FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study.

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2-/PET4- and PET2+/PET4- patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2-/PET4- ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of KIT. A prospective study.

BACKGROUND: Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes. OBJECTIVES: To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course. METHODS: This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and > 4 years of disease course were enrolled. The mean ± SD age at the final evaluation was 13·2 ± 4·8 years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics. RESULTS: Patients presented with maculopapular cutaneous mastocytosis (n = 44), diffuse cutaneous mastocytosis (n = 6) or mastocytoma (n = 3). The mean duration of disease was 12·1 years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2 years) is associated with worse evolution. CONCLUSIONS: PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.

BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial.

BACKGROUND: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. PATIENTS AND METHODS: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. RESULTS: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). CONCLUSIONS: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. CLINICAL TRIAL NUMBER: NCT00144755.

Cardiac arrhythmia and late-onset muscle weakness caused by a myofibrillar myopathy with unusual histopathological features due to a novel missense mutation in FLNC.

Myofibrillar myopathies (MFM) are mostly adult-onset diseases characterized by progressive morphological alterations of the muscle fibers beginning in the Z-disk and the presence of protein aggregates in the sarcoplasm. They are mostly caused by mutations in different genes that encode Z-disk proteins, including DES, CRYAB, LDB3, MYOT, FLNC and BAG3. A large family of French origin, presenting an autosomal dominant pattern, characterized by cardiac arrhythmia associated to late-onset muscle weakness, was evaluated to clarify clinical, morphological and genetic diagnosis. Muscle weakness began during adult life (over 30 years of age), and had a proximal distribution. Histology showed clear signs of a myofibrillar myopathy, but with unusual, large inclusions. Subsequently, genetic testing was performed in MFM genes available for screening at the time of clinical/histological diagnosis, and desmin (DES), αB-crystallin (CRYAB), myotilin (MYOT) and ZASP (LDB3), were excluded. LMNA gene screening found the p.R296C variant which did not co-segregate with the disease. Genome wide scan revealed linkage to 7q.32, containing the FLNC gene. FLNC direct sequencing revealed a heterozygous c.3646T>A p.Tyr1216Asn change, co-segregating with the disease, in a highly conserved amino acid of the protein. Normal filamin C levels were detected by Western-blot analysis in patient muscle biopsies and expression of the mutant protein in NIH3T3 showed filamin C aggregates. This is an original FLNC mutation in a MFM family with an atypical clinical and histopathological presentation, given the presence of significantly focal lesions and prominent sarcoplasmic masses in muscle biopsies and the constant heart involvement preceding significantly the onset of the myopathy. Though a rare etiology, FLNC gene should not be excluded in early-onset arrhythmia, even in the absence of myopathy, which occurs later in the disease course.

Quantification of circulating house dust mite-specific IL-4- and IL-13-secreting T cells correlates with rhinitis severity in asthmatic children and varies with the seasons.

BACKGROUND: Defining suitable markers to diagnose and monitor allergy and its severity is essential to correctly assign patients for specific immunotherapy. Circulating levels of specific IgE are good markers of sensitization, but not of clinically symptomatic allergy. OBJECTIVE: To quantify circulating interleukin (IL)-4- and IL-13-secreting T cells specific for house dust mite (HDM) in children presenting HDM-allergic asthma associated or not with rhinitis and correlate results with clinical symptoms. METHODS: We analysed 26 children with HDM respiratory disease (allergic rhinitis and asthma) together with six children with non-allergic asthma. Peripheral blood mononuclear cells were stimulated with HDM extract in a 24-h ELISpot assay to quantify the number of HDM-specific IL-4- and IL-13-secreting T cells. Asthma severity and control, and rhinitis severity were scored according to the Global Initiative for Asthma (GINA) and the Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines. RESULTS: The number of HDM-specific IL-4- and IL-13-secreting T cells was higher in patients with allergic asthma as compared to patients with non-allergic asthma. It varied with the season of blood sampling with two peaks in the fall and early spring. Independently of the season, the number of HDM-specific IL-4-secreting T cells correlated with rhinitis severity (OR = 2; 95% IC:1.1-3.8; P = 0.04). CONCLUSIONS AND CLINICAL RELEVANCE: Allergen-specific IL-4- and IL-13-producing T cells were only detected in HDM-allergic asthmatic children (not in patients with non-allergic asthma). Their numbers correlated with clinical severity of allergic rhinitis.

Morphological analysis of circulating tumour cells in patients undergoing surgery for non-small cell lung carcinoma using the isolation by size of epithelial tumour cell (ISET) method.

BACKGROUND AND OBJECTIVE: Recurrence rates after surgery for non-small cell lung cancer (NSCLC) range from 25 to 50% and 5-year survival is only 60-70%. Because no biomarkers are predictive of recurrence or the onset of metastasis, pathological TNM (pTNM) staging is currently the best prognostic factor. Consequently, the preoperative detection of circulating tumour cells (CTCs) might be useful in tailoring therapy. The aim of this study was to characterize morphologically any circulating non-haematological cells (CNHCs) in patients undergoing surgery for NSCLC using the isolation by size of epithelial tumour cell (ISET) method. METHODS: Of 299 blood samples tested, 250 were from patients with resectable NSCLC and 59 from healthy controls. The presence of CNHCs was assessed blindly and independently by 10 cytopathologists on May-Grünwald-Giemsa stained filters and the cells classified into three groups: (i) malignant cells, (ii) uncertain malignant cells, and (iii) benign cells. We assessed interobserver agreement using Kappa (κ) analysis as the measure of agreement. RESULTS: A total of 123 out of 250 (49%) patients showed CNHCs corresponding to malignant, uncertain malignant and benign cells, in 102/250 (41%), 15/250 (6%) and 6/250 (2%) cases, respectively. No CNHCs were detected in the blood of healthy subjects. Interobserver diagnostic variability was absent for CNHCs, low for malignant cells and limited for uncertain malignant and benign cells. CONCLUSION: Identification of CTCs in resectable NSCLC patients, using ISET technology and according to cytopathological criteria of malignancy, appears to be a new and promising field of cytopathology with potential relevance to lung oncology.

The retinal pigment epithelium undergoes massive apoptosis during early differentiation and pigmentation of the optic cup.

PURPOSE: The aim of our work was to study apoptosis during the development of the retinal pigment epithelium (RPE) in mice between embryonic day (E) 10.5 and E12.5 and to examine a possible link between apoptosis and pigmentation. METHODS: We collected mouse embryos at E10.5, E11.5, and E12.5 and labeled apoptotic cells in 5-µm paraffin sections, using the terminal deoxynucleotidyl transferase dUTP nick end labeling technique. We counted the total number of cells and the number of apoptotic cells in the early developing RPE and calculated the percentage of apoptosis at each stage. RESULTS: In the C57BL/6J mouse, 17% of the RPE cells were apoptotic at E10.5 compared to 0.9% at E12.5. At E11.5, three-quarters of the RPE cells began to pigment, and apoptotic cells were located mostly in the nonpigmented part. In contrast, in the BALB/c mouse (tyrosinase-deficient) and pJ mouse (carrying mutations in the p gene) hypopigmented strains, the RPE contained significantly fewer apoptotic cells (7.5% and 10.1%, respectively) at E10.5 than controls. Subsequently at E11.5 and E12.5, the two hypopigmented strains displayed different apoptotic patterns; the BALB/c RPE had a similar percentage of apoptotic cells to controls (1.5% and 1.1%, respectively, for BALB/c versus 3.0% and 0.9%, respectively, for C57BL/6J), whereas the pJ RPE contained significantly more apoptosis (7.5% and 3.5%, respectively). Overall we observed differences in the evolution of the relative total number of RPE cells between the three strains. CONCLUSIONS: Apoptosis is a main event during the first stages of normal RPE development, indicating an essential role during RPE differentiation. Moreover, the early apoptotic pattern and possibly the whole early development of the RPE is different between hypopigmented and pigmented strains, as well as between BALB/c and pJ mice. This suggests the existence of regulatory and developmental differences with a more complex origin than just differing pigmentation levels.

Renal blood flow quantification in pigs using contrast-enhanced ultrasound: an ex vivo study.

PURPOSE: The aim of the study was to evaluate a new method for the quantification of renal blood flow using contrast-enhanced ultrasound (CEUS) in an ex vivo pig kidney model. MATERIAL AND METHODS: After approval by the animal ethics committee, 4 pig kidneys were explanted and perfused with Celsior liquid (Imtix Sangstat, Lyon, France) at different flow rates (30, 50, 70 and 90 ml/min) in an ex vivo phantom. A 50 % diluted solution of SonoVue (Bracco, Milano, Italy) was infused in the artery at 0.5 ml/min. CEUS was performed with an Aplio system (Toshiba, Nasu, Japan) using a broadband linear transducer and pulse subtraction imaging. A total of 152 destruction-reperfusion sequences were acquired and cine loops were digitally stored for further quantification. Three different ROIs were placed upon the anterior, posterior cortex and segmental artery. Signal intensity measurements were performed in linear units and perfusion parameters were automatically extracted using dedicated software. Curve fitting was performed using a monoexponential model in which a time delay parameter was introduced. This fit allowed the assessment of the local blood flow into the region of interest (called "contrast-enhanced blood flow" (CEBF)). The artery mean signal intensity was averaged from the ten frames prior to the destruction phase. The normalized CEBF (nCEBF) was calculated as the ratio between CEBF and the mean arterial signal intensity. The CEBF and nCEBF were compared to the true blood flow indicated by the pump flow rate. RESULTS: The CEBF was correlated to the true blood flow only for the posterior cortical ROI (R(2) = 0.45, p = 0.05). The normalization using arterial signals improved CEBF correlation to true blood flow: nCEBF became correlated to the true blood flow when considering all ROIs (R(2)= 0.94, p < 0.0001) and correlation was improved for both anterior and posterior cortical ROIs (R(2)= 0, 93, p = 0.0004; R(2)= 0, 90, p = 0.0005, respectively). However, a significant kidney-dependent effect was observed for the anterior cortical ROI (p = 0.017) but not for the posterior cortical ROI (p = 0.89). CONCLUSION: Normalization using arterial signals significantly improved the estimation of blood flow calculated with CEUS.

Long-term outcome in methylmalonic aciduria: a series of 30 French patients.

OBJECTIVE: To better delineate the natural history of patients with methylmalonic aciduria (MMA). STUDY DESIGN: Thirty patients with vitamin-B12-unresponsive MMA (25 aged 1.5 to 22.0 years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3 y (range: 1.4-19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies. RESULTS: Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5 y (range 1.5-18.6). Renal function further deteriorated in 4 patients within a median period of 5.8 y (range 2-7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut(o), 3 mut- and 5 cblA. Mortality, number of acute decompensations (p=0.031), median MMA urinary excretion (p=0.006) and neurological impairment (p<0.0001) were higher in mut degrees patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut(o) patients and was more severe. CONCLUSIONS: Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut(o) phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.

Differential regulation of Dlg1, Scrib, and Lgl1 expression in a transgenic mouse model of ocular cancer.

PURPOSE: Discs large (dlg), scribble (scrib), and lethal giant larvae (lgl) are major suppressor genes in Drosophila melanogaster. They encode proteins that regulate cell polarity and cell proliferation in Drosophila and mammals. However, their basic oncogenic roles have not yet been established in mouse epithelial ocular cancer. We evaluated the potential implication of these proteins in tumorigenesis of adenocarcinomas originating from the retinal pigmented epithelium of the Trp1/Tag transgenic mouse model. We examined the changes in the distribution and levels of these proteins in mouse ocular tissues from the Trp1/Tag mouse model. METHODS: The expression patterns of theses genes and their corresponding proteins in normal mouse ocular tissues were studied by in situ hibridization and immunohistofluorescence experiments. In addition, variations in mRNA and proteins levels and protein distributions for Dlg1, Scrib, and Lgl1 were analyzed in the ocular tissues from Trp1/Tag transgenic mouse model by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis, and immunohistofluorescence. RESULTS: We found that mouse Dlg1, Scrib, and Lgl1 are widely distributed in normal ocular tissues, particularly in retinal neurons. We found that the three proteins are mislocalized in retinal layers during ocular carcinogenesis. These mislocalizations were correlated to the early dysplastic stages of ocular tumorigenesis. Additionally, the mislocalization of each protein was associated with its downregulation. Decreased levels of these proteins may be considered as late-stage markers of the disease but also as markers of the invasive stage of this cancerous process. This downregulation may be involved in epithelial-mesenchymal transition in this mouse ocular tumoral model. This would be consistent with the downregulation of E-cadherin and upregulation of N-cadherin expression observed in this model. CONCLUSIONS: This is the first study to demonstrate the involvement of Dlg1, Scrib, and Lgl1 in a mouse with ocular adenocarcinoma and the simultaneous involvement of these proteins in the same cancer. Our results indicate that both the mislocalization and downregulation of these proteins may be involved together in ocular carcinogenesis.

Adult celiac disease with severe or partial villous atrophy: a comparative study.

BACKGROUND AND AIMS: While severe villous atrophy (SVA) is the most typical histological feature in adult celiac disease (ACD), partial villous atrophy (PVA) is now also frequently found. So far, the impact of the severity of villous atrophy on the clinical presentation of ACD has been scarcely investigated. We aimed to compare the clinical, biological and immune features and outcomes in ACD patients presenting with PVA at diagnosis versus patients with SVA. PATIENTS AND METHODS: Medical files of 48 patients with ACD diagnosed between 1992 and 2003 were retrospectively studied. The diagnosis was based on the presence of intestinal villous atrophy, with increases in intraepithelial lymphocytes and circulating celiac specific antibodies. Villous atrophy was classified as severe (subtotal and total) or partial. Symptoms, biological signs of malabsorption, immune markers, bone mineral density at diagnosis and response to gluten-free diet were recorded. RESULTS: At diagnosis, ten patients (four M/six F) had PVA and 38 patients (five M/33 F) had SVA, with a median age of 54 and 33 years, respectively (p<0.05). Positivity for specific antibodies, HLA typing and frequency of autoimmune disease at diagnosis were similar in both PVA and SVA patients, as was their response to gluten-free diet. Diarrhea, malabsorption syndrome and osteopenia were independent of the degree of villous atrophy. CONCLUSION: PVA was observed in 21% of patients with ACD. Except for their older age at diagnosis, patients with PVA presented with similar clinical, biological and immune characteristics and outcomes as did patients with SVA.

[Methodological and statistical aspects of equivalence and non inferiority trials]. / Aspects méthodologiques et statistiques des essais d'équivalence et de non-infériorité.

BACKGROUND: - The existence of effective reference treatments means that the superior therapeutic efficacy of new treatments is less marked and thus more difficult to demonstrate statistically. Moreover, the potential value of a new treatment is also based on other criteria, such as costs, ease of use, non invasiveness, and immediate or long-term side effects. In this context, methodological issue becomes one of looking for equivalence or non inferiority of the new treatment in comparison with an existing, high-performance reference treatment. METHODS: - In the present work, we reexamine the statistical rational and methodological features of equivalence and non inferiority trials. RESULTS: - We address equivalence margin choice, hypotheses building, and the different approaches for establishing equivalence (hypothesis testing and confidence intervals). We then discuss key aspects of equivalence trial design and the important methodological quality criteria involved in performing such studies: choice of the reference treatment, subject eligibility criteria, primary endpoint, study population and the required sample size. Lastly, we consider the possibility of adopting a new analytical strategy (non inferiority/superiority). CONCLUSION: - A checklist of items to include when reporting the results of randomized controlled trials (Consolidated Standards of Reporting Trials, the CONSORT recommendations) has been adapted for use in non inferiority and equivalence randomized controlled trials.

An oligonucleotide microarray for mouse imprinted genes profiling.

Genomic imprinting is an epigenetic phenomenon unique to mammals that causes some genes to be expressed according to their parental origin. It results in developmental asymmetry in the function of the parental genomes. We describe here a method for the profiling of imprinted genes based on the development of a mouse imprinting microchip containing oligonucleotides corresponding to 493 genes, including most of the known imprinted genes (IG = 63), genes involved in epigenetic processes (EPI = 15), in metabolism (= 147), in obesity (= 10) and in neurotransmission (= 256) and housekeeping reference genes (= 2). This custom oligonucleotide microarray has been constructed to make data analysis and handling more manageable than pangenomic microarrays. As a proof of concept we present the differential expression of these 493 genes in different tissues (liver, placenta, embryo) of C57BL6/J mice fed different diets. Appropriate experimental strategies and statistical tools were defined at each step of the data analysis process with regard to the different sources of constraints. Data were confirmed by expression analyses based on quantitative real-time PCR. These oligochips should make it possible to increase our understanding of the involvement of imprinted genes in the timing of expression programs, tissue by tissue, stage by stage, in response to nutrients, lifestyles and other as yet unknown critical environmental factors in a variety of physiopathological situations, and in animals of different strains, ages and sexes. The use of oligonucleotides makes it possible to expand this microchip to include the increasing number of imprinted genes discovered.

Bioelectrical impedance in young patients with cystic fibrosis: Validation of a specific equation and clinical relevance.

BACKGROUND: Body composition (BC) analysis based on bioelectrical impedance analysis (BIA) provides conflicting results. The purpose of the study was to validate an equation specific for young patients with cystic fibrosis (CF), describe their BC and investigate its association with lung function. METHODS: Fifty-four young CF patients were evaluated by BIA and dual X-ray absorptiometry (DXA). An empirically derived CF-specific equation for fat-free mass (FFM) estimation by BIA was elaborated after stepwise multivariate regression and the agreement between BIA and DXA was assessed by Bland-Altman plots. The association between BC and lung function was investigated by regression analysis. RESULTS: The mean difference between the BIA and DXA assessment was close to zero. A total of 22.5% of patients (n=9) presented a FFM z-score≤-2. They had a worse pulmonary function and diaphragmatic impairment. Among these 9 patients, 7 had a normal BMI z-score>-1. CONCLUSIONS: BIA, based on a CF-specific equation, is a reliable method for BC assessment and allows the identification of patients at risk of nutritional degradation and bad respiratory prognosis.

Mediastinal tumor size and response to chemotherapy are the only prognostic factors in supradiaphragmatic Hodgkin's disease treated by ABVD plus radiotherapy: ten-year results of the Paris-Ouest-France 81/12 trial, including 262 patients.

PURPOSE: To identify prognostic factors in 262 patients with supradiaphragmatic Hodgkin's disease (HD), clinical stages (CS) I and II, prospectively treated between 1981 and 1988 according to the Paris-Ouest-France (POF) 81/12 protocol by three 1-month cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus methylprednisone (ABVD-MP) followed by subtotal nodal irradiation (RT). PATIENTS AND METHODS: The size of mediastinal tumor (MT) was measured in all patients: 66 did not have MT (NoMT); 105 had a small-size MT (SSMT), ie, mediastinal mass ratio (MMR) less than 0.33; 58 had a medium-size MT (MSMT), ie, MMR > or = 0.33 and less than 0.45; and 33 had a bulky MT (BuMT), ie, MMR > or = 0.45. All patients received three cycles (CS IA, one cycle only) of ABVD-MP; patients in partial remission (PR) or complete remission (CR) after chemotherapy (CT) received supradiaphragmatic RT (involved fields, 40 Gy; adjacent fields, 30 Gy) plus lumboaortic and splenic RT (30 Gy); patients not in CR or PR after CT received salvage CT. RESULTS: Two hundred seventeen patients (82.8%) entered CR after CT and 258 (98.5%) after RT. Ten-year freedom-from-progression (FFP) and survival rateswere 88.6% and 89.4%, respectively. According to univariate analysis, MT size and post-CT status were the only factors to influence both FFP and survival. For patients with NoMT or SSMT, those with MSMT, and those with BuMT, FFP rates were 94.1%, 87.0%, and 63.0% (P < .001), respectively, while corresponding survival rates were 92.6%, 87.2%, and 78.2% (P < .05). FFP rates were significantly different between the patients who achieved CR and those who did not achieve CR after CT: 94.6% versus 65.3% (P < .001); corresponding survival rates were 89.9% and 73.7% (P < .01). Multivariate analysis confirmed that MT size and post-CT status were the only two prognostic factors for FFP; for survival, the same two characteristics, as well as age (< 40 v > or = 40 years), significantly affected prognosis. We were thus able to identify three groups. The 33 patients (12.6%) with a BuMT had 10-year FFP and survival rates of 63.0% and 78.2%, respectively. Of 229 patients without BuMT, the 195 who attained CR after CT had an optimal prognosis (FFP, 96.6%; survival, 93.6%), while those who failed to achieve CR after CT had an intermediate prognosis (FFP, 68.8%; survival, 77.6%). CONCLUSION: These results demonstrate the independent impact on HD prognosis of tumor burden and post-CT status.

Outcome and long-term growth after extensive small bowel resection in the neonatal period: a survey of 87 children.

UNLABELLED: This retrospective study aims to analyze the outcome, the prognosis factors and the long-term growth of children after extensive small bowel (SB) resection in the neonatal period. PATIENTS AND METHODS: 87 children, born between 1975 and 1991 who had undergone extensive neonatal small bowel resection, were followed up over a mean period of 15 years. Anatomical data influencing PN dependency and duration were analyzed. Data on height and weight were collected and compared using growth standards. Final heights were studied for patients who achieved their puberty and compared to predicted height based on Tanner's formula. Patients were analyzed according to PN weaning and growth: children still receiving PN (group A), patients weaned from initial PN but requiring PN once again or enteral feeding (group B), and children with permanent intestinal autonomy (group C). RESULTS: The overall survival is 89.7 %, depending on the date of birth. The duration of PN-dependency varies according to the intestinal length and the presence of the ileocaecal valve (ICV). All patients who remain PN dependent had less than 40 cm of small bowel and/or the absence of ICV. Patients in group B had a mean small bowel length of 35 +/- 19 cm, resection of the ICV in 50 % of cases, and a PN duration of 47.4 +/- 23.8 months. There was a significant decrease in height and weight gain within the 4 years after cessation of PN, requiring enteral or parenteral feeding. Patients in group C had a mean small bowel length of 57 +/- 19 cm, presence of ICV in 81 % of cases and a PN duration of 16.1 +/- 11.4 months. After PN weaning, they grow up normally with normal puberty and final height as predicted from genetic target height. CONCLUSION: PN duration is influenced by the length of residual SB and the absence of ICV. With good anatomic prognosis factors and short duration of initial PN, normal long-term growth may be predicted. Conversely, poor anatomical factors and protracted initial PN require careful monitoring of growth and may sometimes require nutritional support to be restarted. The last group, permanently dependent on PN, might be candidates for intestinal transplantation.

Improvement of diabetic control and acceptability of a three-injection insulin regimen in diabetic adolescents. A multicenter controlled study.

OBJECTIVE: To compare the effectiveness and acceptability of a three-injection insulin regimen with the conventional two-injection therapy in an unselected population of diabetic adolescents. RESEARCH DESIGN AND METHODS: Some 205 patients aged 10-18 yr with IDDM, who were previously treated with two daily insulin injections, were included without any selection into a randomized trial. They were either switched to three (regular prebreakfast, regular prelunch, and [regular+ultralente] predinner) or remained on two ([regular+intermediary] prebreakfast and predinner) subcutaneous injections. They were evaluated after 1 yr of treatment. The major criteria of outcome of efficacy were the concentration of GHb, the frequency of severe hypoglycemia and DKA, and body weight. RESULTS: Of the patients, 82% accepted the three-injection regimen, and 83% accepted the two-injection regimen. At entry into the trial, no significant differences appeared between the two treatment groups nor among patients refusing the allocated regimen. Significant explanatory variables predicting initial diabetes control were duration of disease and adherence to diet. GHb, decreased from 9.8 +/- 0.1 to 9.3 +/- 0.2% (P < 0.05) in the three-injection group, whereas it increased from 9.5 +/- 0.3 to 9.8 +/- 0.3% (P < 0.05) in the two-injection group, resulting in a modest (0.75%) but significant difference (P < 0.05) between GHb change in the two groups. The difference reached 1.4% (P < 0.0002) in patients with GHb > 11.2% at entry. The frequency of hypoglycemia and DKA was similar in the two groups. None of the parameters known to potentially influence glycemic control changed during the trial, and, therefore, the improvement of GHb could be attributed to the pattern of daily insulin distribution per se. CONCLUSIONS: In the general diabetic adolescent population, the efficacy of a three-injection regimen is somewhat superior to that of a conventional two-injection regimen, particularly in patients previously poorly controlled. The acceptability of this regimen being excellent, its increased use should be considered in this age-group.

Exploratory analysis of population pharmacokinetic data from clinical trials with application to isradipine.

Drug level monitoring during routine clinical visits in the course of phase III trials provides a means to document pharmacokinetic variability in a patient population. Such a pharmacokinetic screen was performed for the new calcium antagonist isradipine. A total of 697 blood samples were collected at any time after the morning dose from 252 patients who had received oral doses of isradipine. Three approaches of data analysis based on exploratory (graphical and statistical) techniques were used to relate plasma level to patient demographic data and laboratory parameters. The pharamacokinetics of isradipine seemed to be influenced by the demographic variables of age (already detected in conventional studies) and weight, as well as by the blood serum levels of inorganic phosphorous, uric acid, alkaline phosphatase, and bilirubin, but only to a small, clinically irrelevant extent. The findings from the three approaches were complementary. They suggest that a pharmacokinetic screening in clinical trials is feasible at reasonable experimental cost and effort and provides useful data on interindividual and intraindividual pharmacokinetic variability in patients.

Radioiodine therapy of the autonomous thyroid nodule in patients with or without visible extranodular activity.

UNLABELLED: Patients with an autonomously functioning thyroid nodule (ATN) may be present with various clinical, biochemical and scintigraphic features. To optimize 131I dose planning and treatment timing in these patients, relationships between dosimetric data and clinical follow-up events must be established. METHODS: We retrospectively reviewed the records of 88 patients who received 131I (intended dose of 80 Gy) for an ATN, of whom 39 had evidence of extranodular activity (ENA) and 76 presented with overt thyrotoxicosis. In all of the patients, dosage calculation was monitored to estimate precisely both beta and gamma absorbed doses received by the ATN and the nodule-free lobe. The mean duration of follow-up was 75 mo (max 180) and always included biochemical thyroid tests. Finally, we compared the dosimetric profiles of four dosage schemes which had been normalized by simulation to ensure that the same absorbed dose threshold value was always delivered to the ATN. RESULTS: About 75% of the patients were cured at 6 mo for a mean 305 MBq administered. The absorbed doses delivered to the nodule-free lobe ranged from 12% (no ENA) to 86% (ENA) of the values delivered to the ATN, mainly in the form of beta irradiation. Life-table estimates for hypothyroidism and death were 9.6% and 22% at 75 mo, respectively. Hypothyroidism mainly developed in patients with nonsuppressed TSH levels but regardless of ENA, which often accounted for multifocal disease. CONCLUSION: We suggest that fixed doses bordering on 370 MBq are advizable in younger individuals and in patients with mild thyrotoxocosis, while 555 MBq-740 MBq can be administered in other patients and that ENA indicates multifocal autonomy in patients with toxic ATN and is a further indication for radioiodine treatment which should be begun as soon as possible to avoid the development of cardiac complications.

Influence of dose selection on absorbed dose profiles in radioiodine treatment of diffuse toxic goiters in patients receiving or not receiving carbimazole.

We retrospectively reviewed the records of 224 patients with diffuse goiters treated with radioiodine, half of which received carbimazole. In all the cases, we carefully monitored the calculation of dosage. A lower percentage of early hypothyroidism but a higher failure rate was observed in the carbimazole subgroup. Nevertheless, after one year, a constant (4.5%) incremental rate of hypothyroidism was found regardless of carbimazole administration. Since we were able to precisely estimate the absorbed doses in our series, we evaluated by simulation the dosimetric profiles of nine methods of dose selection (MDS). These MDS were calibrated in such a way that the same threshold value of absorbed dose would always be reached at the thyroid level. We showed that the more elaborate the MDS, the more accurate the irradiation at the thyroid level and the lower the radiation dose administered. In patients not receiving carbimazole, a rapid MDS using modified early uptake measurements to predict the 24-hr actual value was found to be advisable. With patients receiving carbimazole and if a goal is to delay the occurrence of hypothyroidism, we advise MDS based on either a 48-hr uptake or on the calculation of the individual half-life.