Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

The use of traditional, complementary and integrative medicine in Chinese adolescent and young adult patients with cancer: A multicenter cross-sectional study.

PURPOSE: Adolescent and young adult (AYA) patients with cancer often experience unique physical and psychosocial complications. They may turn to traditional, complementary and integrative medicines (TCIM) to address these concerns. To examine the pattern of TCIM use among AYA patients with cancer and explored their preferences regarding TCIM education. METHODS: Between August 2021 and December 2022, 246 patients diagnosed with cancer between 15 and 39 years old were recruited from hospitals in Hong Kong. They completed a structured questionnaire on TCIM use, symptom burden, psychological status and preference on education content. Multivariable logistic regression was used to identify predictors of TCIM use, adjusting for age and sex. RESULTS: Overall, 60.2% reported TCIM use, most commonly vitamins (24.0%) and Chinese herbal medicine (22.0%). The most common reasons for using TCIM were to improve general health (70.9%) and manage chronic symptoms (33.1%). Among patients on active treatment, TCIM users tend to report higher anxiety symptoms (aOR = 1.13, 95% CI = 1.02-1.27). TCIM users who were post-treatment were more likely to have chronic comorbidities (aOR = 3.54, 95% CI = 1.29-11.5). AYA patients indicated that they would like TCIM information to address specific needs, particularly fatigue (53.7%) and psychological problems (54.1%). CONCLUSIONS: The use of TCIM is common among AYA patients with cancer, especially among patients with high symptom burdens. A tailored education programme should be provided based on patients' preferences and needs. Healthcare professionals including oncologists and oncology nurses should communicate with AYA patients about TCIM use and address their needs by making evidence-based referrals/recommendations based on treatment status and symptom burden.

Integrating Complementary Medicine Into the Care of Childhood Cancer Survivors: A Brief Report on the Preliminary Framework and Implementation of an Educational Program.

Background: Existing educational programs typically include limited information on traditional, complementary, and integrative medicine (TCIM) for survivors of childhood cancer. Objectives: This brief report presents the preliminary results of an educational program that aims to promote the safe and effective use of Chinese medicine (CM) among survivors in Hong Kong. Methods: Survivors of childhood cancer, their caregivers, and oncology practitioners were invited to participate in a program that consists of two didactic seminars and a written educational booklet that disseminated information on the use of CM. A structured questionnaire was used to evaluate participants' receptivity toward and perceived relevance of the program. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to discuss the impact of the intervention. Results: Reach: A total of 174 participants attended the seminars, and the seminar recording received over 380 views on social media platforms since April 2021. The hardcopy of the educational booklet was distributed to 43 recipients. The web-version of the booklet was sent to 67 participants and downloaded 143 times. Efficacy: The majority found that the content of the seminar useful (mean score = 5.04/6 points), especially the CM exercise (mean score = 4.88/6 points) and dietary advice (mean score = 4.99/6 points). Intention to adopt: The survivors (or their caregivers) reported that they would adopt advice on food therapies (83.3%) and traditional Chinese health exercises (55.6%) during survivorship. Conclusion: The preliminary data on patient preferences will be applied to further develop educational materials and to establish a TCIM referral network within the cancer survivor community.

Examining patterns of traditional Chinese medicine use in pediatric oncology: A systematic review, meta-analysis and data-mining study.

BACKGROUND: Traditional Chinese medicine (TCM) is becoming a popular complementary approach in pediatric oncology. However, few or no meta-analyses have focused on clinical studies of the use of TCM in pediatric oncology. OBJECTIVE: We explored the patterns of TCM use and its efficacy in children with cancer, using a systematic review, meta-analysis and data mining study. SEARCH STRATEGY: We conducted a search of five English (Allied and Complementary Medicine Database, Embase, PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and four Chinese databases (Wanfang Data, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and VIP Chinese Science and Technology Periodicals Database) for clinical studies published before October 2021, using keywords related to "pediatric," "cancer," and "TCM." INCLUSION CRITERIA: We included studies which were randomized controlled trials (RCTs) or observational clinical studies, focused on patients aged < 19 years old who had been diagnosed with cancer, and included at least one group of subjects receiving TCM treatment. DATA EXTRACTION AND ANALYSIS: The methodological quality of RCTs and observational studies was assessed using the six-item Jadad scale and the Effective Public Healthcare Panacea Project Quality Assessment Tool, respectively. Meta-analysis was used to evaluate the efficacy of combining TCM with chemotherapy. Study outcomes included the treatment response rate and occurrence of cancer-related symptoms. Association rule mining (ARM) was used to investigate the associations among medicinal herbs and patient symptoms. RESULTS: The 54 studies included in this analysis were comprised of RCTs (63.0%) and observational studies (37.0%). Most RCTs focused on hematological malignancies (41.2%). The study outcomes included chemotherapy-induced toxicities (76.5%), infection rate (35.3%), and response, survival or relapse rate (23.5%). The methodological quality of most of the RCTs (82.4%) and observational studies (80.0%) was rated as "moderate." In studies of leukemia patients, adding TCM to conventional treatment significantly improved the clinical response rate (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.49-4.36), lowered infection rate (OR = 0.23; 95% CI = 0.13-0.40), and reduced nausea and vomiting (OR = 0.13; 95% CI = 0.08-0.23). ARM showed that Radix Astragali, the most commonly used medicinal herb (58.0%), was associated with treating myelosuppression, gastrointestinal complications, and infection. CONCLUSION: There is growing evidence that TCM is an effective adjuvant therapy for children with cancer. We proposed a checklist to improve the quality of TCM trials in pediatric oncology. Future work will examine the use of ARM techniques on real-world data to evaluate the efficacy of medicinal herbs and drug-herb interactions in children receiving TCM as a part of integrated cancer therapy.

Use of complementary or alternative medicine and potential interactions with chronic medications among Chinese survivors of childhood cancer.

PURPOSE: This study explored the pattern of complementary or alternative medicine (CAM) use among Chinese survivors of childhood cancer and identified potential drug-CAM interactions and factors predicting CAM use. METHODS: This cross-sectional study recruited 393 survivors of childhood cancer (male, 57.8%; mean age, 17.7 [SD = 7.3] years; mean years post-treatment, 8.8 [SD = 5.0]) from a public hospital in Hong Kong. Participants reported CAM and over-the-counter medications that they used in the past year. Prescription drug data were extracted from pharmacy dispensing records. Potential interactions between concurrent CAM and chronic medications were identified from well-established CAM-drug/herb-drug interaction databases. A multivariate logistic regression was performed to analyze associations of socio-demographic and clinical factors with CAM use. RESULTS: Half (n = 205/393, 52.2%) of the participants reported the use of CAM. The most popular CAMs were traditional Chinese medicine (n = 127/205, 62.0%) and natural products (n = 114/205, 55.3%). Among the 69 survivors (33.7%) concurrently using CAM and chronic medications, one-third (n = 21/69, 30.4%) were at risk of drug-CAM interactions that are of moderate significance. Adult survivors were more likely to use CAM than pediatric survivors (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.31-4.41). Brain tumor survivors were more likely than other solid tumor survivors to use non-oral therapies (OR, 2.70; 95% CI, 1.01-7.72). CONCLUSIONS: The prevalence of CAM use among Chinese survivors of childhood cancer was high. A minority of survivors had a risk of clinically significant CAM-drug interactions. Future studies should focus on survivors' behavior and motivations for CAM use. IMPLICATIONS FOR CANCER SURVIVORS: As the concurrent use of CAM and chronic medications might result in interactions, healthcare providers should proactively identify such interactions and develop referral pathways to promote evidence-based integrative therapies for survivors.

Astragalus polysaccharide has a protective effect on hematopoiesis in an irradiated mouse model and decreases apoptosis in megakaryocytes.

Huangqi, the dried root of Radix Astragali, is an essential herb in Traditional Chinese Medicine and has been used to promote hematopoiesis for centuries. Astragalus polysaccharide (ASPS), the bioactive compound of Huangqi, serves a crucial role in hematopoiesis. The aim of the present study was to investigate the hematopoietic effects, in particular the thrombopoietic effects, and the molecular mechanisms of ASPS using an irradiation­induced myelosuppressive mouse model. Colony­forming unit assays, flow cytometric analysis of apoptosis, ELISAs, Giemsa staining and western blotting were performed to determine the hematopoietic and anti­apoptotic effects of ASPS. The results demonstrated that ASPS enhanced the recovery of red blood cells at day 21 following treatment, as well as platelets and white blood cells at day 14. In addition, ASPS promoted colony formation in all lineages (megakaryocytes, granulocyte monocytes, erythroid cells and fibroblasts). The morphological study of the bone marrow demonstrated that tri­lineage hematopoiesis was preserved in the ASPS­ and thrombopoietin (TPO)­treated groups compared with the control group. The overall cellularity (mean total cell count/area) of the ASPS­treated group was similar to that of the TPO­treated group. Additionally, in vitro experiments indicated that treatment with 100 µg/ml ASPS exhibited the maximum effect on colony formation. ASPS attenuated cell apoptosis in megakaryocytic cells via inhibiting the mitochondrial caspase­3 signaling pathway. In conclusion, ASPS promoted hematopoiesis in irradiated myelosuppressive mice possibly via enhancing hematopoietic stem/progenitor cell proliferation and inhibiting megakaryocytes apoptosis.

Cost-effectiveness of culture-guided antimicrobial prophylaxis for the prevention of infections after prostate biopsy.

BACKGROUND: Clinical findings suggest that the use of rectal culture-guided antibiotic prophylaxis reduces the infection rate following transrectal ultrasound-guided prostate biopsy (TRUSBx). METHODS: A decision-analytic model was designed to compare the outcomes of TRUSBx performed with (rectal culture-guided group) and without (standard ciprofloxacin prophylaxis) rectal swab culture-guided antimicrobial prophylaxis in Hong Kong. The post-biopsy infection rate, infection-related costs, quality-adjusted life years (QALYs) lost for infection, and incremental cost per QALY saved (ICER) were assessed. Model inputs were retrieved from local epidemiology data and the medical literature. A sensitivity analysis was performed to test the robustness of the model results. RESULTS: Base-case analysis showed that the infection rate in the culture-guided group was reduced from 2.42% to 0.23% and saved 0.0002 QALYs, with a lower cost (USD 31.4 versus USD 55.6) (USD 1=HKD 7.8). The number needed to screen to prevent an infection episode was 45.7. The hospital days avoided per 100 patients using culture-guided prophylaxis was 7.08 days. The relative effectiveness of culture-guided antimicrobial prophylaxis versus standard prophylaxis in carriers and non-carriers of FQ-resistant rectal flora were identified as potential influencing factors. In 10000 Monte Carlo simulations, ICERs of the culture-guided group were below the willingness-to-pay threshold 99.12% of the time. CONCLUSIONS: Using rectal culture-guided antimicrobial prophylaxis for men undergoing TRUSBx appears to be a cost-saving strategy to avert post-biopsy infection and QALY loss in Hong Kong.

Feasibility of psychoeducational interventions in managing chemotherapy-associated nausea and vomiting (CANV) in pediatric oncology patients.

PURPOSE: Childhood cancer patients often suffer from Chemotheraphy-Associated Nausea and Vomiting (CANV). To alleviate CANV, relaxation techniques and patient education were combined to develop a multidimensional psychoeducational intervention package. The aim of this pilot study was to assess the feasibility of the two major components, namely, (1) relaxation, and (2) patient education, of a psychoeducational intervention, prior to the commencement of the main study. METHODS: A pre-test-post-test control group design was adopted. Twenty patients were allocated equally to the relaxation group (10 participants) and to the educational group (10 participants). Twenty historical matched control cases were identified to form the control groups. Besides, a process evaluation was adopted to assess the feasibility of the study. RESULTS: In relation to episodes of vomiting on day 3, a significant difference was detected from the results (X(2) = 8.54, p = 0.036), in that fewer patients in the relaxation group experienced vomiting. A significant difference was not found in both the use of antiemetics and body weight between the groups. All subjects in the intervention groups adhered to the intervention and completed the questionnaire without difficulty. Patients and parents perceived the intervention as being moderately useful. CONCLUSIONS: Although the beneficial effect of relaxation and education in alleviating CANV was not well-supported statistically, the findings from descriptive data suggest that these interventions promoted the intake of antiemetics as a preventive method. Both interventions and instruments were well-received by the patients and also by their parents.

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with ß-thalassemia major.

BACKGROUND: Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. DESIGN AND METHODS: Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3(rd) year, allowing cardiac iron removal to be analyzed over three years. RESULTS: Mean deferasirox dose during year 3 was 33.6 ± 9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ± 39.1% at baseline to 17.1 ms ± 62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 ± 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ± 1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥ 20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7%). CONCLUSIONS: Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

Polysaccharides from the root of Angelica sinensis promotes hematopoiesis and thrombopoiesis through the PI3K/AKT pathway.

BACKGROUND: Dozens of Traditional Chinese Medicine (TCM) formulas have been used for promotion of "blood production" for centuries, and we are interested in developing novel thrombopoietic medicines from these TCMs. Our previous studies have demonstrated the hematopoietic effects of DangGui BuXue Tong (DBT), a formula composed of Radix Angelicae Sinensis and Radix Astragali in animal and cellular models. As a step further to identify and characterize the active chemical components of DBT, we tested the hematopoietic and particularly, thrombopoietic effects of polysaccharide-enriched fractions from the root of Radix Angelicae Sinensis (APS) in this study. METHODS: A myelosuppression mouse model was treated with APS (10 mg/kg/day). Peripheral blood cells from APS, thrombopoietin and vehicle-treated samples were then counted at different time-points. Using the colony-forming unit (CFU) assays, we determined the effects of APS on the proliferation and differentiation of hematopoietic stem/progenitor cells and megakaryocytic lineages. Using a megakaryocytic cell line M-07e as model, we analyzed the cellular apoptosis progression with and without APS treatment by Annexin V, Mitochondrial Membrane Potential and Caspase 3 assays. Last, the anti-apoptotic effect of APS on cells treated with Ly294002, a Phosphatidylinositol 3-Kinse inhibitor (PI3K) was also tested. RESULTS: In animal models, APS significantly enhanced not only the recovery of platelets, other blood cells and their progenitor cells, but also the formation of Colony Forming Unit (CFU). In M-07e cells, we observed the anti-apoptotic effect of APS. Treatment by Ly294002 alone increased the percentage of cells undergoing apoptosis. However, addition of APS to Ly294002-treated cells significantly reduced the percentage of cells undergoing apoptosis. CONCLUSIONS: APS promotes hematopoiesis and thrombopoiesis in the mouse model. This effect likely resulted from the anti-apoptosis activity of APS and is likely to involve the PI3K/AKT pathway.

Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias.

UNLABELLED: Background Following a clinical evaluation of deferasirox (Exjade) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged >or=2 years) with transfusional hemosiderosis from various types of anemia. DESIGN AND METHODS: The recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. RESULTS: The 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). Conclusions Analysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

Magnetic resonance imaging assessment of cardiac and liver iron load in transfusion dependent patients.

BACKGROUND: Magnetic resonance imaging (MRI) is an emerging tool to assess organ-specific iron load in patients with transfusion dependent anemia. OBJECTIVE: We performed MRI T2 star (T2*) assessment in 44 transfusion dependent patients to study the prevalence of cardiac and liver iron overload and the relationship of T2* measurement with various clinical and biochemical parameters. RESULT: Mean age of the study subjects was 19.9 years (range 8.8-32.3) and the mean cardiac T2* was 23.4 +/- 13.8 msec. Fifty percent of the subjects had abnormal cardiac T2* (below 20 msec). Cardiac T2* was not found to have any correlation with serum ferritin or liver T2*. Liver T2* value was abnormal in 79% of the subjects and it correlated inversely with both current and 12 months average serum ferritin (r = -0.44, P = 0.003; r = -0.46, P = 0.002). Clinical parameters including age, duration of transfusion, age starting iron chelation therapy, and ratio between transfusion volume and desferrioxamine dosage were not correlated with cardiac and liver T2*. CONCLUSION: We conclude that iron overload in heart and liver is common in our transfusion dependent patients. Liver T2* has inverse correlation with serum ferritin. Cardiac T2* does not have any correlation with the various clinical and biochemical parameters.

Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin.

BACKGROUND: Doxorubicin (DOX) is an important antineoplastic agent. However, the associated cardiotoxicity, possibly mediated by the production of reactive oxygen species, has remained a significant and dose-limiting clinical problem. Our hypothesis is that the hematopoietic/megakaryocytopoietic growth factor thrombopoietin (TPO) protects against DOX-induced cardiotoxicity and might involve antiapoptotic mechanism exerted on cardiomyocytes. METHODS AND RESULTS: In vitro investigations on H9C2 cell line and spontaneously beating cells of primary, neonatal rat ventricle, as well as an in vivo study in a mouse model of DOX-induced acute cardiomyopathy, were performed. Our results showed that pretreatment with TPO significantly increased viability of DOX-injured H9C2 cells and beating rates of neonatal myocytes, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. TPO ameliorated DOX-induced apoptosis of H9C2 cells as demonstrated by assays of annexin V, active caspase-3, and mitochondrial membrane potential. In the mouse model, administration of TPO (12.5 microg/kg IP for 3 alternate days) significantly reduced DOX-induced (20 mg/kg) cardiotoxicity, including low blood cell count, cardiomyocyte lesions (apoptosis, vacuolization, and myofibrillar loss), and animal mortality. Using Doppler echocardiography, we observed increased heart rate, fractional shortening, and cardiac output in animals pretreated with TPO compared with those receiving DOX alone. CONCLUSIONS: These data have provided the first evidence that TPO is a protective agent against DOX-induced cardiac injury. We propose to further explore an integrated program, incorporating TPO with other protocols, for treatment of DOX-induced cardiotoxicity and other forms of cardiomyopathy.

Umbilical cord blood transplantation in Chinese children with beta-thalassemia.

To evaluate factors affecting outcome of sibling umbilical cord blood transplantation in Chinese children with thalassemia. The authors conducted a retrospective review of all patients undergoing such transplants in a single institution. Nine children with thalassemia major were diagnosed at a median age of 12 months. They received irregular blood transfusions and suboptimal iron chelation therapy before transplant. Sibling cord blood transplant was performed at a median of 5.5 years (range 3.5-10 years). Six donors were HLA-identical; three were one- to three-antigen mismatched. The mean number of nucleated cells infused was 6.6 x 10(7)/kg (range 3.4-12.7); the mean number of CD34+ cells infused was 3.8 x 10(5)kg (range 0.6-11.7). Seven patients had engraftment of donor cells. The median number of days to achieve a neutrophil count of > 0.5 x 10(9)/L was 19 days (range 10-25); the median number of days to achieve a platelet count of > 20 x 10(9)/L was 33 days (range 19-63). Of the six patients who received HLA-identical transplants, one developed grade 2 and two developed grade 1 acute graft-versus-host disease. Two of the three patients receiving mismatched cord blood did not achieve engraftment, and the other one engrafted but developed grade 4 acute graft-versus-host disease. Two patients subsequently developed secondary graft rejection and had autologous marrow regeneration before day 60 posttransplantation. With a median follow-up of 49 months (range 38-64), eight patients survived but only four were transfusion-independent. Umbilical cord blood transplant appears to have a higher chance of nonengraftment and secondary rejection. A more intensive immunosuppressive conditioning regimen may be required.

White matter and cerebral metabolite changes in children undergoing treatment for acute lymphoblastic leukemia: longitudinal study with MR imaging and 1H MR spectroscopy.

PURPOSE: To assess the development of white matter and cerebral metabolite changes during and after treatment in children with acute lymphoblastic leukemia. MATERIALS AND METHODS: Twenty-three children (10 boys, mean age of 6.3 years; 13 girls, mean age of 6.6 years) with acute lymphoblastic leukemia were examined prospectively with magnetic resonance (MR) imaging and MR spectroscopy at 0, 8, and 20 weeks and 1, 2, and 3 years after diagnosis. White matter changes were diagnosed on the basis of hyperintense abnormalities on T2-weighted MR images. Single-voxel hydrogen 1 MR spectroscopy results from the right frontoparietal region of 21 children who received intravenous high-dose methotrexate were analyzed for cerebral metabolite changes. Multilevel models were used to assess the change in metabolites from baseline levels at subsequent follow-up. RESULTS: At 20 weeks, MR spectroscopy showed a significant reduction (P <.05) of mean N-acetylaspartate to choline ratio and increase in mean choline to creatine ratio (P <.05) in the children given high-dose methotrexate. This decline in N-acetylaspartate to choline ratio subsequently reversed and increased, possibly because of normal age-related brain maturation. Seventeen of 21 (81%) children showed metabolite changes at MR spectroscopy, while five of 22 (23%) showed white matter changes at MR imaging at 20 weeks. One more child developed white matter changes at 32 weeks. The associated changes resolved or reduced with time. CONCLUSION: MR spectroscopy demonstrated metabolite changes in the brain after high-dose methotrexate treatment in the absence of structural white matter abnormalities at MR imaging. MR spectroscopy might thus be a more sensitive method of monitoring the effects of high-dose methotrexate in the brain.

Patterns of bone diseases in transfusion-dependent homozygous thalassaemia major: predominance of osteoporosis and desferrioxamine-induced bone dysplasia.

OBJECTIVE: To study the radiographic skeletal changes in transfusion-dependent homozygous beta-thalassaemia. MATERIALS AND METHODS: This was a retrospective review of radiographs of 41 homozygous beta-thalassaemic patients over 3 years. These included 55 left hand radiographs for bone age, 37 chest radiographs, 7 scanograms of lower limbs, 8 knee radiographs and 3 skull radiographs. The radiographs were evaluated for the skeletal changes owing to medullary expansion, as well as for the skeletal dysplasia related to desferrioxamine therapy. The combined cortical width of the mid shaft of the second metacarpal was measured on left hand radiographs to assess osteoporosis. RESULTS: Sixteen patients had radiographic evidence of desferrioxamine-induced bone dysplasia. These included metaphyseal sclerosis in long bone ( n=16), irregular sclerosis at the costochondral junction ( n=3) and platyspondyly ( n= 1). Two patients had radiographic evidence of medullary expansion with widening of medulla and marked thinning of cortex in the tubular bones. Osteoporosis, as indicated by thinning of metacarpal cortex, was noted in 17 patients (8 with and 9 without desferrioxamine-induced bone dysplasia). CONCLUSIONS: With provision of the modern regime of regular transfusion and desferrioxamine chelation, desferrioxamine-induced bone dysplasia was a much more frequently detected radiographic abnormality in beta-thalassaemia major than radiographic features owing to medullary expansion. Osteoporosis, as indicated by thinned metacarpal cortices, remained a frequent feature irrespective of the status of the skeletal dysplasia.