Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma.

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

Molecular characterization of a novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma between the T-cell receptor delta-deleting elements (TRDREC and TRAJ61) and the hypothetical gene C12orf42.

Chromosomal aberrations have diagnostic, prognostic, and therapeutic relevance in hematologic malignancies. By combining fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR), we established a fast, robust approach to precisely characterize chromosomal breakpoints. Using this approach, we clarified at the molecular level novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma. The translocation occurred during the deletional rearrangement of the T-cell receptor delta gene (TRD), which is a pivotal step in T cell differentiation toward the alpha/beta vs. the gamma/delta lineage. We found that this rearrangement disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 gene into proximity of the TRA enhancer, which encodes a member of the basic helix-loop-helix family of transcription factors and is overexpressed in thyroid and lung cancers.

Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group.

PURPOSE: Little is known about the outcome of pediatric patients with lymphoblastic lymphoma (LBL) who suffer from progressive disease or relapse. PATIENTS AND METHODS: We analyzed the pattern of LBL relapses after current non-Hodgkin's lymphoma Berlin-Frankfurt-Muenster (BFM) frontline therapy between April 1990 and March 2003. Relapse therapy was according to acute lymphoblastic leukemia (ALL) -Relapse-BFM protocols or ALL-BFM protocols for high-risk patients. RESULTS: Twenty-eight (11%) of 251 registered patients with precursor T-cell LBL (T-LBL) and six (8%) of 73 patients with precursor B-cell LBL (pB-LBL) suffered from relapse. Of the 28 patients with T-LBL, one died from infection during relapse chemotherapy, 18 failed to achieve stable remission and died from disease progression, and nine reached allogeneic stem-cell transplantation (SCT). Two of these nine patients who underwent SCT died from transplantation-associated toxicity, three died from disease progression, and four are still alive. These four patients are in second remission of their lymphoma for 48, 68, 125, and 131 months, respectively, after allogeneic SCT. One of the four patients developed colon adenocarcinoma 47 months after SCT. Of the six patients with pB-LBL who experienced relapse, one patient died as a result of toxicity of relapse chemotherapy, two died from disease progression after chemotherapy, and three received allogeneic SCT. Of these, two died from subsequent disease progression, and one is still alive 57 months after allogeneic SCT. CONCLUSION: Using modern conventional therapy in the frontline treatment of LBL, 10% of patients suffer from progressive disease or relapse. Because of the extremely poor reinduction success, the salvage rate for these patients is poor, with only a 14% (SE = 6%) overall survival. Long-term survival was only achieved in those few patients who were able to undergo an allogeneic SCT.

Ovarian tumor in a 12-year old female with severe hypothyroidism: A case of Van Wyk and Grumbach syndrome.

We report a 12-year-old female presenting with an abdominal tumor. Diagnostic workup revealed giant bilateral ovarian cysts, severe hypothyroidism as well as an elevation of CA 125. We refrained from ovariectomy, which would be necessary for a malignant tumor, in view of an evident Van Wyk and Grumbach syndrome. The patient promptly responded to L-thyroxine with complete regression of all symptoms. Hypothyroidism should be considered in the evaluation of ovarian cysts. Although the Van Wyk and Grumbach syndrome is rare, it is crucial to rule it out in order to avoid unnecessary ovarian surgery when thyroid replacement is completely sufficient.

Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL.

The emergence of non-Hodgkin lymphoma (NHL) during childhood and adolescence as a secondary neoplasm (SN) after previous cancer other than NHL is rare. To describe the characteristics and outcome of NHL following previous cancer other than NHL in children and adolescents, this study analysed the data of patients reported to the NHL-Berlin-Frankfurt-Münster study centre from 1986 to 2005. Out of the total of 2968 NHL-patients registered, 11 patients were assessed as having suffered from NHL as a proven SN. Four additional children had most likely suffered from NHL as an SN, but a late relapse of the first neoplasm could not be ruled out unequivocally. In the patients with proven SN, median age at diagnosis of the primary malignancy was 3.9 years (range 2-11.7). The median age at diagnosis of NHL was 7.6 years (range 4.7-18). Only lymphoblastic (n = 7) and diffuse large B-cell (n = 4) lymphomas were diagnosed as SN. The estimated 5-year event-free survival from time of diagnosis of NHL was 91% [95% confidence interval (CI) 74-100%] in patients with proven SNs and 84% (95% CI 63-100%) when the patients with probable SNs were included in the analysis. We concluded that secondary NHL in children and adolescents confers a favourable prognosis.

Mortality and morbidity of neonates born at <26 weeks of gestation (1998-2003). A population-based study.

OBJECTIVE: To describe mortality and morbidity of neonates born at <26 weeks' gestation in a contemporary population-based cohort. METHODS: We analyzed data of neonates born at <26 weeks between 1998 and 2003 in the Federal State of Hesse, Germany. Survival was calculated at 28 days and at discharge from hospital. RESULTS: Out of a total of 800 births, 572 infants were liveborn. Among those admitted for neonatal intensive care, 62.3% survived until day 28. Among the neonates followed until death or discharge, 59.6% were discharged home. Logistic regression analyses showed the following variables to be associated with an increased risk of death: Twins (Odds Ratio (OR) 3.7; 95% Confidence Interval (CI) 1.34-10.26), multiple birth >or=3 (OR 8.14; CI 1.23-53.86), intraventricular hemorrhage (IVH) >or=grade III (OR 4.79; CI 1.89-12.14), clinical risk index for babies score >15 (OR 2.9; CI 1.09-7.76), and a gestational age or=grade III and/or periventricular leukomalacia in 15%, and severe retinopathy of prematurity in 29.8%. CONCLUSIONS: This study provides outcome data derived from a contemporary population-based cohort. Mortality and complication rates remain high.

Fanconi anemia in a neonate with pancytopenia.

We report the case of a newborn infant with Fanconi anemia with congenital thrombocytopenia and development of pancytopenia during the neonatal period. The boy showed no malformations characteristic for Fanconi anemia.

Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: a prospective study.

OBJECTIVES: To investigate the effects of small for gestational age (SGA) in preterm infants on growth and development until the age of 22 months. STUDY DESIGN: Seventy-four preterm infants being born SGA (birth weight <10th percentile) were compared with 74 appropriate for gestational age (AGA) infants matched prospectively according to gestational age with respect to growth parameters and neurodevelopment (using Griffiths developmental scores) at the age of 22 months corrected age. RESULTS: Birth weight was significantly lower in SGA-infants compared to AGA-infants (1503 g (430-2205 g) versus 1995 g (680-3300 g); P<0.0001 (median and range)). There were no significant differences regarding the median gestational age (34 weeks), gender distribution, mode of delivery, umbilical artery pH, and APGAR-scores. Mean Griffiths-scores did not differ significantly between both groups (96.7% versus 97.6%). Developmental retardation was diagnosed in 9 SGA-infants versus 10 AGA-infants. Within the total group a positive correlation was observed between gestational age and developmental scoring. Body weight, head circumference, and height were significantly lower in SGA-infants at 22 months corrected age. CONCLUSION: No significant differences regarding neurodevelopmental outcome at 22 months were observed between SGA- and AGA-infants. SGA-infants did not show catch-up growth.

Increased risk of bronchopulmonary dysplasia and increased mortality in very preterm infants being small for gestational age.

OBJECTIVE: The objective was to evaluate the impact of being born small for gestational age (SGA) on neonatal mortality and neonatal pulmonary morbidity in preterm infants <32 weeks of gestation. METHODS: We reviewed the data reported prospectively to the quality assurance program of the Federal State of Hesse, Germany, from 1990 to 1996 of infants <32 weeks of gestation. SGA was defined as birth weight below the 10th percentile. Mann Whitney U tests were used to compare continuous variables and Fisher's exact tests to analyze differences in dichotomous variables between preterm SGA neonates and preterms born appropriate for gestational age (AGA). The effect of SGA and other potential risk factors for neonatal death and bronchopulmonary dysplasia, i.e., requiring a fraction of inspired oxygen >0.21 at day 28, was tested by multivariable analyses. RESULTS: Data from 1,365 infants were analyzed. One hundred and eighty-three neonates were SGA (mean [SD] birth weight 789 [179] g; mean [SD] gestational age 28.9 [1.7] weeks) and 1,182 were AGA (mean [SD] birth weight 1,260 [348] g; mean [SD] gestational age 28.8 [2.1] weeks). Neonatal mortality and the rate of bronchopulmonary dysplasia were significantly higher in SGA neonates (23 vs. 11% and 28 vs. 14%, respectively). There was a statistically significant association of SGA with neonatal death (odds ratio [OR] = 4.54, 95% confidence interval [CI] 2.56, 8.04) and bronchopulmonary dysplasia (OR=3.80, 95% CI 2.11, 6.84). CONCLUSION: SGA neonates below 32 weeks gestation are a high-risk group regarding neonatal mortality and neonatal pulmonary morbidity.