Acute lymphoblastic leukemia in children: correlation of musculoskeletal manifestations and immunophenotypes

Purpose Studies on musculoskeletal manifestations (MSM) of childhood acute lymphoblastic leukemia (ALL) have yielded variable findings with regard to their clinical impact. We investigated the significance for differential diagnosis, treatment and outcome of musculoskeletal complaints as presenting symptoms of ALL, and their correlation with leukemia immunophenotypes, for which data is lacking. Methods Data on 783 children in the national study for childhood ALL between 1984 and 2003 were reviewed retrospectively. Statistical analysis examined possible relationships between MSM at the time of diagnosis and demographic and clinical data, biological features of leukemia (peripheral blood counts, immunophenotype and main cytogenetic aberration), response to initial prednisone treatment, and outcome. Results Of 765 children with data on orthopaedic complaints, 240 presented with MSM (31.4%). Among these children, B cell precursor (BCP) was much more common (209/576, 36.3%) than T cell ALL (25/176, 14.2%). Patients with MSM had lower white blood cell counts (WBC) (median of 9 vs. 20 × 10⁹/L, P < 0.001) and percentage of blast cells in the peripheral blood at diagnosis compared to those without (median of 27 vs. 53%, P < 0.001). Hepatomegaly and splenomegaly were less common in MSM group (67 vs. 53% <3 cm, P < 0.001, and 63 vs. 50% <3 cm, P < 0.001, respectively). Poor response to initial treatment with prednisone was recorded in 7.1% of patients with MSM versus 11.5% of those without (P = 0.086). The analysis revealed no independent effect of MSM on event-free survival (EFS), after correcting for differences in EFS related to immunophenotype or initial WBC. Conclusions MSM occur mostly in children with BCP ALL who present with less involvement of extramedullary organs, low peripheral blood blasts and white blood cells counts. These findings highlight the importance of including ALL in the differential diagnosis of MSM even in the presence of an apparently normal peripheral blood count. Our study also suggests that MSM are caused by leukemic cells with enhanced biological propensity to remain relatively confined within the intramedullary bone-marrow space.     

Segmental Liver Transplantation from Non-Heart Beating Donors—An Early Experience with Implications for the Future

We report our experience of pediatric liver transplantation with partial grafts from non-heart beating donors (NHBD). Controlled donors less than 40 years of age with a warm ischemia time (WI) of less than 30 min were considered for pediatric recipients. Death was declared 5 min after asystole. A super-rapid recovery technique with aortic and portal perfusion was utilized. Mean donor age was 29 years and WI 14.6 min (range 11–18). Seven children, mean age 4.9 years (0.7–11), median weight 20 kg (8.4–53) received NHBD segmental liver grafts. Diagnoses included seronegative hepatitis, neonatal sclerosing cholangitis, familial intrahepatic cholestasis, hepatoblastoma, primary hyperoxaluria and factor VII deficiency (n = 2).The grafts included four reduced and one split left lateral segments, one left lobe and one right auxiliary graft. Mean cold ischemia was 7.3 h (6.2–8.8). Complications included one pleural effusion and one biliary collection drained percutaneously. At 20 months (10–36) follow-up all children are alive and well with functioning grafts.
Donation after cardiac death is a significant source of liver grafts for adults and children with careful donor selection and short cold ischemic times.     

Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct size after focal ischemia in rats.

Cerebral ischemic preconditioning protects against stroke, but is clinically feasible only when the occurrence of stroke is predictable. Reperfusion plays a critical role in cerebral injury after stroke; we tested the hypothesis that interrupting reperfusion lessens ischemic injury. We found for the first time that such postconditioning with a series of mechanical interruptions of reperfusion significantly reduces ischemic damage. Focal ischemia was generated by permanent distal middle cerebral artery (MCA) occlusion plus transient bilateral common carotid artery (CCA) occlusion. After 30 secs of CCA reperfusion, ischemic postconditioning was performed by occluding CCAs for 10 secs, and then allowing for another two cycles of 30 secs of reperfusion and 10 secs of CCA occlusion. Infarct size was measured 2 days later. Cerebral blood flow (CBF) was measured in animals subjected to permanent MCA occlusion plus 15 mins of bilateral CCA occlusion, which demonstrates that postconditioning disturbed the early hyperemia immediately after reperfusion. Postconditioning dose dependently reduced infarct size in animals subjected to permanent MCA occlusion combined with 15, 30, and 60 mins of bilateral CCA occlusion, by reducing infarct size approximately 80%, 51%, and 17%, respectively. In addition, postconditioning blocked terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling-positive staining, a marker of apoptosis, in the penumbra 2 days after stroke. Furthermore, in situ superoxide detection using hydroethidine suggested that postconditioning attenuated superoxide products during early reperfusion after stroke. In conclusion, postconditioning reduced infarct size, most plausibly by blocking apoptosis and free radical generation. With further study it may eventually be clinically applicable for stroke treatment.     

Best-practice algorithms for the use of a bilayered living cell therapy (Apligraf®) in the treatment of lower-extremity ulcers

Tissue-engineered skin substitutes such as Apligraf have emerged over the past 20 years as among the most carefully studied and efficacious of the advanced wound modalities. These products have been proven as effective enhancements to general wound care, promoting wound closure particularly in instances where conventional wound care fails. Marketed for hard-to-heal wounds since 1998, Apligraf has become part of standard wound care in many wound centers across the United States. Despite this situation, few general wound care guidelines incorporate advanced and active wound-healing technologies, such as tissue-engineered skin products. Because of this deficiency, appropriate patient selection and proper use of these product remain largely unaddressed within the general wound care community. Here, we describe the development of guidelines surrounding optimal use of the bilayered living cell therapy, Apligraf, in the treatment of the two types of lower extremity ulcers for which the product is FDA approved: venous leg ulcer and diabetic foot ulcer. The guidelines detailed in this article focus on the identification and selection of patients who are at risk for failure of standard wound care therapy and thus appropriate for Apligraf treatment. The intended audience for these guidelines is the general wound care practitioner, for whom the developed treatment algorithms and accompanying figure legends should provide practical, user-friendly direction simplifying both patient selection and appropriate use of Apligraf within the context of good wound-healing practice.     

Newer aspects of antiarrhythmic drug development: Introduction

Although cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re-evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drugs.     

Immunopathology of glomerulonephritis associated with chronic woodchuck hepatitis virus infection in woodchucks (Marmota monax).

Retrospective analysis of necropsy findings of 705 woodchucks was performed to determine the prevalence and morphology of immune-mediated glomerulonephritis, its relationship to woodchuck hepatitis virus (WHV) infection, and the presence of major WHV antigens. Twenty-six woodchucks had glomerular lesions. Renal tissue of the 26 animals was evaluated histologically and immunohistochemically for immune-mediated glomerulonephritis. Of these 26 animals, immune-mediated glomerulonephritis was diagnosed in six, all of which were chronic WHV carriers. Membranous glomerulonephritis was identified in three animals, two of which also had mesangial proliferation. Host immunoglobulin was present within the mesangium and along capillary loops in all three. Woodchuck hepatitis virus core antigen (WHcAg) was present along capillary loops of two of these animals, one membranous and one mixed, and in the mesangium of all three. Woodchuck hepatitis virus surface antigen (WHsAg) deposition was similar to WHcAg deposition but was only present along capillaries in those animals with mixed nephritis. The remaining three animals had mesangial proliferation. WHsAg and host immunoglobulin deposition were predominately mesangial; WHcAg was not detected. Transmission electron microscopy showed thickening of the capillary loop basement membranes and subepithelial electron-dense deposits in animal one, and deposits in the mesangium in animal six.     

Measurement of γ-enolase release, a new method for selective quantification of neurotoxicity independently from glial lysis

We have developed a sensitive enzymatic-immunoassay to quantify the level of gamma-enolase (a specific neuronal enzyme) which is released from cultured cells after exposure to various toxins. We show that this method can estimate selectively neuronal cell death without significantly interfering with glial cell death. Indeed, no gamma-enolase is released when glial cells are killed with free-radical producing agents. Experiments comparing the levels of neuronal cell death induced by NMDA or free-radical producing drugs, performed either by measuring gamma-enolase release or using the classical fluorescein diacetate method, yielded similar results. In addition to selectively follow neuronal death in a mixed population of neurons and glial cells, this method provides a way of determining the cell death kinetics from a single culture dish, since enolase can be measured on small samples taken from the culture medium. Finally, we propose these two methods as being complementary and useful neuronal and other cellular death indexes and also to understand the complex problem of glial influence on neuronal survival or death.     

Surgically debulked malignant pleural mesothelioma: Results and prognostic factors

Background: We analyzed morbidity and mortality, sites of recurrence, and possible prognostic factors in 95 (78 male, 17 female) patients with MPM on phase I–III trials since 1990. A debulking resection to a requisite, residual tumor thickness of ≤ 5 mm was required for inclusion. Methods: Preoperative tumor volumes were determined by three-dimensional reconstruction of chest computerized tomograms. Pleurectomy (n=39) or extrapleural pneumonectomy (EPP; n=39) was performed. Seventeen patients could not be debulked. Preoperative EPP platelet counts (404,000) and mean tumor volume (491 cm³) were greater than that seen for pleurectomy (344,000, 114 cm³). Results: Median survival for all patients was 11.2 months, with that for pleurectomy 14.5 months, that for EPP 9.4 months, and that for unresectable patients 5.0 months. Arrhythmia (n=14; 15%) was the most common complication, and there were two deaths related to surgery (2.0%). Tumor volume of >100 ml, biphasic histology, male sex, and elevated platelet count were associated with decreased survival (p<0.05). Both EPP and pleurectomy had equivalent recurrence rates (27 of 39 [69%] and 31 of 39 [79%], respectively); however, 17 of 27 EPP recurrences as opposed to 28 of 31 pleurectomy recurrences were locoregional (p₂=0.013). Conclusions: Debulking resections for MPM can be performed with low operative mortality. Size and platelet count are important preoperative prognostic parameters for MPM. Patients with poor prognostic indicators should probably enter nonsurgical, innovative trials where toxicity or response to therapy can be evaluated. Presented at the 49th Annual Cancer Symposium of The Society of Surgical Oncology, Atlanta, Georgia, March 21–24, 1996.