor bulk, and circulating malignant cells; blood tests included lymphocyte, granulocyte, platelet, hematocrit, serum lactate dehydrogenase (LDH), interleukin 2 receptor, and human antimouse antibody levels. In the multivariate analysis, LDH and Karnofsky performance status were the parameters that best predicted survival, complete and partial remission, and time to progression; interleukin 2 receptor and LDH best predicted complete remission. These prognostic factors for radioimmunotherapy outcome are consistent with the pretherapy characteristics observed to be significant for chemotherapy.

Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies.

This study was designed to evaluate dosimetric, pharmacokinetic, and other treatment-related parameters as predictors of outcome in patients with advanced B-lymphocytic malignancies. Fifty-seven patients were treated with radiolabeled Lym-1 antibody in early phase trials between 1985 and 1994. Logistic regression and proportional hazards models were used to evaluate treatment parameters for their ability to predict outcome, taking into account patient risk group based on Karnofsky performance status and serum lactic dehydrogenase. The occurrence of a partial or complete response (31 of 57 patients) and development of human antimouse antibody (HAMA) predicted improved survival using a time-dependent proportional hazards model. The final multivariate model for survival with parameters significant at P

A comparison of point-of-care instruments designed for monitoring oral anticoagulation with standard laboratory methods.

Our study compared point-of-care (POC) device monitoring with traditional clinical laboratory methods device of patients on oral anticoagulant therapy. The POC devices used in the study were Coumatrak, CoaguChek, CoaguChek Plus, Thrombolytic Assessment System (TAS) PT-One, TAS PTNC, TAS PT, Hemachron Jr. Signature, ProTime Microcoagulation System, and Medtronics ACT II. The clinical laboratory method used thromboplastins with different ISI values: Innovin and Thromboplastin C Plus (TPC). All POC INRs showed strong correlation with both laboratory methods, with correlation coefficients of >0.900. All POC methods demonstrated a significant (p <0.05) difference in INR values, except the TAS PTNC and ACT II INRs (p: 0.12 and 0.71 respectively) when compared with Innovin INRs. All POC INRs were significantly different from TPC generated INRs (p <0.05). Comparisons of the POC INRs to the group mean of the POC methods, show higher correlation (R>0.93), but there were still significant (p<0.05) differences noted between the POC group INR mean and CoaguChek Plus, ACT II, TAS PT-One, TAS PTNC, and Hemachron Jr Signature INRs. These data indicate that POC INR biases exist between laboratory methods and POC devices. Until a suitable whole blood INR standardization method is available, we conclude that clinicians using point-of-care anticoagulation monitoring should be aware of differences between POC and parent laboratory values.

Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques.

HYPOTHESIS: Children who undergo cardiopulmonary bypass (CPB) are proportionally more hemodiluted than adults who undergo CPB. Current methods of monitoring high-dose heparin sulfate anticoagulation are dependent on fibrinogen level. Because of the decreased fibrinogen levels in children, current methods of monitoring heparin anticoagulation overestimate their level of anticoagulation. DESIGN: Prospective controlled trial. MAIN OUTCOME MEASURE: Production of thrombin (adequacy of anticoagulation). METHODS: Children and adults undergoing cardiac surgery who received CPB were anticoagulated in the standard fashion as directed by activated clotting time (ACT) results. Each subject had blood sampled at baseline; heparinization; start of the CPB; CPB at 30, 60, and 90 minutes; and at termination of CPB. Samples were used to assess anticoagulation with the Heparin Management Test (less dependent on fibrinogen level than ACT). We also assessed 2 subclinical markers of thrombosis, thrombin-antithrombin complexes and prothrombin fragment F1.2; a marker of procoagulant reserve, fibrinogen; the natural antithrombotic, antithrombin; and heparin concentration. RESULTS: Ten children and 10 adults completed the study. Children had lower fibrinogen levels than adults throughout CPB (P<.05). All adults had both therapeutic ACT and Heparin Management Test levels measured throughout CPB. Although children had therapeutic ACT levels, their Heparin Management Test levels were subtherapeutic while undergoing CPB. The children had significantly higher thrombin-antithrombin complexes and prothrombin fragment F1.2 than adults, indicating ongoing thrombin production (P<.01). The increases in thrombin-antithrombin complexes and prothrombin fragment F1.2 in children were inversely proportional to their weight. CONCLUSIONS: Children undergoing CPB with heparin dosing adjusted to optimize the ACT manifest inadequate anticoagulation (ongoing thrombin formation). High-dose heparin anticoagulation therapy in children undergoing CPB should be directed by tests (like the Heparin Management Test) that are less dependent on fibrinogen level than ACT.

Regulation of pancreatic amylase by dietary carbohydrate in chronic alcoholic rats.

The nutritional adequacy of dietary ingredients is essential for optimal food consumption and growth of animals. Dietary carbohydrate levels regulate pancreatic amylase synthesis. Ethanol diets with 36% of total calories from ethanol and 11% from carbohydrate are nutritionally inadequate, whereas a 26% ethanol diet made isocaloric to the 36% alcohol diet by the addition of maltose-dextrins provides all nutrients in amounts recommended for normal growth. Young rats fed the modified ethanol diet for 3 months consume 101.4 ml of diet daily compared to 66.5 ml by those on the 36% ethanol diet. Increased food consumption results in (a) similar amounts of alcohol consumption (3.6 vs. 3.3 g/day), (b) a threefold enhancement in carbohydrate intake (5.1 vs. 1.7 g/day), and (c) a normal growth rate (6.7 vs. 3.1 g/day). Both the acinar content of amylase (20.2 +/- 0.3 micrograms/mg of protein) and the acinar response to cholecystokinin-octapeptide in 36% ethanol diet-fed rats are significantly reduced compared to those of 26% ethanol diet-fed rats (34.1 +/- 5.6 micrograms/mg of protein). These results confirm (a) the nutritional adequacy of the 26% ethanol diet compared to the 36% ethanol diet, and (b) that carbohydrate inadequacy, and not ethanol consumption per se, is the primary cause of pancreatic amylase insufficiency in chronic alcoholic rats.

Reversal by glucose of pancreatic amylase insufficiency in chronic alcoholic rats.

Carbohydrate consumption regulates pancreatic amylase synthesis in rats. The Lieber-DeCarli 36% alcohol diet employed in chronic alcohol studies and the isocaloric control diet contain 11 and 47% of total calories from carbohydrates, respectively. Young rats fed ad libitum the 36% ethanol diet for 2 weeks obtained 1.2 g/day of carbohydrate, whereas those pair-fed with control diet received 5.8 g/day. Rats fed the 36% ethanol diet and given an intramuscular injection of a solution of 1.5 g of glucose daily for 2 weeks received twofold greater amounts of carbohydrate than saline-injected controls (2.7 versus 1.2 g). These changes in carbohydrate intake produced proportionate changes in pancreatic amylase levels. The secretory responses to cholecystokinin-octapeptide (CCK8) of acini from control and glucose-injected rats were significantly higher compared with those in the saline-injected or noninjected alcohol groups. The blood alcohol levels in glucose-injected rats were markedly reduced compared with other alcohol groups (71.7 versus 274.9 mg/dl) despite similar amounts of ethanol ingestion daily (2.4 g) in the three groups. In vitro experiments with acini from rats fed a nutritionally optimal diet revealed that high pharmacologic concentrations of ethanol, while inducing basal secretion, inhibited CCK8-stimulated amylase secretion. These results indicate that: (a) the amount of alcohol consumption does not correlate with either the levels of blood alcohol or of pancreatic amylase; (b) the carbohydrate availability in rats regulates pancreatic amylase levels despite significant levels of alcohol in blood; (c) blood alcohol levels observed in vivo may not affect synthetic and secretory processes of amylase in pancreatic acini.

Alcohol and the blood.

Pathologic effects of ethanol on hematopoietic tissue can result directly from alcohol ingestion or from secondary nutritional deficiencies or hepatic disease. The clinician will often confront an array of overlapping syndromes in the alcoholic patient which involve abnormalities of erythrocytes, leukocytes, and platelets.

Cholecystokinin-induced secretion and synthesis of amylase and cationic trypsinogen by pancreatic acini isolated from rats given an ethanol diet.

Effects of chronic alcohol intake on secretion and synthesis of amylase and cationic trypsinogen (CT) were studied with pancreatic acini isolated from male Sprague-Dawley rats fed a Lieber-DeCarli ethanol or control diet for 30 days. Pancreatic acini were incubated in a media containing increasing concentrations of cholecystokinin octapeptide (CCK-8: 0-1000pM) followed by addition of [3H]leucine. Amylase and CT secreted in the media and those labeled in acini were quantitated. Basal and CCK-stimulated secretion of CT was not different in alcoholic and control groups. On the other hand, a dose-response curve of CCK-stimulated amylase secretion from alcoholic acini was markedly reduced with both basal and maximal secretion decreased to only 40% of controls. Basal incorporation of [3H]leucine into amylase was reduced by 70% in alcoholic acini compared to controls while that into CT was not different in the two groups. CCK-8 exhibited a biphasic effect on [3H]leucine incorporation into both enzymes in alcoholic acini: low concentrations of CCK-8 (less than 100pM) increased the incorporation whereas high concentrations (greater than 100pM) decreased it. However, in control acini, CCK-8 induced progressive suppression of the incorporation into these enzymes, the pattern of which was similar to that previously observed in fasted rats (Am. J. Physiol. 241:G116-G112, 1981). This difference in the response pattern resulted in significantly higher rates of CCK-8 induced incorporation into CT in alcoholic acini. These results suggest that the differences observed may possibly be attributable not only to alcohol intake but also to the differences in carbohydrate intake and in temporal patterns of diet consumption.

Enhanced ratio of linoleic acid to arachidonic acid in erythrocyte phosphatidylcholine in rats during withdrawal from ethanol.

Male Sprague-Dawley rats were pair-fed for 8 weeks either an alcohol diet or a control diet made isocaloric with dextrose. Those on the alcohol diet were then fed the control diet for 3 days and both groups were killed. Analysis of the fatty acid composition of the various blood lipids showed that the relative level of 18:2 to 20:4 was significantly greater in the phosphatidylcholine fraction from erythrocytes of rats withdrawn from alcohol as compared to that from control animals. It has been suggested that in alcohol-fed animals the hepatic capacity to produce 20:4 from 18:2 is reduced. Therefore the increase in the ratio of 18:2/20:4 in erythrocyte phosphatidylcholine could serve as an index to detect the liver malfunction and to confirm recent chronic alcohol consumption.

Changes in relative levels of linoleate to arachidonate in erythrocyte phosphatidylcholine in rats fed ethanol and arachidonate.

Young male Sprague--Dawley rats were fed ad lib. for 4 weeks a liquid diet containing 34% of the calories as ethanol and 35% as fat (25 wt % linoleate). The ratio of the levels of linoleic acid to arachidonic acid (18:2/20:4) in erythrocyte phosphatidylcholine (PC) from alcohol-fed rats was greater than that from rats fed an isocaloric control diet. The increased 18:2/20:4 ratio in tissue lipids of animals ingesting ethanol is thought to be due to the reduced production of arachidonate from linoleate. In the present study we tested whether dietary arachidonate would mask the effects of alcohol on the 18:2/20:4 ratio in erythrocyte PC. Analysis of the fatty acid composition of erythrocyte PC of rats fed a diet supplemented with arachidonate showed that ethanol feeding did not alter the 18:2/20:4 ratio.

Changes in lipids of lung lavage in monkeys after chronic exposure to ambient levels of ozone.

A group of 8 sub-adult bonnet monkeys (Macaca radiata) was exposed to 0.3 ppm ozone (O3) and another group of 7 monkeys to 0.15 ppm O3 for 8 h/day for 90 days. A third group of 4 monkeys was exposed to 0.15 ppm O3 for 8 h/day for 21 days. The control group consisted of 7 monkeys which breathed filtered air for 90 days. Levels of linoleic and arachidonic acids in the total lipids from lung lavage increased about 2-fold in those exposed to O3 as compared to the levels in the controls. Furthermore, the relative level of cholesterol ester (CE) decreased and phosphatidylcholine (PC) increased markedly with chronic exposure of animals to O3. Enhanced polyunsaturated fatty acid (PUFA) composition in lung lavage and changes in the levels of CE and PC may be related to animals' adaptation to O3-exposure.

Changes in the levels of polyunsaturated fatty acids in the lung and lecithin cholesterol acyl transferase activity in plasma of monkeys exposed to ambient levels of ozone.

A group of 8 sub-adult bonnet monkeys (Macaca radiata) was exposed to 0.15 ppm ozone (O3) and another group of 8 to 0.3 ppm O3, 8 h/day, for 90 days. Four monkeys in the control group breathed filtered air during this period. Polyunsaturated fatty acids (PUFA) comprised about 22% of total fatty acids in the lungs of controls. The PUFA level decreased to about 90% and 6% in monkeys exposed to 0.15 ppm and 0.3 ppm O3, respectively. Lecithin cholesterol acyl transferase (LCAT) activity in the plasma of monkeys exposed to 0.15 ppm O3 was similar to that in the controls. However, the LCAT activity of plasma was significantly increased by the exposure of monkeys to 0.3 ppm O3.

A new method for measuring D-dimer using immunoturbidometry: a study of 255 patients with suspected pulmonary embolism and deep vein thrombosis.

D-Dimer testing has been suggested as a non-invasive method for the exclusion of pulmonary embolism (PE) and deep vein thrombosis (DVT). In this study, we compared a new method, the Miniquant D-dimer (Biopool International, Ventura, California, USA) to other previously validated D-dimer methods used for the purpose. Patients who were undergoing a definitive diagnostic study for thromboembolism had a blood sample drawn at that time. A whole-blood D-dimer (SimpliRed; Agen Biomedical Ltd, Brisbane, Australia) test was performed, and residual plasma was frozen and later analyzed using two enzyme-linked immunosorbent assay (ELISA) methods (D-dimer Gold; Agen, and Asserachrome D-Di; Stago International, Parsippany, New Jersey, USA) and the Miniquant D-dimer. Once all samples were analyzed, the correlation and accuracy of the Miniquant was compared with the ELISA method using Spearman's regression and Dunn's multiple paired comparison. All D-dimer methods were compared with radiographic studies. The data was analyzed collectively and segregated into in-patient (n = 112) and out-patient (n = 143) populations. The Miniquant D-dimer sensitivity, specificity and negative predictive value (NPV) for all patients were 95, 21, and 94% for DVT, and 100, 26, and 100% for PE. This new D-dimer method demonstrates acceptable sensitivity in patients with PE and DVT and, based on the high NPV of this method, it can be used for the exclusion of thromboembolism.

Evaluation of a new automated quantitative d-dimer, Advanced D-Dimer, in patients suspected of venous thromboembolism.

The objective of our study was to evaluate the performance characteristics of a new automated d-dimer, the Advanced D-Dimer (Dade Behring Inc., Deerfield, IL) for use in the diagnosis of venous thromboembolism (VTE). To do this we compared the Advanced D-Dimer to existing d-dimer methods using established target cut-off values in patients suspected of VTE who were to undergo definitive radiographic studies for VTE. We studied hospitalized patients and outpatients who were suspected of having VTE and who had whole blood d-dimer performed. The patients who underwent a diagnostic study for VTE had their D-dimer results used to determine sensitivity, specificity and negative predictive values. There was relatively poor correlation between the Advanced D-Dimer and D-Dimer Gold (r = 0.63; t-test: P < 0.005) and Asserachrome D-Di (r = 0.58; t-test: P < 0.005). The Advanced D-Dimer target cutoff values for excluding VTE in hospitalized and outpatients were < or = 1800 microg/L and < or = 1500 microg/l respectively. There were 139 patients suspected with pulmonary embolism (PE) and 328 evaluated for deep vein thrombosis (DVT). There were 24 patients with PE, and 43 with DVT. The Advanced D-Dimer had comparable sensitivity, specificity and negative predictive values (96, 43, 98% for PE and 96, 48, 99% for DVT respectively) to other d-dimer methods used for that purpose. We conclude that the Advanced D-Dimer correlates relatively poorly with enzyme-linked immunosorbent assay methods. This poor correlation is likely due to incorrect reporting units and concentration. When these factors are corrected correlations improved. Compared to existing d-dimer methods used for VTE exclusion, the high sensitivity and negative predictive value would suggest that this method can be used as part of a diagnostic algorithm for the exclusion of PE and DVT.

Solitary extramedullary plasmacytoma five years after successful cardiac transplantation: case report and review of the literature.

We document the occurrence of a solitary extramedullary plasmacytoma (SEP) in a cardiac transplant patient. The diagnosis of plasma cell malignancy was confirmed by histopathologic and immunohistochemical examination of a nodular skin lesion. A complete systemic evaluation showed no evidence of metastatic disease. The patient was treated locally with radiation therapy (RT), but disseminated multiple myeloma developed 4 months after diagnosis. A variety of tumors have been reported to develop in the cardiac or renal transplant recipient, although plasma cell malignancies are rare. To our knowledge, this is the first reported case of an SEP in an organ transplant recipient.

Reduction of essential fatty acid deficiency in rat fed a low iron fat free diet.

Young male rats were fed ad libitum for 8 weeks a low iron fat-free (FF-Fe) diet or a fat-free diet supplemented with iron (FF+Fe). The relative levels of 16:1 and 18:1 to 18:0 in the total fatty acids of liver and other tissues (plasma, erythrocytes and intestinal mucosa) were considerably decreased because of a lack of dietary iron. In rats fed the FF-Fe diet, the levels of essential fatty acids (18:2 omega 6 + 20:4 omega 6) in tissues were 2- to 3-fold greater than in the corresponding tissues of rats fed the FF+Fe diet. Eicosatrienoic acid (20:3 omega 9) levels in tissue lipids from rats fed the FF+Fe diet were high (8-16%), whereas they were low (2-5%) in the case of animals fed the FF-Fe diet. The proportion of 20:4 in total fatty acids of tissues was 2- to 3-fold greater in rats fed the FF-Fe diet than when they were fed the FF+Fe diet. Therefore, the relative levels of 20:3 omega 9/20:4 omega 6 varied from 1-2.9 in tissue lipids of rats fed the FF+Fe diet, while it varied only from 0.2-0.3 in animals fed the FF-Fe diet. These results suggest that a lack of dietary iron may reduce the synthesis of 16:1, 18:1, 20:3 and 20:4 and the metabolism of 20:4.

Reduction in medium chain acids and monoenoic acids in livers and plasma of rats fed eicosa-5,8,11, 14-tetraynoic acid.

Male Sprague-Dawley rats were fed for 8 weeks a corn oil (CO) diet or a hydrogenated coconut oil (HCNO) diet. These diets were fed in the absence or presence of eicosa-5,8,11,14-tetraynoic acid (TYA). The inclusion of TYA in the HCNO diet reduced the levels of 12:0 and 14:0 in the total fatty acids of livers and plasma. With either diet, the presence of TYA caused an alteration in the fatty acid composition of these tissues so as to reduce the values of the ratios: 16:1/16:0, 18:1/18:0. and 20:4/18:2. These results suggest that dietary TYA can influence the hepatic metabolism of medium chain fatty acids and that it may inhibit the desaturase enzyme involved in the synthesis of not only 20:4 but also of monoenoic fatty acids.

Alcohol ingestion and levels of hepatic fatty acid synthetase and stearoyl-CoA desaturase activities in rats.

Male Sprague-Dawley rats were fed, ad libitum for 30 days, a fat-free (FF) liquid diet containing 34% of the calories as ethanol or a control FF diet in which alcohol was replaced by an isocaloric amount of dextrins. The cytosolic fatty acid synthetase and the microsomal stearoyl-CoA desaturase activities in the livers of rats fed the alcohol diet were about half of those observed in the livers of control rats. The conclusion is that chronic ethanol consumption depresses the activities of these lipogenic enzymes in the liver.

Morphology and fatty acid composition of reticulocytes from phenylhydrazine-treated rats.

Reticulocytosis was induced in rats by injecting phenylhydrazine, a potent oxidizing agent. Red cell morphology was analyzed by scanning electron microscopy. The majority of red cells from rats given injections of phenylhydrazine were types 2 and 3 echinocytes. Stomatocytes were also observed, but pitted lobular reticulocytes were not detected. Echinocytes have not previously been observed in reticulocyte populations. In the reticulocytes, the relative levels of 16:1 and 18:1 were significantly greater than in erythrocytes. These differences in monoenoic acids may be due to the presence of endoplasmic reticulum, the site of desaturase activity in reticulocytes. Of all the fatty acids, the polyunsaturates are the most susceptible to attack during peroxidation. However, the polyunsaturated fatty acid composition of reticulocytes was similar both to that of erythrocytes and to reported values of young erythrocytes isolated by density. Therefore, it is unlikely that lipid peroxidation caused the formation of echinocytes.