Rapid haemoglobin A and S quantification using Tosoh HLC-723G8 in variant mode for patients with sickle cell disease.

The management of life-threatening complications in patients with sickle cell disease (SCD) requires an accurate and reproducible quantification of haemoglobin A (HbA) and S (HbS) with a short turnaround time and 24-7 availability. We propose a novel method for quantifying HbA and HbS using the glycated haemoglobin (HbA1c) assay on a Tosoh HLC-723G8 (G8) analyser in variant mode. HbA and HbS results obtained using our method highly correlated with results obtained using a reference method (r > 0.99 for 124 samples of patients with SCD or sickle cell trait). Our method met laboratory requirements for linearity (coefficient of variation [CV] and bias <5%), between-run and within-run reproducibility (CV <10%) and carryover (<0.5%) over the range of HbS and HbA values expected in a therapeutic context. Using the G8 analyser in variant mode is viable for monitoring HbA and HbS concentrations in dire situations. This method is easy to use, quick (1.6 min per sample), and automatable and produces highly reproducible results without significant bias. Finally, it does not require modifications to the analytical pipeline recommended by the supplier, enabling a 24-7 availability without disrupting routine monitoring of HbA1c in the laboratory.

Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients).

BACKGROUND: The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month. METHODS: We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups. RESULTS: Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30-793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4-236]), neutrophils < 2 × 109/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 109/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3-83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93-0.99]). CONCLUSIONS: Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 109/L or platelets < 300 × 109/L.

Clinical and biological specificity of beta-thalassemia intermedia: a case report.

We report the case of a nine-year-old girl, of Moroccan origin, hospitalised for fever and stomach ache. The clinical and biological investigations showed merely a moderate enlargement of the spleen associated with discrete regenerative hemolytic anemia. The etiologic analysis of the hemolysis was completed by the electrophoresis of hemoglobin (Hb) that revealed total absence of HbA, with the presence of 98.7% of HbF and 1.3% of HbA2. These results led to a diagnosis of ß0 thalassemia associated with an intermediate phenotype, i.e. beta thalassemia intermedia (BTI). The molecular study of the ß-globin gene evidenced a homozygous mutation at codon 35 of the exon 2 TAC>TAA (HBB: c.108C>A) leading to the premature stop codon. The study of several polymorphisms involved in the regulation of the expression of HbF concords with the intermediate phenotype found in the patient. This observation offers an opportunity to redefine BTI and further explore its clinical and genetic specificity.

Time to diagnosis of Ewing tumors in children and adolescents is not associated with metastasis or survival: a prospective multicenter study of 436 patients.

PURPOSE: The time to diagnosis (TtD) of Ewing tumors is one of the longest among pediatric tumors. Its precise consequences, however, have not been studied well. We analyzed the distribution of TtD for Ewing tumors in children and adolescents and its association with clinical features, tumor characteristics, surgical outcome, and long-term survival. PATIENTS AND METHODS: We analyzed prospectively collected data from two multicenter clinical trials of patients younger than 21 years old who had Ewing bone tumors treated in France between 1988 and 2000. Clinical and tumoral features, TtD, and outcome associations were studied by univariable and multivariable analyses. RESULTS: The median TtD for the 436 patients was 70 days (interquartile range, 27 to 146 days), with no significant decrease during the study period (P > .2). The factors associated with long TtD were older age and some tumor sites (pelvis, extremities of limbs). Increased tumor volume and decreased histologic response to chemotherapy were associated with long TtD on univariable analysis (P < .05) but not after adjustment. Presence of a nerve or spinal-cord compression at diagnosis, presence or site of metastasis, surgical treatment, mutilating surgery, complete resection, or survival were not associated with TtD. CONCLUSION: TtD of Ewing tumors was long, especially for adolescents and for certain tumor sites, and did not improve over time. But TtD was not associated with metastasis, surgical outcome, or survival. These findings could be used to comfort parents at diagnosis and in expert testimony produced for malpractice claims.

Delays in diagnosis of paediatric cancers: a systematic review and comparison with expert testimony in lawsuits.

Delayed diagnosis of paediatric cancers is reported regularly and is a source of remorse for physicians and parents and a leading cause of malpractice claims. We did a systematic review of information about the distribution, determinants, and consequences of time to diagnosis of paediatric malignancies and compared these findings with those of court-appointed expert witnesses in malpractice claims in Canada and France. Time to diagnosis varied widely between tumour types in the 98 relevant studies (medians ranged from 2-260 weeks) without any significant decrease with time. Determinants of a long delay in diagnosis included older age, qualification of the first physician contacted, non-specific symptoms, histological type, and tumour localisation. Delayed diagnosis was associated with poor outcome for retinoblastoma and possibly for leukaemia, nephroblastoma, and rhabdomyosarcoma (data were insufficient for definitive conclusions). It was not associated with an adverse outcome for most CNS tumours, osteosarcoma or Ewing's sarcoma, and, paradoxically, was frequently associated with better outcomes than was short time to diagnosis in these cancers. A third of the court-appointed experts provided testimony concordant with the medical literature. The relations between delay in diagnosis and outcome are complex and probably depend more on tumour biology than on parental or medical factors.

Long time to diagnosis of medulloblastoma in children is not associated with decreased survival or with worse neurological outcome.

BACKGROUND: The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae. PATIENTS AND METHODS: This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome. RESULTS: The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31-121, range 3-457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup. CONCLUSIONS: We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims.

Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study.

Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis.

Anti-insulin-like growth factor 1 receptor antibody EM164 (murine AVE1642) exhibits anti-tumour activity alone and in combination with temozolomide against neuroblastoma.

Insulin-like growth factor 1 receptor (IGF-1R) is overexpressed in many tumours and contributes to tumourigenicity, cell proliferation, metastasis and resistance, thus representing a promising therapeutic target. The human IGF-1R antagonistic monoclonal antibody EM164 (murine AVE1642) has shown activity in adult cancers and is being evaluated in patients with advanced malignancies. We investigated the EM164 for its therapeutic potential against childhood neuroblastoma. EM164 at 0.07, 0.7 and 7 µg/mL exhibited anti-proliferative activity against all nine cell lines tested in (3)H-thymidine incorporation assay in vitro. Cell proliferation after EM164 exposure ranged between 24% and 80% compared to controls. Sensitivity was independent from culture serum conditions, intensity of IGF-1R expression and IGF-II secretion, although associated with inhibition of AKT activation. In vivo, EM164 administered intravenously at 40 mg/kg twice weekly for 4 weeks yielded significant tumour growth delays (TGD) of 13.4d in advanced stage IGR-N91 and 12.9 d in SK-N-AS tumours compared to controls (p = 0.02 and p = 0.0059, respectively). Simultaneous treatment of EM164 0.7 µg/mL and temozolomide resulted in enhanced activity in vitro. In vivo, treatment with temozolomide at the maximum tolerated dose (100mg/kg/d for 5 consecutive days) and EM164 yielded a significantly greater TGD of 29.1d (p<0.01) and two complete tumour regressions (CR) compared to 18.1d (p = ns) and one CR for EM164 alone and 16.1d (p = ns) for temozolomide alone. Our results demonstrate the potential of the anti-IGF-1R antibody alone and in combination with alkylating agents and support the therapeutic development of the AVE1642 for aggressive neuroblastoma.

Severity of acute gastroenteritis in infants infected by G1 or G9 rotaviruses.

BACKGROUND: Group A rotaviruses are the main viral causative agent of acute diarrhea, and cause considerable morbidity in children. G9 rotaviruses have recently emerged all over the world and are thought to give more severe symptoms because of a lack of previous exposure and the absence of maternal antibodies in patients. OBJECTIVES: To determine the clinical severity of G9 infections compared to G1 infections in hospitalized children. STUDY DESIGN: The prospective study was conducted from 2004 to 2007 in French children under 5 years old hospitalized for acute gastroenteritis. The rotaviruses were detected in stools by ELISA tests and genotyped by RT-PCR on the basis of their outer capsid proteins. The duration of hospitalization, the Vesikari clinical score, and the requirement for intravenous rehydration were compared. RESULTS: The stools from 370 children were analyzed and 162 stools infected by G1 (n=76) or G9 (n=86) rotaviruses were analyzed. Age and gender distribution were similar in the two groups as was the mean duration of hospitalization (2.7 days). The Vesikari scores were 12.96 and 12.83 in G1P[8] and G9P[8] groups (p=0.417), respectively, in which 55.3 and 53.5% of the children, respectively, were rehydrated with an intravenous line. CONCLUSIONS: No difference in severity was found between G1 and G9 rotavirus infections. Rigorous surveillance to monitor changes in the ecology of rotavirus infections is necessary, as emerging strains are more likely to cause severe gastroenteritis and not respond to current rotavirus vaccines.

Uncomplicated outcome after an accidental overdose of nevirapine in a newborn.

We report the first case of a massive accidental overdose of nevirapine in a 1-week newborn, due to confusion between nevirapine (Viramune) and nelfinavir (Viracept). The drug was eliminated spontaneously and quickly. We only observed mild neutropenia and hyperlactatemia, which regressed on its own without any clinical complication. Despite the good evolution of this massive overdose, physicians should be aware of confusion risks between some antiretroviral drugs.