Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus.

Adult Philadelphia chromosome-positive (Ph+) or BCR-ABL-positive (BCR-ABL+) acute lymphoblastic leukemia (all) is an acute leukemia previously associated with a high relapse rate, short disease-free survival, and poor overall survival. In adults, allogeneic hematopoietic cell transplant in first remission remains the only proven curative strategy for transplant-eligible patients. The introduction of tyrosine kinase inhibitors (tkis) in the treatment of patients with Ph+ or BCR-ABL+ all has significantly improved the depth and duration of complete remission, allowing more patients to proceed to transplantation. Although tkis are now considered a standard of care in this setting, few randomized trials have examined the optimal use of tkis in patients with Ph+ all. Questions of major importance remain, including the best way to administer these medications, the choice of tki to administer, and the schedule and the duration to use. We present the results of a systematic review of the literature with consensus recommendations based on the available evidence.

Digitoxin poisoning: prevention by spironolactone.

Spironolactone (Aldactone(R)) protects the rat against the production of myocardial necroses and other manifestations of digitoxin poisoning.

Patient eligibility for hematopoietic stem cell transplantation: a review of patient-associated variables.

Assessing patient eligibility for hematopoietic stem cell transplantation (HSCT) remains a complex, multifaceted challenge. Among these challenges, the paucity of comprehensive clinical data to guide decision making remains problematic coupled with unclear trade-offs between patient, disease and local HSCT center factors. Moreover, it is unclear that the modification of poor patient characteristics will improve post-HSCT outcomes. However, the use of Comorbidity Indices and Comprehensive Geriatric Assessments helps meet this challenge, but may be limited by overlapping patient characteristics. The increasing consideration for pre-HSCT psychosocial assessments and interventions remains to be studied. Ultimately, the decision to proceed with a HSCT remains interdisciplinary while considering the available evidence discussed in this review.

Overnight storage of autologous stem cell apheresis products before cryopreservation does not adversely impact early or long-term engraftment following transplantation.

To reduce costs and avoid inconvenient overtime work, our institution changed policy in September 2000 so that autologous stem cell apheresis products were stored overnight before cryopreservation rather than immediately processed. This retrospective review was conducted to evaluate the possible impact of this policy change on hematopoietic engraftment following autologous stem cell transplantation (ASCT). In total, 229 consecutive lymphoma patients who underwent a single, unpurged ASCT in Calgary between January 1995 and November 2003 were evaluated. Of these patients, 131 patients' autografts underwent immediate processing and cryopreservation before September 2000, and 98 patients' autografts underwent next-day cryopreservation after overnight storage following this date. Results of univariate and multivariate analyses demonstrated no adverse effect of overnight storage before cryopreservation on the number of days to initial engraftment of platelets or neutrophils, on the proportion of patients with low blood counts 6 months post-ASCT, or on lymphoma relapse rates or overall survival post-ASCT. These data suggest that overnight storage of the autograft before cryopreservation does not adversely affect graft viability or influence long-term disease status, and support the continued use of overnight storage of stem cells before cryopreservation as a convenient, cost reduction measure.

Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.

On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.

Relationship between dietary proteins, their in vitro digestion products, and serum cholesterol in rats.

A relationship was assessed between the amino acid composition of 9 protein sources or of their in vitro digestion products and total serum cholesterol in rats. Three animal proteins (casein, beef, fish) and 6 vegetable proteins (soy, pea, peanut meal, rapeseed, oatmeal, wheat gluten) were tested. The intact protein sources were submitted to an enzymatic proteolysis according to a new in vitro digestion method. Each protein source was hydrolyzed for 30 min with pepsin at pH 1.9, then with 10 mg pancreatin at basic pH in a dialysis cell. The digestion products diffused through the dialysis membrane of the cell and were collected by a circulating sodium phosphate buffer over a 6-h period. They were likely to correspond to end products luminal in vivo digestion. The aromatic and the basic amino acids were present in higher proportions in the digestion products than in the intact protein sources, reflecting the specificity of the proteolytic enzymes. Total serum cholesterol was measured on male Sprague-Dawley rats fed cholesterol-free or cholesterol-enriched (1% cholesterol, 0.5% cholic acid) semipurified diets containing protein sources. Total serum cholesterol ranged from 70 mg/dl with the pea diet to 98 mg/dl with the peanut meal diet in rats fed cholesterol-free diets and from 163 mg/dl with the wheat gluten diet to 313 mg/dl with the casein diet in rats fed the cholesterol-enriched diets. These results suggested no specific effect of protein from animal or vegetable origin on total serum cholesterol in rats. In rats fed cholesterol-enriched diets, significant correlations were observed between total serum cholesterol and tyrosine content or leucine/isoleucine ratio of digestion products. These correlations were stronger than those observed with intact protein sources.

Circadian variation of food intake and digestive tract contents in the rat.

The variation of food intake and digestive tract contents over a period of 24 hours was measured in the free feeding rat kept under a 12:12 hr light:dark cycle (lights on at 0700 hr). After a cessation between 0700 and 1000 hr, the rate of food intake increased progressively during daytime followed by a marked increase and a plateau after lights went off. In the dark, dry matter in the stomach was almost ten times the levels of the light phase. In the major part of the high feeding period, the rates of food intake and gastric emptying equilibrated. Dry matter content of the intestine also followed circadian variations that were specific for each segment. The time-to-time content of the mid-gut segment was closely related to gastric emptying. The extent of dry matter absorption in the proximal intestine decreased continuously from the time lights went on and reached a minimum at 22 hr. Absorption in the distal segments was much less subjected to variation over 24 hours. In the free feeding situation, the changes induced by the light cycle on the rhythm of food intake were accompanied by marked modifications of digestive tract contents including those of the intestine. Data indicate a close relationship between gastric function and the middle portion of the intestine.

Effect of protein treatment on the enzymatic hydrolysis of lysinoalanine and other amino acids.

Lysinoalanine (LAL) release from alkali-treated proteins by proteolytic enzymes could be measured on a large scale using an in vitro digestion method based on a two-step hydrolysis with pepsin and pancreatin. The hydrolysis was carried out in a dialysis bag, and the digestion products collected and analyzed. Applying this procedure to alkali-treated soybean and rapeseed protein showed that the release of LAL was not related to its concentration in the protein. Instead, LAL release depended on the nature of the protein, the length of the treatment, and the presence of untreated protein. The enzymatic procedure was also used to measure the release of other amino acids in treated and untreated proteins. This in vitro method could directly measure beneficial and adverse effects of processing on amino acid digestibility.

Relationship between protein digestion products and plasma cholesterol in the rat.

Male Sprague Dawley rats were fed cholesterol-free or cholesterol-enriched purified diets containing 15% protein during 3 weeks. Three animal proteins and 6 plant proteins were used in the diets. Results indicated no specific effect of dietary proteins on serum cholesterol related to their animal or plant origin. Dietary proteins were also subjected to a pepsin-pancreatin in vitro digestion. Significant positive correlations were observed between serum cholesterol of rats fed cholesterol-enriched diets, and the tyrosine content of digestion products. This correlation was higher than that observed with intact dietary proteins. A following study showed that tyrosine supplementation may increase plasma cholesterol when diets contain a protein from which tyrosine is slowly released during enzymatic hydrolysis, indicating a relationship between the availability of dietary amino acids during digestion and plasma cholesterol. It has also been shown that this tyrosine effect was not mediated through plasma thyroid hormones.

Digestion and absorption of food: usefulness and limitations of in vitro models.

The digestion and absorption of food is a spatiotemporal and dynamic process involving complex enzymatic and transport reactions, and it is illusive to try to reproduce in a single model all these biochemical and physiological events. A more practical and realistic approach is to separately evaluate the specific contributions of oral and gastric digestion, intestinal digestion by pancreatic enzymes, brush-border hydrolysis, and eventually intestinal absorption and enterocyte metabolism. The models proposed must be versatile enough to be able to modify their conditions of operation according to physiological adaptation to food. Enzymatic preparations must be kept close to physiological conditions in regard to their nature and their mode of operation. A digestion cell and a peptidase bioreactor were developed for this purpose. The challenge is to find a way to integrate all these data. This can be partially achieved by selecting techniques that allow the collection and isolation of reaction products from one step for use as substrates for the next event. Various models are presented to illustrate this concept as applied to food protein.

Extent of damage to amino acid availability of whey protein heated with sugar.

The effect of heat treatments, at various water activities (aW), on digestibility and on the availabilities of amino acids of whey protein samples in the presence of lactose was estimated by an in vitro digestion method with continuous dialysis. Four aW (0.3, 0.5, 0.7 and 0.97), three temperatures (75, 100 and 121 degrees C) and three heating periods (50, 500 and 5000 s) were selected. The initial lysine:lactose molar ratio was 1:1. Amino acid profiles showed that excessive heating of whey (121 degrees C, 5000 s) destroyed a significant proportion of cystine at all aW, lysine at aW 0.3, 0.5 and 0.7, and arginine at aW 0.5 and 0.7. At aW 0.3, 0.5 and 0.7, protein digestibility decreased (P less than 0.05) as the temperature increased from 75 to 121 degrees C for a heating period of 5000 s, and as the heating time was prolonged, from 500 to 5000 s at 121 degrees C. Excessive heating also decreased (P less than 0.05) the availabilities of all amino acids at aW 0.3, 0.5 and 0.7. The availabilities of lysine, proline, aspartic acid, glutamic acid, threonine, alanine, glycine and serine were particularly affected. Severe heating at aW 0.97 did not seem to favour the Maillard reaction, but the availabilities of cystine, tyrosine and arginine were decreased, probably as a result of structural modifications of the protein upon heating. Heating whey protein concentrates in the presence of lactose not only affected lysine, but also impaired enzymic liberation of other amino acids, according to the severity of heat treatments and aW.

Circadian variation in intestinal protein content in rat fed ad libitum.

The circadian variation in protein content in the digestive tract was studied in parallel with food intake in the free-feeding rat maintained under a 12:12 hr light:dark cycle (lights on at 07 hr). Rate of ingestion of a casein-based diet increased progressively during daytime, but most of the intake occurred in the dark. Gastric emptying of proteins lagged by a 3-hr interval behind intake. N content in the intestine divided equally into three segments also increased in the dark. The rise was specific for each segment with the most marked rise in the second segment. Endogenous N levels were high and accounted for at least two thirds of intestinal N levels. There was no net absorption of N in the first intestinal segment due to dilution by endogenous proteins. Absorption was at an average of 70% in the second segment and reached 85% in the distal intestine. The amino acid composition of intestinal protein content reflected endogenous proteins much more than casein. Specific trypsin activity increased distally. The appearance of nitrogenous material (alpha-amino N) in portal blood also followed a circadian variation reflecting the pattern of food intake. In spite of their high level in the intestine, endogenous proteins did not lead to an appreciable appearance of nitrogenous material in the blood except at 10 hours. Results indicate that fluctuation in food intake is accompanied by complex variations in protein contents of the digestive tract. Endogenous protein levels were high and seemed to have a slow turnover.

Specific role of endopeptidases in modulating the nature of protein digestion products.

The impact of various endopeptidases on the nature of protein digestion products was measured with the digestion cell technique. After a 30 min pepsin pre-digestion, casein and rapeseed concentrates were hydrolyzed with various amounts of pancreatin, trypsin and/or chymotrypsin. This hydrolysis was performed in a dialysis tube (molecular weight cut-off 1000) with continuous collection of the digested material. The addition of pure trypsin or chymotrypsin to pancreatin (Enzyme:Substrate 1:25) did not change the digestibility of casein. Only a higher pancreatin level (Enzyme:Substrate 1:12.5) increased the total protein digestibility without affecting the amino acid spectra. Rapeseed digestibility was markedly increased by the addition of pure trypsin to pancreatin. Lysine and arginine, target amino acids of trypsin, were favored at the expense of chymotrypsin and elastase target amino acids. Supplementation of pancreatin with chymotrypsin enhanced rapeseed digestibility without affecting the relative amino acid digestibility. The impact of a higher pancreatin ratio (Enzyme:Substrate 1:12.5) was similar to that of enriched pancreatin but the rate of amino acid release was modified. The differences between protein sources were mainly attributed to protein structure.

Effect of dietary proteins on time-dependent changes in plasma amino acid levels and on liver protein synthesis in rats.

The effects of four dietary proteins on plasma amino acid (PAA) levels in portal vein and aorta and on hepatic ribosome aggregation were investigated in rats fed 10% protein diets ad libitum. Proteins studied were beef, casein, rapeseed and soybean. Measurements were made at 2000, 2300, 0200, 0500 and 0800 h. Portoaortic differences in essential amino acids (EAA) in plasma were calculated and compared to dietary EAA to verify the time-dependent changes in their intestinal absorption. Each protein generated different variations in portal and aortic PAA levels. Rapeseed produced the lowest plasma concentrations of EAA, but its portoaortic differences were as large as those of the other proteins. With each protein, proportions of EAA in plasma (in contrast to concentrations) tended to remain constant in portal vein and aorta over the 12-h period. Significant correlations between portoaortic differences and dietary EAA were found in all groups, but at varying times, indicating that the kinetics of intestinal absorption were dependent on the protein fed. So were variations in liver polysome distribution. For rapeseed and soybean, times of most active protein synthesis were 0200 and 0500 h; with beef and casein, variations between sampling times were not significant. No direct relationship was found between magnitude and composition of PAA portoaortic differences and ribosome aggregation. Thus these two parameters were both affected by dietary proteins, but no synchrony was evidenced between them.

In vitro amino acid digestibility of food proteins as measured by the digestion cell technique.

The digestibility of proteins and individual amino acids of nineteen selected foods was determined by an in vitro assay. Samples were hydrolysed with pepsin for 30 minutes in an acidic medium; the pH was then raised to 7.5 and the mixture poured into the dialysis bag (molecular weight cut-off 1000) of a digestion cell with pancreatin. Digestion products, mixtures of free amino acids and low molecular weight peptides which pass through the dialysis membrane, were collected for 6 hours by sodium phosphate buffer circulation. All proteins from animal sources displayed a digestibility similar to casein, except for breakfast sausage. Vegetable proteins showed intermediate digestibility, except for cereals (lower) or peanut butter (higher). Target amino acids of enzymes were generally more readily hydrolysed. However, compared to other animal proteins, glycine in milk products, valine, isoleucine, methionine and lysine in breakfast sausage and hot dog, and histidine in tuna were more easily released. Overheating of non-fat dried milk not only reduced the lysine digestibility, but also that of methionine, phenylalanine, histidine and cystine. Among vegetable proteins, wheat products were characterized by a relatively greater release of threonine, isoleucine and histidine, and peas by a lower digestibility of methionine and lysine. Proline of soy isolate and isoleucine of pinto bean were resistant to hydrolysis while arginine of pinto beans and of rice-wheat-gluten was easily released.

Changes in serum and urinary uric acid levels in normal human subjects fed purine-rich foods containing different amounts of adenine and hypoxanthine.

The effect of ingesting some purine-rich foods (beef liver, haddock fillets and soybeans) on uric acid metabolism was investigated in 18 male subjects with no history of gout or kidney disorder. In a crossover design, three isoenergetic and isonitrogenous meals were fed to volunteers during a 3-week period. Only the content of uricogenic bases (adenine and hypoxanthine) varied among the test meals. Ingestion of all experimental meals caused an increase in serum uric acid levels at 120 minutes and this increase was more marked (about twofold) with haddock and soybean ingestion. In all groups, the postprandial serum uric acid levels at 240 minutes were lower than those obtained at 120 minutes, but still remained elevated in comparison to the fasting level. The test foods had little or no effect on serum and urinary creatinine values. As expected, 24-hour urinary uric acid excretion was similar for the three test meals due to the isonitrogenous load of proteins and purines. Assessment of each purine base content rather than the total purine content of foods should be considered in future recommendations for hyperuricemic individuals.

Relationship between dietary tyrosine and plasma cholesterol in the rat.

The present study was undertaken to measure the effects of dietary tyrosine added to fish protein and peanut meal on plasma cholesterol and plasma thyroid hormone levels in the rat. These dietary proteins were chosen because they contain similar amounts of tyrosine but release it at different rates during enzymatic hydrolysis. Casein was chosen as the reference protein. Supplementation was used to obtain tyrosine levels similar to that of casein. Male Sprague-Dawley rats were fed cholesterol-enriched diets containing 15% protein. After 3 weeks of experimental feeding, total postprandial plasma cholesterol was similar in the casein and peanut meal groups and significantly lower in the fish group. When added to the fish diet, tyrosine caused an increase in plasma cholesterol to a level similar to that of the casein group, whereas supplementation had no effect on plasma cholesterol of rats fed the peanut meal diet. The effects of dietary proteins or of tyrosine supplementation on cholesterol levels of the (density less than 1.006 g/mL) lipoprotein fraction were comparable, but not all significant, to those observed on total plasma cholesterol. In addition, casein and fish diets induced significantly higher levels of plasma triiodothyronine (T3) and lower levels of plasma thyroxine (T4) than did the peanut meal diet. However, the addition of tyrosine to the fish or the peanut meal diet did not modify the plasma thyroid hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Refractory proctosigmoiditis caused by myointimal hyperplasia of mesenteric veins: report of a case.

PURPOSE: Proctosigmoiditis occurring in young adults is usually idiopathic and usually responds to medical management. If the process progresses to pancolitis and is refractory to medical management, proctocolectomy may be required. Myointimal hyperplasia of mesenteric veins, though rare, may also cause proctosigmoiditis, but this entity, in contrast to the idiopathic variety, does not respond to medical management; surgical excision limited to the involved colonic segment is curative. Because the treatment of the two entities differs significantly, it is important to distinguish them diagnostically. The purpose of this case report is to increase awareness of myointimal hyperplasia of mesenteric veins and to emphasize the clinical features that distinguish it from idiopathic proctosigmoiditis. METHODS: We report the case of a twenty-two-year-old male with an inflammatory process involving the distal colon and rectum, initially thought to be idiopathic proctosigmoiditis. The inflammation did not respond to an extensive course of medical management, and the patient developed complications associated with both the disease process and his medical therapy. Surgical resection of the rectosigmoid was performed. RESULTS: Histologic examination of the resected colon revealed the underlying process to be colonic ischemia caused by myointimal hyperplasia of mesenteric veins not associated with idiopathic inflammatory bowel disease or systemic vasculitis. CONCLUSION: Proctosigmoiditis caused by myointimal hyperplasia of mesenteric veins and idiopathic proctosigmoiditis may present in a similar fashion. Although patients with myointimal hyperplasia of mesenteric veins do not respond to medical management, segmental resection is usually curative, and long-term drug therapy or even proctocolectomy can be avoided. Physicians should consider the possibility of myointimal hyperplasia of mesenteric veins when patients with apparent idiopathic proctosigmoiditis do not respond to medical therapy.