Efficacy of constraint-induced movement therapy compared with bimanual intensive training in children with unilateral cerebral palsy: a systematic review.

OBJECTIVE: To systematically review the evidence on the effect of constraint-induced movement therapy compared with bimanual intensive training in children with unilateral cerebral palsy. DATA SOURCES: Seven electronic databases (Cinahl, Cochrane Library, EMBASE, Ovid MEDLINE, PEDro, PsycINFO, PubMed) were searched from database inception through December 2016. METHODS: A systematic review was performed using the American Academy of Cerebral Palsy and Developmental Medicine and Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Standardised mean differences (effect sizes) were calculated for each study and outcome. RESULTS: Nine studies met the eligibility criteria. All studies provided level II evidence. Methodological quality was high in two studies, moderate in four studies and low in three studies. The methodology, participant and intervention characteristics were heterogeneous. The participants' ages ranged from 1.5 to 16 years. Their initial hand function ranged from Manual Ability Classification System Level I to Level III. The total intervention dose ranged from 24 to 210 hours and duration from one week to ten weeks. The studies measured outcomes assessing unimanual and bimanual hand and arm function, participation and attainment of individualised goals. Overall, the effect sizes did not favour one of the interventions at short- or long-term follow-up. The 95% confidence intervals were broad, indicating inaccurate precision of the effect sizes. Pooling of the data for a meta-analysis was judged to be of little clinical value owing to heterogeneity. CONCLUSION: It is not possible to conclude whether constraint-induced movement therapy or bimanual intensive training is more effective than the other in children with unilateral cerebral palsy.

No benefit of treatment with cyclophosphamide and autologous blood stem cell transplantation in multifocal motor neuropathy.

INTRODUCTION: Patients with multifocal motor neuropathy (MMN) usually respond to intravenous immunoglobulin (IVIG), but because of the short-lasting effect the treatment must be given repeatedly. Remission after treatment with high-dose cyclophosphamide has recently been reported in one patient refractory to IVIG. CASE REPORT: Here we report on a patient who responded to IVIG, but temporarily deteriorated dramatically after treatment with high-dose cyclophosphamide and autologous blood stem cell transplantation. Today the situation is the same as before the treatment with cyclophosphamide and blood stem cell transplantation, i.e. IVIG is given every 4 weeks. CONCLUSION: Our patient did not benefit from the treatment with high-dose cyclophosphamide and autologous blood stem cell transplantation. The effect of treatment with high-dose cyclophosphamide in MMN seems to be difficult to predict and that should be paid attention to if this type of treatment is considered.

Interactions between cladribine (2-chlorodeoxyadenosine) and standard antileukemic drugs in primary cultures of human tumor cells from patients with acute myelocytic leukemia.

The semiautomated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein in microtiter plates, was used for in vitro evaluation of Cladribine (2-chlorodeoxyadenosine, CdA) interactions with five standard antileukemic drugs: amsacrine (Am), etoposide (VP16), daunorubicin (Dnr), cytosine arabinoside (AraC), and mitoxantrone (Mit). Samples from 31 patients with acute myelocytic leukemia (AML) were tested with continuous drug exposure. A large heterogeneity with respect to cell kill was observed for all combinations tested. An additive model provided a significantly better fit of the data compared to the effect of the most active single agent of the combination (Dmax) only for CdA+AraC. When the frequency of additive and synergistic interactions were calculated according to the multiplicative concept for drug interactions, the highest frequencies were observed for CdA+AraC and CdA+Dnr. This interaction pattern was confirmed by isobologram analysis. Cross-resistance analysis revealed high correlations between CdA and AraC whereas the correlations were weaker between CdA and the other drugs. The highest frequency of synergistic interactions was obtained for AraC+CdA, despite their cross-resistance. Of the non-cross-resistant drugs tested, Dnr appears to be the most effective adjunct to CdA in terms of interactions at the cellular level.

Regeneration of functional and activated NK and T sub-subset cells in the marrow and blood after autologous bone marrow transplantation: a prospective phenotypic study with 2/3-color FACS analysis.

The phenotypic reconstitution of lymphoid cells in the bone marrow and peripheral blood was examined prospectively in 27 patients who underwent autologous bone marrow transplantation (ABMT) for leukemia/lymphoma. Patterns of activation within NK and T cell subsets as well as T sub-subsets were studied with monoclonal antibodies in two- and three-color FACS analysis. NK-like cells (CD16+) were found to be increased in the peripheral blood and bone marrow after ABMT. The expression of two activation markers, 4F2 and HLA-DR, was sustainedly increased within this subset. High numbers of CD4+ and CD8+ T cells carrying surface HLA-DR were found early after ABMT both in blood and marrow. The T suppressor inducer cell sub-subset (CD45R+ CD4+) was severely depressed in both the blood and marrow 6-9 months post-ABMT. Using three-color FACS analysis, half of this T sub-subset was shown to express HLA-DR+. The levels of T suppressor effector-like cells (CD11+ CD8+) remained within the normal range in both peripheral blood and bone marrow during follow-up. The HLA-DR expression was elevated and equally distributed between the CD11- CD8+ and CD11+ CD8+ sub-subset cells. There was no major impact of marrow T cell purging or CMV carrier status on the phenotypic NK/T cell reconstitution. The present results provide an immune phenotypic basis for the suggested generation of anti-leukemic NK-like and T suppressor-like activity after ABMT.

No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease.

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte-macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels

Stimulation of NK cell, T cell, and monocyte functions by the novel immunomodulator Linomide after autologous bone marrow transplantation. A pilot study in patients with acute myeloid leukemia.

Immunostimulatory therapy is at present considered after autologous bone marrow transplantation (ABMT) in order to mimic the allogeneic graft-versus-leukemia effect and thereby reduce the relapse rate. In a pilot study, five adults with acute myeloid leukemia were treated with the new immunomodulator Linomide post-ABMT. Linomide (0.3 mg/kg/week orally) was given in cycles of three weeks followed by three weeks of rest for up to six months. During treatment periods cyclic increases of CD56+CD3- and CD16+ NK cells were observed in parallel with enhanced cytotoxic activity of patient cells against both the NK-sensitive K562 and NK-resistant Daudi cell lines. A cyclic increase of CD14+ monocytic cells was also recorded. The proliferative responses of patient cells to PHA and allogeneic cells (MLC) were enhanced during Linomide therapy. The in vitro production of TNF alpha, IFN gamma, and IL-1 followed the same cyclic increase during treatment periods. Side effects were generally mild, and no harmful effects on engraftment were seen. Linomide therapy after ABMT thus induces a broad immunostimulation that offers a potential benefit with regard to leukemia-free survival.

B lymphocyte regeneration in marrow and blood after autologous bone marrow transplantation: increased numbers of B cells carrying activation and progression markers.

The reconstitution of B cells in the bone marrow and peripheral blood was prospectively studied in 27 patients undergoing autologous bone marrow transplantation (ABMT). No major differences in B cell regeneration patterns were recorded between patients receiving marrows purged of B cells (anti-CD10 + 19; n = 17) and patients receiving unpurged marrows (n = 10). Compared with healthy controls, elevated absolute and relative numbers of B cells were recorded in the blood and marrow at +6 and +12 months in both groups of patients. CD23+ B cells were severely depressed during the first three months post ABMT, indicating immaturity. A twofold increase in B cells carrying the activation marker 4F2 was recorded in the marrow at +1 month. Serum immunoglobulin levels (IgG, IgA, IgM) were within low-normal range throughout the study. The depressed B cell responses reported after allogeneic and autologous BMT could in part be explained by the low expression of the CD23 antigen on B cells after such therapy.

Impaired glucose tolerance after autologous bone marrow transplantation.

In this study we investigated glucose tolerance in relation to autologous bone marrow transplantation (ABMT). In 13 adult patients with acute myeloblastic (AML) or lymphoblastic (ALL) leukaemia in complete remission (CR), intravenous glucose tolerance test (IVGTT) was performed 1 month before and 6 months after ABMT. Patients with AML in CR received, as myeloablative therapy, cyclophosphamide combined with busulphan or total body irradiation (TBI). ALL patients received total body irradiation in combination with vincristine, daunorubicin, Ara-C, cyclophosphamide and prednisone. Before ABMT all patients, in spite of the intensive chemotherapy given for remission induction and consolidation, had a normal glucose tolerance. However, 6 months after the transplantation the k-value (rate of glucose elimination) for this group of patients had decreased (p less than 0.01). The trend towards impaired glucose tolerance was correlated with lower peak insulin values during IVGTT (p less than 0.05). Thus, the myeloablative therapy in connection with ABMT caused an impairment of pancreatic beta-cell function. No patient has hitherto developed clinical diabetes mellitus.

Pulmonary function and complications subsequent to autologous bone marrow transplantation.

Risk factors for early pulmonary complications occurring within the first 3 months after autologous bone marrow transplantation (BMT) were analysed in 158 consecutive adults. The long-term effects of autologous BMT on pulmonary function were analysed in 102 patients, who had survived free of disease for > 6 months after autologous BMT. Pulmonary function tests were performed before, at 6 and 12 months after autologous BMT and thereafter annually. The median follow-up was 12 (6-60) months. The incidence of early pulmonary complications was 16% (26 of 158). Idiopathic interstitial pneumonitis was seen in 11% of patients treated with total body irradiation (TBI). Single dose TBI was the major risk factor as regards early pulmonary complications but restrictive pulmonary disturbances and impaired diffusing capacity prior to autologous BMT were also significant risk factors. In both non-TBI and TBI-treated patients a mild restrictive ventilatory dysfunction and impaired diffusing capacity was noted 6 months after autologous BMT. In non-TBI-treated patients, these disturbances had resolved completely within 2 years whereas the lung volumes of TBI-treated patients were persistently reduced by 10% of their pre-autologous BMT values during follow-up. However, dysfunctions rarely progressed 6 months after autologous BMT. In most patients, ventilatory dysfunction was slight and had no clinical significance.

Haemolytic uraemic syndrome and renal dysfunction following BEAC (BCNU, etoposide, ara-C, cyclophosphamide) +/- TBI and autologous BMT for malignant lymphomas.

Twenty-four patients autografted for malignant lymphoma have been followed. All were conditioned with BEAC (BCNU, etoposide, ara-C, cyclophosphamide), in 10 patients combined with total body irradiation (TBI) 7.5 Gy. Within 1 month of ABMT, a capillary leak syndrome was seen in four patients (one death) and isolated pericarditis in one. Nineteen patients survive disease-free at > or = 6 months, median (range) 24 (11-48) months. In 15 of 19 patients, a decrease in glomerular filtration rate (GFR) of > 20% was observed, 6 (6-24) months after ABMT. In six of these patients (five treated with TBI), the renal dysfunction was still progressing 11-36 months after ABMT. Five patients (four conditioned with TBI) developed a haemolytic uraemic syndrome (HUS) with Coombs negative haemolytic anaemia, platelet consumption and renal impairment, with onset 3-6 months after ABMT. Haemolysis and platelet consumption, but not renal impairment, were reversible in all patients. One death from HUS was seen. Because of the adverse effects described we have abandoned the combination of BEAC with TBI.

Busulfan concentration in relation to permanent alopecia in recipients of bone marrow transplants.

Alopecia is an important long-term complication after bone marrow transplantation (BMT). The aim of this study was to analyze the influence of busulfan concentration on the development of permanent alopecia. Sixty five patients who survived for at least 6 months after BMT were studied. The median follow-up was 2.1 years (range 0.5-5.7 years). Thirty one patients (47%) had some degree of alopecia and 19 of these patients had extensive alopecia. The mean minimum busulfan concentration was 656 +/- 222 ng/ml in patients who developed alopecia compared with 507 +/- 224 ng/ml in those who did not (P = 0.005). Patients with more extensive alopecia had higher busulfan concentrations than patients with less significant abnormalities. In multivariate analysis, alopecia was associated with busulfan concentrations higher than the median (OR 3.43; 95% CI 3.04-3.88), allogeneic transplantation (OR 2.56; 95% CI 2.28-2.88) and female sex (OR 1.96; 95% CI 1.73-2.88). There was no association between alopecia and chronic graft-versus-host disease. High busulfan concentrations may contribute to the development of permanent alopecia and the risk for alopecia should be considered when choosing the conditioning regimen before BMT.

High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients.

The aim of this study was to investigate the importance of busulfan concentrations for short- and long-term survival in autologous (ABMT) and allogeneic (BMT) bone marrow transplant recipients. One hundred and seventy-three patients were included in the study; 87 ABMT and 85 BMT patients. All patients received busulfan 1 mg/kg four times daily for 4 days followed by cyclophosphamide 60 mg/kg/day for 2 days. Busulfan concentrations were measured and the mean concentration calculated for each patient. There was no difference in busulfan concentrations between BMT and ABMT patients. Patients who died before day 100 had significantly higher busulfan concentrations than patients surviving beyond day 100 (719 ng/ml vs 589 ng/ml; P < 0.02). BMT patients who had busulfan concentrations in the highest quartile had significantly worse disease-free survival (DFS) and survival compared to other patients. The transplant-related mortalities (TRM) at 100 days were 29 and 14% in patients in the highest quartile and remaining patients, respectively. There was no difference in relapse incidence. High busulfan concentrations were associated with increased TRM but no difference in either survival or DFS could be found for the ABMT patients. Monitoring of busulfan concentrations is important in reducing the risk for TRM in patients undergoing bone marrow transplantation.

Thyroid function after autologous bone marrow transplantation.

Thyroid function was prospectively analysed in 111 consecutive patients in relation to autologous bone marrow transplantation (ABMT). Median follow-up time was 12 (range 3-60) months. As part of the conditioning treatment 58 patients had received total body irradiation (TBI) as a single dose of 7.5 Gy (dose rate 0.15 Gy/min). Thyroxine, triiodothyronine, thyrotropin (TSH) and thyroid antibodies were analysed before ABMT, every third month during the first year afterwards and then once annually. Thyroid dysfunction was seen in 20 patients (after TBI in 16, after non-TBI treatments in four). Five of these, all treated with TBI, developed primary hypothyroidism and in 15 compensated hypothyrosis, transient in eight (40%), was seen. There was a highly significant (p less than 0.001) increase, within the normal range, in median TSH level, prior to ABMT compared with 1 year following ABMT. In patients who developed thyroid dysfunction, the TSH level before ABMT was significantly higher (p less than 0.001) than in those who remained euthyroid. In four patients persistent elevated thyroid antibody titers appeared and in two of them hypothyrosis developed. No correlation between thyroid dysfunction and age was noted. The findings are similar to those after allogeneic BMT described by others.

Foscarnet for pre-emptive therapy of CMV infection detected by a leukocyte-based nested PCR in allogeneic bone marrow transplant patients.

Fifteen allogeneic BMT patients in a phase II study were given foscarnet 60 mg/kg twice daily for 14 days as pre-emptive therapy against CMV disease. CMV infection was diagnosed by a leukocyte-based nested PCR. All 15 patients were evaluable for toxicity. One patient did not fulfill the inclusion criteria of two consecutively positive CMV PCR tests and therefore was not evaluable for efficacy. Thus, 14 of 15 patients were evaluable for development of CMV disease. None of the patients developed CMV disease and all 14 assessable patients had a negative CMV isolation at the end of therapy. None of the 15 patients had to discontinue therapy due to toxicity. Six patients reported mild gastrointestinal disturbances, three patients headaches, and three patients mild urethritis or hemorrhagic cystitis. Serum-electrolyte disturbances were common including abnormal magnesium, potassium and calcium levels. Two patients developed mild serum-creatinine increases requiring adjustment of the foscarnet dosage according to protocol. We conclude that a dosage of foscarnet of 60 mg/kg given twice daily seems to be safe and effective in preventing CMV disease in allogeneic BMT recipients. A study comparing foscarnet and ganciclovir is indicated.

Tetanus immunity in autologous bone marrow and blood stem cell transplant recipients.

The aims of this study were to assess long-term immunity and reimmunization responses against tetanus toxoid in recipients of autologous stem cell grafts and to compare immune status in patients who underwent ABMT or autologous blood stem cell transplantation (APBSCT). Ninety patients were included in the study; 52 had received ABMT and 38 APBSCT. Thirty of 52 ABMT patients (58%) and 25 of 38 APBSCT patients (66%) had protective antibody levels against tetanus before transplantation (P = NS). The rate of seropositivity had decreased at 1 year after transplantation; 15 of 52 (29%) ABMT patients and 18 of 38 (47%) APBSCT patients (P = NS) were still positive after 1 year. There were no cases of spontaneous recovery in seronegative patients. Most patients were reimmunized with three doses of tetanus toxoid given at 12, 13, 14 and or 18 months after transplantation. All immunized patients had protective immunity against tetanus at 1 year after vaccination. These results suggest that humoral immunity is defective both after ABMT and after APBSCT and in both cases the loss of immunity seems to be similar. Reimmunization of patients who have undergone ABMT or APBSCT is necessary to obtain protective immunity against tetanus.

Specific T and B cell immunity to measles after allogeneic and autologous bone marrow transplantation.

Lymphocyte stimulation with measles virus antigen (MLY) and ELISA for measles IgG antibodies were performed on 60 patients after allogeneic bone marrow transplantation (BMT), and on 59 patients after autologous bone marrow transplantation (ABMT). The T cell response was significantly higher in the 75 measles seropositive patients than in the 29 seronegative patients (P < 0.001), but not significantly different from the MLY in the 15 patients with uncertain serologic reactivity. When the patient group was divided according to type of transplant, the T cell response to measles was also significantly higher in seropositive patients than in seronegative patients after both ABMT (P < 0.001) and after BMT (P < 0.05). Twenty-three seronegative children who were measles vaccinated after BMT had a significantly higher T cell response to measles (7100 c.p.m.) than 17 seronegative non-vaccinated children (100 c.p.m.; P < 0.01). No significant difference was seen in the T cell response in 12 seronegative children vaccinated after ABMT (2500 c.p.m.) compared to seven children not vaccinated (2800 c.p.m.; NS). Seroconversion after vaccination was more frequent in children after BMT (20/23; 87%) compared to ABMT (5/12; 42%; P < 0.05) but no significant difference was found in the T cell response. Therefore, most patients who lost IgG antibodies to measles after bone marrow transplantation also lost their T cell response to measles. A T cell response to measles developed in most patients who seroconverted after vaccination. Failure to develop antibodies to measles in ABMT patients after revaccination may depend on a persisting T cell immunity.

Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy.

A patient with acute myeloblastic leukemia received high-dose busulfan (1 mg/kg by mouth every 6 h for 4 days) as myelo-ablative therapy for autologous bone marrow transplantation. Rapid entry of busulfan into the cerebrospinal fluid (CSF) was observed. Plasma and CSF concentrations of busulfan were comparable during the 4 days of treatment. The elimination half-lives of busulfan in plasma and CSF were 2.6 h and 2.8 h respectively during the first 12 h after the last dose.

Renal function after autologous bone marrow transplantation.

Seventy-two out of 102 consecutive patients autografted for various hematologic and lymphoid malignancies had a relapse-free survival of greater than 6 months after autologous bone marrow transplantation (ABMT) and were evaluated for long-term effect of the treatment on the renal function. The myeloablative therapy included total body irradiation (TBI) in a single fraction of 7.5 Gy in 41/72 patients. Mean glomerular filtration rate (GFR) showed a significant decrease (p less than 0.01) and serum creatinine and serum urea an increase (p less than 0.05) 6 months after ABMT. Twelve of 72 patients (17%) developed renal dysfunction defined as greater than 25% decrease in GFR, in most cases accompanied by hematuria and proteinuria. Onset was 3-6 months after ABMT. Some patients have later improved considerably, but others continue to deteriorate in renal function. The single most important risk factor for renal dysfunction after ABMT was irradiation. Renal damage was most frequent in lymphoma patients conditioned with BEAC (carmustine [BCNU], etoposide, cytarabine, cyclophosphamide) followed by irradiation, suggesting that this drug combination might have potentiated the toxicity of irradiation. Nephrotoxic antibiotics probably contributed to renal damage in individual cases. Young age did not appear to be a risk factor. Our data indicate that combined treatment with BEAC and TBI should be used with caution and that renal function should be monitored in all patients after bone marrow transplantation to detect any new toxicity patterns of the various conditioning regimens currently used.

Pulmonary function after autologous bone marrow transplantation in children.

Forty-two children receiving bone marrow autografts were studied prospectively regarding acute pulmonary complications; there was no procedure-related mortality and only one case of interstitial pneumonitis. An analysis was also made of the pulmonary function tests (PFTs) of the 27 autografted children who were disease-free and had been followed up for at least 1 year (median 4.1 years, range 1.1-7.6 years). PFTs were performed before and 6, 12, 24, 36 and 60 months after autologous BMT. The mean pre-transplant values of total lung capacity (TLC), vital capacity (VC) and forced expiratory volume in one second (FEV1) were close to predicted but 6 months after autologous BMT there was a statistically significant decrease (11, 13 and 15% below baseline, respectively) in patients receiving total body irradiation in their conditioning regimen. There was some but not complete recovery with time. DLCO remained low throughout the study, irrespective of the conditioning regimen. In summary, acute pulmonary complications were few and PFTs showed only modest changes from baseline after ABMT. At the latest follow-up no respiratory symptoms had reportedly occurred in any of the children and the chest radiographs were normal. Although the results are promising so far, long-term follow-up is necessary to evaluate the final outcome in these children.

Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients.

The aims of the present study were (1) to investigate and quantify the pharmacokinetics, including inter-occasion variability and covariate relationships, of busulphan in BMT patients and (2) to develop a user-friendly initial dosing and therapeutic drug monitoring (TDM) strategy for the treatment of those patients with busulphan. The pharmacokinetics of busulphan was studied in 64 adults and 12 children who received busulphan (1 mg/kg) four times daily for 4 days. A one-compartment model with first order absorption and a lag time was sufficient in describing the concentration-time profile. Oral clearance (CL/F) was found to be correlated to weight (+1.2%/kg), ALT (-13%/microcat/l) and concomitant phenytoin treatment (+21%). CL/F and the volume of distribution (V/F) were estimated to 9.23 l/h and 39.3 l, respectively, in a typical individual. Inter-occasion variability (9.4%) in CL/F was estimated to be less than inter-individual variability (28%), a prerequisite for the value of TDM. Bayesian CL/F estimates based on three samples were in good accordance with those based on all samples. The final population model was implemented into the program Excel. The resulting flexible and easy to use dosing program might be used for both initial and, requiring only three plasma samples, maintenance dose individualization of busulphan therapy.