The effect of hydroxcarbamide therapy on survival of children with sickle cell disease

Although evidence is accumulating that hydroxycarbamide decreases mortality among adults with sickle cell disease (SCD), there are no published data regarding the effect of hydroxycarbamide on mortality among children. The Paediatric Hydroxycarbamide Program was established to treat children with SCD aged 3–18 years if they met disease severity criteria. Mortality data and clinical/laboratorial effects of hydroxycarbamide were retrospectively collected for the first 9 years of the Program. Mortality among those who received hydroxycarbamide was compared to that of untreated children. Among 1760 subjects, 267 received hydroxycarbamide at a median dose of 20·8 mg/kg/d (range 10–32) for a median of 2 years (range 0·1–6·5). Survival among hydroxycarbamide‐treated children was significantly greater than that among untreated ones (99·5% vs. 94·5%, P = 0·01), due primarily to fewer deaths from acute chest syndrome and infection. Hydroxycarbamide therapy was significantly associated with increases in haemoglobin concentration, fetal haemoglobin, mean corpuscular volume, and reduction in platelet counts, reticulocytes and neutrophils. Toxicity was minimal and predominantly mild reversible neutropenia. Significantly fewer hospitalizations and emergency room visits, and shorter admissions were observed among hydroxycarbamide‐treated subjects, when compared to the 12‐month period prior to treatment initiation. Hydroxycarbamide therapy reduces disease severity and is probably associated with decreased mortality among children with SCD.     

Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1·3 mg/m² on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2·5–10·0 mg/m²) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7·5 mg/m² and bortezomib 1·3 mg/m². The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD ( n  = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD ( P  < 0·05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.     

A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma

In this open‐label, multicentre, phase 1 study a fully human anti‐CD40 antagonist monoclonal antibody, lucatumumab, was evaluated in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to determine the maximum tolerated dose (MTD) based on dose‐limiting toxicities (DLTs). Secondary objectives included safety, pharmacokinetics, pharmacodynamics and antimyeloma activity. Twenty‐eight patients, enrolled using a standard ‘3 + 3’ dose escalation, received one or two (n = 3) cycles of lucatumumab 1·0, 3·0, 4·5 or 6·0 mg/kg once weekly for 4 weeks. Common lucatumumab‐related adverse events were reversible, mild‐to‐moderate infusion reactions. Severe adverse events were anaemia, chills, hypercalcaemia and pyrexia (7% each). DLTs included grade 4 thrombocytopenia, grade 3 increased alanine aminotransferase and grade 4 increased lipase (n = 1 each). The MTD was 4·5 mg/kg. At doses ≥3·0 mg/kg, sustained receptor occupancy (≥87%), observed throughout weekly infusions up to 5 weeks after the last infusion, correlated with an estimated half‐life of 4–19 d. Twelve patients (43%) had stable disease, and one patient (4%) maintained a partial response for ≥8 months. These findings indicate that single‐agent lucatumumab was well tolerated up to 4·5 mg/kg with modest clinical activity in relapsed/refractory MM, warranting further study as a combination therapy.     

Comparison of three doses of leuprolide acetate in the treatment of central precocious puberty: preliminary results

Objective  Depot luteinizing-hormone releasing hormone (LHRH) agonist have been widely used for the treatment of central precocious puberty (CPP), but the optimal doses to obtain hormonal suppression are still unknown, especially in patients with higher weights. The goal of our study was to compare the efficacy of three leuprolide acetate (LA) preparations, suppressing gonadotropin secretion in patients with CPP.
Design  In an open 12-month protocol, we evaluated LA 7·5 mg/month, 11·25 and 22·5 every 3 months.
Patients  Fourteen girls with CPP and weights over 30 kg.
Measurements: Clinical, radiological and laboratory follow-up: GnRH test plus LH, FSH 40 min post analogue was performed periodically.
Results  Pretreatment basal and LHRH stimulated LH levels between groups were not different. Basal and LHRH stimulated LH levels decreased significantly between baseline and from 3 up to 12 months of therapy in all groups ( P  =   0·001). GnRH stimulated LH peak <2 IU/l, the main efficacy criterion was met in 80, 75 and 100% of the children at 6 months in the 7·5, 11·25, 22·5 mg doses respectively. By 12 months, 100% of patients had LH suppressed to <2 IU/l.
Conclusions   These results affirm that 3-month injections may be a satisfactory alternative for the therapy of children with CPP to avoid monthly injections. In addition, suppression of LH occurs sooner in the 3-month 22·5 mg LA dose compared to the 3-month 11·5 mg; therefore, adequate dosing may be important for optimal outcome. Further investigation is needed in more patients over 30 kg, with longer treatment duration, and ultimately final height consideration.     

Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia

MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC₅₀ (concentration lethal to 50%) of 0·23 μmol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0–12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22·3) or del(17p13·1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3–4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.     

Hydroxycarbamide alters erythroid gene expression in children with sickle cell anaemia

Sickle cell anaemia (SCA) is a severe debilitating haematological disorder associated with a high degree of morbidity and mortality. The level of fetal haemoglobin (HbF) is well-recognized as a critical laboratory parameter: lower HbF is associated with a higher risk of vaso-occlusive complications, organ damage, and early death. Hydroxycarbamide treatment can induce HbF, improve laboratory parameters, and ameliorate clinical complications of SCA but its mechanisms of action remain incompletely defined and the HbF response is highly variable. To identify pathways of hydroxycarbamide activity, we performed microarray expression analyses of early reticulocyte RNA obtained from children with SCA enrolled in the HydroxyUrea Study of Long-term Effects (NCT00305175) and examined the effects of hydroxycarbamide exposure in vivo. Hydroxycarbamide affected a large number of erythroid genes, with significant decreases in the expression of genes involved in translation, ribosome assembly and chromosome organization, presumably reflecting the daily cytotoxic pulses of hydroxycarbamide. Hydroxycarbamide also affected expression of numerous genes associated with HbF including BCL11A, a key regulator of baseline HbF levels. Together, these data indicate that hydroxycarbamide treatment for SCA leads to substantial changes in erythroid gene expression, including BCL11A and other potential signalling pathways associated with HbF induction.     

Pretreatment angiogenic cytokines predict response to chemoimmunotherapy in patients with chronic lymphocytic leukaemia

Serum levels of pro-[vascular endothelial growth factor (VEGF)] and anti-[thrombospondin-1 (TSP)] angiogenic cytokines were prospectively measured in a phase II trial of chemoimmunotherapy (CIT) for chronic lymphocytic leukaemia (CLL) patients ( n  = 56). Pretreatment VEGF levels were lower among patients who achieved complete remission (CR) or nodular partial remission (nPR) relative to those with partial remission (PR) or stable/progressive disease (median 122·0 pg/ml vs. 246·8 pg/ml; P  = 0·03). VEGF:TSP ratio was lower (anti-angiogenic phenotype) among patients who achieved CR/nPR. The pretreatment VEGF:TSP ratio also correlated with overall survival ( P  = 0·008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT.     

Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease

Prevention of erythrocyte dehydration by specific blockade of the transport pathways promoting loss of potassium (K) is a potential therapeutic strategy for sickle cell (SS) disease. Dietary magnesium (Mg) pidolate supplementation over a 4-week period has been shown to inhibit K-Cl co-transport and reduce dehydration. We report here the results in 17 of 20 patients with SS disease treated in an open-label unblinded study of the effects of long-term (6 months) oral Mg pidolate administration (540 mg Mg/d). A significant decrease (P < 0.0025) was observed with Mg therapy in the distribution widths for red cell mean cell haemoglobin concentration (MCHC) (haemoglobin distribution width; HDW), reticulocyte mean cell volume (red cell distribution width of reticulocytes; RDWr) and MCHC (reticulocyte HDW; HDWr), activity of red cell K-Cl co-transport, Na/Mg exchanger and Ca2+-activated (Gardos) K+ channel, whereas red cell K and Mg contents were significantly increased. Hb levels and absolute reticulocyte counts did not change with Mg therapy. Two patients did not complete the trial because of diarrhoea and one did not complete the trial for unrelated reasons. Although the median number of painful days in a 6-month period decreased from 15 (range 0-60) in the year before the trial to 1 (range 0-18; P < 0.0005) during the period of Mg therapy, no firm conclusion on therapeutic efficacy could be drawn from this unblinded open-label trial.     

The efficacy and safety of nibentan for pharmacological cardioversion in patients with persistent atrial fibrillation and flutter: the role of dose limitation and magnesium sulfate administration

The aim of the study was to evaluate the influence of magnesium sulfate on the efficacy and safety of pharmacological cardioversion with nibentan (NB) in doses up to 0,125 mg/kg in patients with persistent atrial fibrillation (AF) and flutter (AFL). Calculated dose of NB was 0.125 mg/kg. It was administered as 2 bolus injections (0.0625 mg/kg each) performed with the interval of 15 minutes. The study included 64 patients (pts) (45 male, age 54+/-9,9 years) with persistent AF (n=56) and AFL (n=8) with median arrhythmia duration 6,7+/-6,8 months (8 days to 36 months). Pts were divided into two groups. In the first (I) group NB was used without preliminary magnesium sulfate administration, in the second group (II) magnesium sulfate was injected in a dose of 50 mg/kg, followed by 0.83 mg/kg/min infusion before NB administration. There was no difference between groups in conversion rates of atrial arrhythmias: 74% and 69%, in groups I and II, respectively (p>0.4). Mean effective dose of NB was the same in investigated groups - 0.09 mg/kg. Administration of initial dose of NB (0.0625 mg/kg) converted AF/AFL to sinus rhythm within 15-min interval in 29.7% of patients. Efficacy of full dose of NB (0.125 mg/kg) was 100% in AFL, 68% in AF. No side effects were registered after initial injection of 0.0625 mg/kg. After administration of 2 boluses (0.125 mg/kg) "torsade de pointes" developed in 2 pts (3%). Magnesium sulfate administration had no influence on NB efficacy and rate of its proarrhythmic events. Limitation of NB total dose to 相似文献   

Differential modulation of adhesion molecule expression by hydroxycarbamide in human endothelial cells from the micro- and macrocirculation: potential implications in sickle cell disease vasoocclusive events

Background

All the cellular partners of the vascular system and especially endothelial cells are involved in the pathophysiology of the vasoocclusive crises associated with sickle cell disease. In sickle cell disease, circulating cells adhere abnormally to endothelial cells in a chronic pro-inflammatory context. Hydroxycarbamide is the only drug with demonstrated efficacy to reduce the frequency of vasoocclusive crises. Here, we investigated the effects of hydroxycarbamide and/or cytokines on the expression of genes related to adhesion events in endothelial cells from three different vascular sites.

Design and Methods

Endothelial cells representative of the macro- (HUVEC) or microcirculation (TrHBMEC and HPMEC) were grown in the presence or absence of hydroxycarbamide and/or cytokines (TNFα and IFNγ). Expression of genes encoding adhesion proteins was analyzed by RQ-PCR, ELISA, flow cytometry, in situ ELISA for extracellular matrix proteins, and Western blot.

Results

In cells from the microcirculation, expression of TSP-1, vWF, and PECAM-1 genes was decreased by hydroxycarbamide and/or cytokine treatment at the mRNA level. In the macro-circulation their expression was unaffected or increased. Hydroxycarbamide significantly decreased vWF incorporated in the TrHBMEC extracellular matrix. CD36 mRNA was strongly down-regulated by cytokines in HPMEC, the only cell type in which it is expressed. Hydroxycarbamide decreased soluble PECAM-1 in HUVEC supernatants.

Conclusions

Our results highlight the heterogeneity of vascular endothelial cell responses to hydroxycarbamide and/or cytokines depending upon their origin. They also suggest that hydroxycarbamide has an anti-adhesogenic effect on endothelial cells, but by mechanisms which could vary according to their macro- or microcirculation and organ origin.     

Long-term sequential deferiprone–deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial

A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone–deferoxamine (DFO–DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8–12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP–DFO patients compared with DFP-alone patients ( P  = 0·005). Kaplan–Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P  = 0·3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP–DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs. This trial was registered at http://www.clinicaltrials.gov as # NCT00733811.     

Tucaresol increases oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxy-phenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro . We administered tucaresol to sickle cell patients in the steady state to examine the anti-sickling effect in vivo. Oral doses of tucaresol or placebo were given to nine stable sickle cell patients (aged 17–39 years; tucaresol, six; placebo, three) for 10 d. The first two patients on tucaresol were scheduled to receive a loading dose of 800 mg or 1200 mg (depending on bodyweight) for the first 4 d, followed by maintenance doses of 200 or 300 mg for the next 6 d. Due to concerns over the sharp rise in haematocrit in one patient, subsequent cohorts received 300 mg tucaresol daily throughout the dosing period. The oxygen affinity of haemoglobin S was increased in all patients receiving tucaresol, with between 10% and 24% of the haemoglobin modified, dependent on dose. In all patients on tucaresol, haemolysis was reduced with rises in haemoglobin of 0.9–3.7 g/dl (mean 2.2 g/dl), falls in lactate dehydrogenase of 16–52%, and a halving of the irreversibly sickled cell counts. These effects were apparent within a few days and persisted for 1–2 weeks following discontinuation of the drug. Three of the six patients on tucaresol developed fever and cervical lymphadenopathy, with onset between days 7 and 11 from start of drug. Further evaluation of the tolerability and efficacy of tucaresol in sickle cell patients is necessary.     

A new 'total' activin B enzyme-linked immunosorbent assay (ELISA): development and validation for human samples

Background and objective  There are currently no sensitive and specific assays for activin B that could be utilized to study human biological fluids. The aim of this project was to develop and validate a 'total' activin B ELISA for use with human biological fluids and establish concentrations of activin B in the circulation and fluids from the reproductive organs.
Design  The new ELISA was validated and then used to measure activin B levels in the circulation of healthy participants, IVF patients, pregnant women and in ovarian follicular fluid and seminal plasma.
Patients and measurements  Healthy adult subjects ( n  = 143), subjects from an IVF clinic ( n  = 27) and pregnancy groups ( n  = 29) were sampled.
Results  The sensitivity of the assay was 0·019 ng/ml. Validation of the activin B ELISA showed good recovery (90·7 ± 9·8%) and linearity in biological fluid and cell culture media and low cross-reactivity with related analytes (inhibin B = 0·077% and activin A = 0·0034%). There was a negative correlation between activin B concentration ( r  = −0·281, P  < 0·011) and females with increasing age. Patients attending IVF clinics had significantly lower levels of activin B compared with gender-matched control subjects. Ovarian follicular fluid and seminal plasma had 50–80 fold higher levels of activin B (mean = 5·35 and 3·66 ng/ml respectively) than sera (mean = 0·071 ng/ml).
Conclusions  This fully validated ELISA for activin B offers a tremendous utility for measuring this protein in a variety of normal physiological processes and in various clinical pathologies.     

Efficacy and safety of deferasirox doses of >30 mg/kg per d in patients with transfusion-dependent anaemia and iron overload

The highest approved dose of deferasirox is currently 30 mg/kg per d in many countries; however, some patients require escalation above 30 mg/kg per d to achieve their therapeutic goals. This retrospective analysis investigated the efficacy (based on change in serum ferritin levels) and safety of deferasirox >30 mg/kg per d in adult and paediatric patients with transfusion-dependent anaemias, including β-thalassaemia, sickle cell disease and the myelodysplastic syndromes. In total, 264 patients pooled from four clinical trials received doses of >30 mg/kg per d; median exposure to deferasirox >30 mg/kg per d was 36 weeks. In the overall population there was a statistically significant median decrease in serum ferritin of 440 μg/l ( P  < 0·0001) from pre-dose-escalation to the time-of-analysis; significant decreases were also observed in adult and paediatric patients, as well as β-thalassaemia patients. The adverse event profile in patients who received deferasirox doses of >30 mg/kg per d was consistent with previously published data. There was no worsening of renal or liver function following dose escalation. Deferasirox >30 mg/kg per d effectively reduced iron burden to levels lower than those achieved prior to dose escalation in patients with transfusion-dependent anaemias. This has important implications for patients who are heavily transfused and may require higher doses to reduce body iron burden.     

Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure

Hydroxycarbamide (hydroxyurea) provides laboratory and clinical benefits for adults and children with sickle cell anaemia (SCA). Given its mechanism of action and prior reports of genotoxicity, concern exists regarding long-term toxicities and possible carcinogenicity. We performed cross-sectional analyses of chromosome stability using peripheral blood mononuclear cells (PBMC) from 51 children with SCA and 3-12 years of hydroxycarbamide exposure (mean age 13·2 ± 4·1 years), compared to 28 children before treatment (9·4 ± 4·7 years). Chromosome damage was less for children receiving hydroxycarbamide than untreated patients (0·8 ± 1·2 vs. 1·9 ± 1·5 breaks per 100 cells, P = 0·004). There were no differences in repairing chromosome breaks after in vitro radiation; PBMC from children taking hydroxycarbamide had equivalent 2 Gy-induced chromosome breaks compared to untreated patients (30·8 ± 16·1 vs. 31·7 ± 8·9 per 100 cells, P = not significant). Radiation plus hydroxycarbamide resulted in similar numbers of unrepaired breaks in cells from children on hydroxycarbamide compared to untreated patients (95·8 ± 44·2 vs. 76·1 ± 23·1 per 100 cells, P = 0·08), but no differences were noted with longer exposure (97·9 ± 42·8 breaks per 100 cells for 3-6 years of hydroxycarbamide exposure vs. 91·2 ± 48·4 for 9-12 years of exposure). These observations provide important safety data regarding long-term risks of hydroxycarbamide exposure for children with SCA, and suggest low in vivo mutagenicity and carcinogenicity.     

Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide

Hydroxycarbamide therapy has been associated with significant oscillations in peripheral blood counts from myeloid, lymphoid and erythroid lineages in patients with polycythaemia vera and chronic myeloid leukaemia. We retrospectively evaluated serial blood counts over an 8‐year period from 44 adult patients with sickle cell disease receiving hydroxycarbamide. Platelet counts, leucocyte counts, haemoglobin values and reticulocyte counts, apportioned by hydroxycarbamide status, were analysed using a Lomb‐Scargle periodogram algorithm. Significant periodicities were present in one or more counts in 38 patients receiving hydroxycarbamide for a mean duration of 4·81 years. Platelet and leucocyte counts oscillated in 56·8% and 52·3% of patients, respectively. These oscillations generally became detectable within days of initiating therapy. During hydroxycarbamide therapy, the predominant periods of oscillation were 27 ± 1 d for platelet counts and 15 ± 1 d for leucocyte counts. Despite an absolute decrease in leucocyte and platelet counts during hydroxycarbamide treatment, the amplitudes between nadirs and zeniths remained similar regardless of exposure. Our observations appear consistent with previously proposed models of cyclic haematopoiesis, and document that hydroxycarbamide‐induced oscillations in blood counts are innocuous phenomena not limited to myeloproliferative disorders as described previously. We speculate the known cell cycle inhibitory properties of hydroxycarbamide may accentuate otherwise latent constitutive oscillatory haematopoiesis.     

Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia

The safety and efficacy of the combination clofarabine/cyclophosphamide/etoposide were evaluated in children with advanced acute lymphoblastic leukaemia (ALL). The study enrolled 25 paediatric patients (median age 12·5 years) with either refractory ( n  = 17; 68%) or multiple relapsed ( n  = 8; 32%) ALL to receive clofarabine 40 mg/m², cyclophosphamide 400 mg/m² and etoposide 150 mg/m², daily for 5 consecutive days. No patient died from treatment-related complications. The most common adverse events were febrile neutropenia, mucositis and reversible liver toxicity; no case of liver veno-occlusive disease was reported. The overall remission rate was 56%: 13 patients (52%) achieved complete remission (CR) and one (4%) CR without platelet recovery (CRp). In seven of the 13 (54%) patients achieving CR, remissions were of sufficient duration to allow patients to receive allogeneic haematopoietic stem cell transplantation. The probability of CR/CRp was greater in the 17 patients with B cell precursor ALL than in the eight with T-ALL (76% vs. 12%, respectively, P  <   0·01). The 18-month overall survival probability was 39% and 0% in patients who did or did not respond to the treatment, respectively ( P  <   0·01). These data suggest that the clofarabine/cyclophosphamide/etoposide regimen is well tolerated and can induce clinical response in a relevant proportion of children with refractory/multiple relapsed ALL.     

Bisphosphonate‐associated osteonecrosis of the jaw: does it occur in children?

Background  Bisphosphonate use in adult patients has been linked to osteonecrosis of the jaw (ONJ). This complication has not been systematically assessed in a paediatric population receiving bisphosphonates.
Objective  To assess our cohort of paediatric patients treated with intravenous bisphosphonate for occurrence of ONJ.
Design  Observational study at a tertiary children's hospital.
Patients  A total of 42 paediatric patients with osteoporosis who received bisphosphonate infusions for a mean of 6·5 years (SD 2·7 years) were assessed clinically and radiographically for possible ONJ. Among 42, 37 patients had received disodium pamidronate 1 mg/kg/dose at a mean cumulative dose of 19·8 mg/kg and zoledronic acid (ZA) 0·05 mg/kg/dose at a mean cumulative dose of 0·49 mg/kg; four had received ZA and one received pamidronate alone. Invasive dental treatment during bisphosphonate treatment, a known risk factor for osteonecrosis, was specifically assessed.
Results  In all patients assessed, including 11 who had invasive dental treatment, there were no cases of osteonecrosis.
Conclusion  ONJ has so far not been demonstrated in this patient group.     

Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with a poor prognosis following first relapse. We present a subgroup analysis of an open-label phase II trial investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL. Oral lenalidomide 25 mg was self-administered once daily on days 1–21 every 28 d for up to 52 weeks, according to tolerability or until disease progression. The primary endpoint was overall response rate (ORR) and secondary endpoints were duration of response, progression-free survival (PFS) and safety. Among 15 patients with MCL with a median disease duration of 5·1 years and a median of four prior treatments, the ORR was 53%. Three patients (20%) had a complete response and 5 (33%) had a partial response. The median duration of response was 13·7 months and median PFS was 5·6 months. Four of five patients who relapsed after transplantation and two of five patients who previously received bortezomib responded to lenalidomide. The most common grade 4 adverse event was thrombocytopenia (13%) and the most common grade 3 adverse events were neutropenia (40%), leucopenia (27%) and thrombocytopenia (20%). In conclusion, oral lenalidomide monotherapy is well tolerated and active in relapsed or refractory MCL.     

Low-dose pioglitazone and low-dose flutamide added to metformin and oestro-progestagens for hyperinsulinaemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months

Context and aim  Metformin plus oestro-progestagen is a combination treatment for non-obese women with hyperinsulinaemic androgen excess. We explored whether low-dose pioglitazone (Pio) and flutamide (Flu) has readily detectable add-on effects.
Design patients, intervention  Randomized, double-placebo pilot study over 24 months; 38 women with hyperinsulinaemic androgen excess (mean age 20 years; BMI 23·7 kg/m²); all women received metformin and an oestro-progestagen for 24 months, and add-on Flu (62·5 mg/day; 21/28 days) for 18 months. A first randomization was performed at start of the study, for Pio (7·5 mg/day; 21/28 days) vs. Pio-placebo, with a cross-over of Pio subgroups at 18 month. A second randomization was performed at 18 months, for Flu vs. Flu-placebo until 24 months.
Main outcomes  Intima media thickness (IMT); body composition by absorptiometry; abdominal fat partitioning by magnetic resonance; circulating glucose, insulin, IGF-I, androgens, LDL : HDL ratio, RBP4, vaspin.
Results  Add-on effects of Pio included a gain of lean mass (mirrored by a loss of fat) and an accelerated lowering of IMT ( P  ≤ 0·001). Add-on effects of flutamide included a further reduction of androgen excess. Between 0 and 18 months, women lost a quarter of their visceral fat ( P <  0·001; independently of Pio); beyond 18 months, a rebound of visceral fat occurred in women who had stopped Pio and Flu. Between 0 and 24 months, insulin sensitivity increased, as did circulating RBP-4 and vaspin (all P  = 0·001).
Conclusion  Low-dose Pio and Flu further improve long-term markers – such as IMT, lean mass and visceral fat – when jointly added to a treatment of metformin plus an oestro-progestagen in non-obese women with hyperinsulinaemic androgen excess.