Children with hyperdiploid but not triple trisomy (+4,+10,+17) acute lymphoblastic leukemia have an increased incidence of extramedullary relapse on current therapies: a single institution experience

To evaluate the outcome of children with high hyperdiploid acute lymphoblastic leukemia (hHDALL) treated at the author's institution. One hundred thirty-five consecutive children with B-precursor ALL were diagnosed between 1991 and 2002: 38 (28.1%) hHDALL and 97 (71.9%) non-hHDALL. In the hHDALL group, 11/38 (28.9%) relapsed at a median interval of 2.8 years (range: 0.8-5.0 years) with 9/11 relapses occurring at the end or after the completion of therapy. Three (27.3%) relapses were isolated hematopoietic (BM), while eight (72.7%) were either isolated extramedullary (EM) relapses (n=6; Testis: 4; CNS: 2) or combined hematopoietic and extramedullary relapses (n=2; BM + CNS: 1; BM + Testis: 1). For the non-hHDALL group, 29/97 (29.9%) relapsed. Unlike the hHDALL group, the non-hHDALL group experienced hematopoietic relapses (62%; n=18) more frequently than isolated extramedullary (27.5%; n=8: Testis: 1; CNS: 7) or combined hematopoietic and extramedullary relapses (10.3%; CNS + BM: 3), with 24/29 (82.8%) of the relapses occurring on therapy. Relapses in hHDALL frequently involved EM sites (P=0.053). Presence of triple trisomy of +4,+10,+17 at diagnosis had a protective effect against relapse (P<0.05). Five-year EFS for the hHDALL and non-hHDALL patients was similar, 70.5+/-7.5% and 66.4+/-4.9%, respectively. Five-year OS for the hHDALL patients was significantly higher than for the non-hHDALL patients, 92+/-4.5% vs. 74.1+/-4.5%, P=0.038. Biologically significant differences exist between relapse patterns of hHDALL and non-hHDALL cases related to relapse sites and time periods when relapses occur. hHDALL relapses continue to be chemo-sensitive.     

Switch movements and the myosin crossbridge stroke

The myosin II motor from Dictyostelium discoideum has been engineered to contain single tryptophan residues at strategic locations to probe movements of switch 1 and switch 2. The tryptophan residue at W501 probes movement of the relay helix and indirectly reports on switch 2 movement. This probe suggests that there is an equilibrium between the switch 2 open- and closed-states when the γ-phosphate position is occupied. Actin does not appear to greatly affect this equilibrium directly, but has indirect influence via switch 1. The latter region has been probed by introducing tryptophan residues at positions 239 and 242. The kinetics of the actomyosin ATPase in solution is discussed with respect to recent crossbridge models based on high-resolution crystal structures. To whom correspondence should be addressed: Tel.: +44-(0)-116-229-7048; Fax: +44-(0)-116-229-7018; E-mail: crb5@le.ac.uk     

The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review.

Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of acute myeloid leukemia (AML) in children is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in the table entitled “Summary of Treatment Recommendations Made by the Expert Panel for Pediatric Acute Myeloid Leukemia” and were reached unanimously by a panel of experts in AML. The identified priority areas of needed future research in pediatric AML include: What is the role of risk group stratification, including the role of cytogenetics, in selection of patients for allogeneic SCT, especially those in first CR? What is the appropriate timing and use of alternative donor SCT, given that matched unrelated donor SCT appears to yield outcomes equivalent to matched related donor SCT? What is the role of reduced intensity SCT (including the use of fludarabine-based preparative regimens) and/or other immunomodulatory approaches to maximize the graft-versus-leukemic effect? and What is the role of biologically targeted agents (ie, tyrosine kinase inhibitors, farnesyl transferase inhibitors, Flt-3 inhibitors, etc) in the treatment of AML, including induction, consolidation, conditioning regimens, and after SCT?     

Immune privilege induced by cotransplantation of islet and allogeneic testicular cells

Objective To induce islet allograft long- term survival through cotransplantation of islet cells with sertoli cells. Methods Testicular sertoli cells were prepared by digestion with collagenase, trypsin an d DNase, and were cultured for 48 hours. Collagenase digested and Ficoll purifi ed donor (Wistar rat) islets were cotransplanted with allogeneic sertoli cells i n the absence of systemic immunosuppression. Terminal deoxynucleotidyl transfer ase- mediated X- dUTP nick- end labeling (TUNEL) was used to label apoptosis of lymphocytes surrounding the islet graft. Results Cotransplantation of islets and 1×10(7) sertoli cells reversed the diabetic sta te for more than 60 days in 100% (6/6) of the chemically diabetic Sprague Dawley rats. Grafts consisting of islets alone or islets plus 1×10(5) sertoli cells survived only for 5-6 days. Apoptosis of lymphocytes surrounding the islets was quite clear. Conclusion Cotransplantation of islets with FasL［+］ sertoli cells induces local immune priv ilege and allows long- term graft survival without systemic immunosuppression.     

Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia: a report of POG study 9296

PURPOSE: A previous Pediatric Oncology Group (POG) study showed high incidence of secondary acute myelogenous leukemia (AML) in children treated for T-cell acute lymphoblastic leukemia (T-ALL) or higher-stage lymphoblastic lymphoma. To prevent secondary neoplasms, induce prolonged asparagine depletion, and maintain high event-free survival (EFS) in children with newly diagnosed T-ALL or higher-stage non-Hodgkins lymphoma (NHL), we designed this pilot study to determine feasibility and safety of substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase. PATIENTS AND METHODS: Forty-five patients were entered, 29 with T-ALL and 16 with higher-stage NHL. Forty-two of 45 patients achieved complete remission (CR), and 27 completed the therapy in continuous CR. Treatment consisted of 4-week induction then 6 weeks consolidation and ten 9-week maintenance cycles. Therapy primarily comprised antimetabolites, anthracyclines, alkylating agents, and asparaginase. Expected chemotherapy duration was 100 weeks. RESULTS: Forty-two of 45 patients achieved CR, and 27 completed therapy. The most common toxicities were Grade 3 or 4 myelosuppression after cyclophosphamide/cytarabine and allergic reactions to asparaginase. Two died of sepsis early in maintenance. Five-year EFS was 68.5% (SE 9.1%) for T-ALL and 81.3% (SE 9.8%) for NHL. Five-year EFS was 73.1% (SE 6.8%) for the entire cohort. No patients treated entirely on this study developed secondary neoplasms. One patient taken off study for asparaginase toxicity was treated with multiagent therapy that contained teniposide, and died from secondary myelodysplasia (sMDS)/AML. CONCLUSION: Substituting methotrexate/mercaptopurine for teniposide/cytarabine and PEG-asparaginase for native asparaginase in a dose-intensive regimen was feasible in children and young adults with newly diagnosed T-ALL or higher-stage NHL. EFS was not compromised and secondary neoplasms were decreased.     

MDA Publications

This article evaluates all the EEG parameters suggested in the literature that undergo changes due to anaesthetic dose, and suggests a set of EEG parameters that act as best signatures of anaesthetic state of a patient. This set of EEG parameters is validated by an artificial neural network.

Primary objective: The purpose of this study is to arrive at a set of EEG parameters that ‘best’ distinguish between awake and anaesthetized states of human patients for halothane anaesthesia.

Methods and procedures: A total of 21 EEG parameters were evaluated for 40 patients. Stepwise discriminant analysis (SDA) pruned them to a set of five parameters. They were fed to a 5–3–1 artificial neural network (ANN) for classification into awake and anaesthetized state. To confirm the results, variance analysis was applied to the set of 21 parameters. Five parameters were finalized after validation by the ANN.

Main outcomes and results: The classification accuracy of the ANN with SDA parameters was found to be 96%. With variance analysis parameters, it returned an accuracy of 100%.

Conclusion: The set of five EEG parameters - approximate entropy, average frequency, Lempel Ziv (LZ) complexity, delta power and beta power forms the best set to distinguish between awake and anaesthetized state of human patients. Variance analysis is a better tool to converge at the optimal set than SDA.     

Prevalence of osteoporosis and incidence of hip fracture in women - secular trends over 30 years

Background  

The number of hip fractures during recent decades has been reported to be increasing, partly because of an increasing proportion of elderly women in the society. However, whether changes in hip fracture annual incidence in women are attributable to secular changes in the prevalence of osteoporosis is unclear.