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.

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.

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.

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.

Comparison of in vitro systems of protein digestion using either mammal or fish proteolytic enzymes.

Hydrolysis of three different proteins by either crude fish digestive extracts or purified mammal proteases was assayed using two different in vitro systems. The closed system was a modification of the pH-stat method including a previous acid digestion. The open system used a digestion cell containing a semi-permeable membrane which allowed continuous separation of the final products of hydrolysis with a molecular cut-off of 1000 Da. Assays in both systems resulted a similar arrangement of the tested proteins in relation to their ability to be hydrolyzed, with casein>fish meal> or =soybean meal. With the exception of casein, no significant differences were found between results produced by any of the enzyme sources using the closed system. In constrast, significantly higher hydrolysis of all proteins was produced by mammal enzymes under conditions operating in the open system. Differences in the rate of release of amino acids measured in this latter system were related both to the type of protein and the origin of the enzymes. When using purified mammal enzymes, release of lysine or phenylalanine from casein and soybean was high, but low from fishmeal. Isoleucine and valine present in fishmeal were preferentially hydrolyzed by commercial enzymes, but glycine and proline by fish enzymes.

Hairy cell leukemia.

The standard therapy for hairy cell leukemia (HCL) is with the nucleoside analogs, 2"-deoxycoformycin (dCF) or 2-chlorodeoxyadenosine (CdA), which produce morphologic complete remissions (CRs) in the majority of patients, although residual hairy cells can frequently be detected by molecular or immunologic techniques. Relapses continue to occur over time, but most patients respond well to retreatment with the same agent. The longest follow-up is for patients treated with dCF, where the 5- and 10-year relapse-free survival rates are 80% to 85% and 67% to 76%, respectively. dCF is usually administered as 4 mg/m2 intravenously every second week until CR followed by two additional treatments for consolidation. CdA is administered as 0.09 mg/kg/d x 7, by continuous intravenous infusion, although it may be equally effective when given as daily boluses or subcutaneously. More recent studies have suggested that CdA, 0.15 mg/kg intravenously weekly x 6, produces equivalent response rates, while reducing the risk of febrile neutropenia (which occurs in approximately 50% of patients using the standard regimen). We have found this to be a very simple, safe, and effective regimen. Both dCF and CdA should be used with caution in the presence of renal or hepatic dysfunction, and both are contraindicated in the presence of active infection. Interferon-alfa (3 x 10(6) U subcutaneously three times per week for 12 months) produces inferior response rates but is less likely to cause febrile neutropenia. It can be considered for initial treatment for patients with active infection, patients at high risk of febrile neutropenia, and patients who cannot tolerate or are resistant to the nucleoside analogs. Splenectomy is now rarely performed in HCL, but it is required for splenic rupture and may be of value in "splenic" HCL or those with massive splenomegaly and hypersplenism. In preliminary studies, monoclonal antibodies directed against CD20 or CD25 also show activity in HCL, but their roles in this disease require further study.

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.

Quantitative comparison of casein and rapeseed proteolysis by pancreatin.

The problem of quantitative comparison of kinetic curves was solved for casein and rapeseed pancreatin hydrolysis in a membrane reactor, which ensured the measurement of proteolysis kinetics for the products with a molecular weight of less than 1000. Coordinates were derived which provided good linearization of kinetic curves and the determination of relative rate constants irrespective of reagent concentrations, E0/S0 ratio and time intervals of kinetic measurements. When the relative rate constants of the release of the individual amino acid residues in the low-weight proteolysis products were compared, trypsin-dependent constants (for Lys and Arg residues) were found to be two times less for rapeseed than for casein, and chymotrypsin-dependent constants (for Tyr and Phe residues) were approximately 1.3 times higher for rapeseed than for casein. Statistical analysis demonstrated that the distribution of constants was narrower for rapeseed than for casein. Differences between target (Arg, Lys, Tyr and Phe) and non-target constants of release in the form of peptides and free amino acids, or in the form of free amino acids only, were attributed on the differences in the peptide bond masking for casein and rapeseed proteins. Computer simulation of proteolysis kinetics was performed by PROTEOLYSIS program package to confirm the dependence of rate constant distribution on the state of masking.

The effect of milk fermentation by Lactobacillus helveticus on the release of peptides during in vitro digestion.

This study evaluated the effect of protein hydrolysis by lactic acid bacteria during milk fermentation on the release of amino acids and peptides duing subsequently simulated peptic and pancreatic digestion. After digestion with trypsin, we compared the elution patterns of proteins and peptides obtained from unfermented milk and from milk fermented by Lactobacillus helveticus under pH control, using HPLC gel filtration and reverse-phase HPLC. The results indicate that milk fermentation affects the release of some amino acids during simulated gastrointestinal digestion and has a major impact on the modification of protein elution profiles obtained after digestion with trypsin. We conclude that proteolysis during fermentation may lead to the formation of novel peptides during gastrointestinal digestion.

Digestion patterns of endogenous and different exogenous proteins affect the composition of intestinal effluents in humans.

The purpose of this work was to determine if endogenous luminal proteins are stimulated differently by various dietary proteins and if their digestibility differs from that of dietary proteins. Intestinal effluents were collected from the jejunum of four volunteers who had previously fasted or ingested either casein or soybean proteins. After separating the jejunal digested fraction (nonprotein nitrogen) by dialysis, the protein nitrogen fractions of the effluents and of the protein sources were further hydrolyzed in vitro in a digestion cell with simultaneous dialysis of the digestion by-products. The results indicated a higher (P < 0.05) gastrojejunal absorption of casein (64.5 +/- 2.5%) compared with soybean protein (49.9 +/- 4.1%) in humans. Compared with fasting conditions, protein ingestion increased both the total nitrogen and protein nitrogen of the endogenous nitrogen fraction slightly (P < 0.05) but had no effect on the nonprotein nitrogen fraction. The amino acid profiles of the nonprotein nitrogen in the effluents differed from those of both the protein sources and their mixtures with endogenous secretions. This was attributed to the specific release of amino acids by pancreatic enzymes as measured in vitro. The hydrolysis patterns of amino acids were determined by the structure of food proteins and their interaction with endogenous proteins. Soybean and endogenous nitrogen had equivalent digestibilities when measured in vitro.

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.

In vivo and in vitro gastric emptying of milk replacers containing soybean proteins.

Gastric digestion of three milk replacers for which protein was provided either exclusively by milk powder or partially (50%) by heated soybean flour or soybean protein concentrate was studied in vivo and in vitro. In vivo gastric emptying of protein fractions of the diets was measured in six preruminant calves fitted with reentrant duodenal cannulas and used in a double 3 x 3 Latin square design. In vitro gastric emptying was studied after hydrochloric acid and rennet digestion in an artificial stomach. In vivo and in vitro flow rates of 12% TCA-insoluble N and total N were higher for the soybean diets than for the milk protein diet, indicating that the incorporation of soybean protein prevented casein from clotting. Because of this faster gastric emptying, proteolysis in the stomach was reduced. However, gastric emptying of NPN (12% TCA-soluble N) was significantly decreased only in vitro. No difference existed between the two milk replacers containing either soybean flour or soybean protein concentrate. In vivo and in vitro results were correlated, suggesting that the in vitro method could be used to predict gastric digestion of protein fractions in vivo.

Impact of exocrine pancreatic adaptation on in vitro protein digestibility.

An in vitro enzymic method was used to study the kinetics of digestion of casein and rapeseed proteins. After a predigestion step with pepsin (EC 3.4.23.1), the protein substrates were submitted to a 24 h hydrolysis either with pancreatin or pancreatic juices of pigs adapted either to casein or rapeseed diets and whose enzyme activities were different. After 3, 6 and 24 h of in vitro digestion, dialysates were collected and analysed for content of nitrogen, amino acids and low-molecular-weight peptides. For a long-term hydrolysis (24 h), overall digestibility of both substrates was not affected by the composition of pancreatic enzyme mixtures. However, at the beginning of hydrolysis a significant effect of pancreatic juices was observed, i.e. individual amino acid digestibility was generally higher when casein pancreatic juice was used for hydrolysis and their relative pattern of release was modified. For both substrates the proportion of amino acids released as low-molecular-weight peptides was not affected by the enzyme mixture used and made up about two-thirds of the total digested material. It is concluded that exocrine pancreatic adaptation to protein sources does not affect the total capacity of protein digestion. However, the changes in initial kinetics of release of amino acids are more dependent on the nature of the protein tested than on the composition of pancreatic enzyme mixtures.

Digestibility and amino acid composition of digesta at the end of the ileum in preruminant calves fed soyabean protein.

The ileal digestion of 3 milk substitutes in which skim milk powder was either the only protein source (control diet) or was partially replaced (50%) by a heated soybean flour (SF diet) or an alcohol-treated soyabean protein concentrate (SC diet) was studied in 6 preruminant calves which were fitted with an ileo-caecal re-entrant cannula. The apparent digestibility of total nitrogen and amino acids was lower with the SF and SC diets than with the control diet (0.89, 0.89 and 0.94, respectively, for amino acid nitrogen). Assuming that true digestibility was complete with the control diet, the values were lower with the SF and SC diets, especially for cystine, threonine, valine, isoleucine, leucine and histidine. With the SF and SC diets, digesta contained more aspartic acid and glutamic acid but less threonine, sulfur amino acids, lysine, serine and alanine than with the control diet. The additional undigested fractions obtained with the SF and SC diets compared to the control diet were rich in aspartic and glutamic acids, and poor in arginine, suggesting that partially degraded dietary fractions different from the whole soyabean escaped digestion in the small intestine; these fractions probably originated mainly from glycinin. No significant differences were observed between the 2 soyabean diets.

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.

In vivo and in vitro gastric emptying of protein fractions of milk replacers containing whey proteins.

In vivo and in vitro gastric emptying of protein fractions of three milk replacers containing either milk protein (control), a mixture (50:50 on a CP basis) of milk protein and native whey protein concentrate, or a mixture (50:50 on a CP basis) of milk protein and heated whey protein concentrate was studied. In vivo gastric emptying was measured in three preruminant calves fitted with reentrant duodenal cannulas and used in a 3 x 3 Latin square design. In vitro gastric emptying was determined after enzymatic digestion in an artificial stomach. In vivo and in vitro flow rates of protein N (12% TCA-insoluble N) and total N were higher for milk replacers containing whey proteins than for control. Gastric emptying of NPN (12% TCA-soluble N) was slightly higher for diets containing whey proteins than for that containing milk proteins. Gastric emptying of all protein fractions was similar for the two milk replacers containing whey proteins. In vivo and in vitro results were significantly correlated, suggesting that the in vitro method reproduced conditions for proteolysis and could be used to predict gastric digestion of protein fractions.

Effects of diets containing casein and rapeseed on enzyme secretion from the exocrine pancreas in the pig.

The effect of dietary protein on enzyme activity of pancreatic juice was studied in ten growing, castrated, Large White male pigs. Animals, fitted with permanent cannulas in the pancreatic duct and in the duodenum, were divided into two groups receiving either casein or rapeseed concentrate as a protein source. After a 15 d adaptation period to the experimental diet, the volume of pancreatic secretion was significantly higher, whereas the protein concentration was lower in the casein group compared with the rapeseed group. No statistical difference was observed in the daily protein output between groups. Total secreted activities of carboxypeptidase A (EC 3.4.17.1), and elastase (EC 3.4.21.36) were higher in the casein group during the nocturnal period, whereas total activities of trypsin (EC 3.4.21.4), chymotrypsin (EC 3.4.21.1), carboxypeptidase B (EC 3.4.17.2) and amylase (EC 3.2.1.1) in pancreatic secretions during the post-prandial periods were increased by the ingestion of the rapeseed diet. It is concluded that the pancreatic enzyme secretion is sensitive to the nature of the protein ingested.

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.