Martin Zimmermann

Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase

To evaluate the clinical benefit of the prophylactic use of urate oxidase in children with non-Hodgkins lymphoma (NHL), we analyzed the incidence and complications of tumor lysis syndrome (TLS) in children with B-cell acute lymphoblastic leukemia (B-ALL) or stage III/IV Burkitts lymphoma and a lactate dehydrogenase (LDH) level ≥500xa0U/l before and after the introduction of a protocol amendment to use urate oxidase for the prophylaxes of TLS. Data from 1791 children with NHL enrolled in the two subsequent multicenter studies NHL-BFM 90 and 95 were evaluated. The presence of the side effects TLS, anuria, sepsis, and other complications during the first 2xa0weeks after admission were registered. Until March 1996, no urate oxidase was used (period 1). From November 1997 all children with B-ALL or stage III and IV B-NHL and LDH ≥500xa0U/l should receive urate oxidase prophylactically (period 3). In between (period 2), urate oxidase was given in a minority of hospitals therapeutically. Initial chemotherapy was identical. Altogether, 78 children (4.4%) developed a TLS. Patients with B-ALL had the highest risk to develop a TLS (26.4%) followed by B-ALL/Burkitts lymphoma and a LDH ≥500xa0U/l (14.9%). In period 1, 16.1% and 9.2% of the latter children developed a TLS or anuria, respectively, compared to 12.3% and 6.2% in period 3 (p=NS). The incidence of sepsis remained unchanged (5.0% vs 4.6%). In children with B-ALL the differences in the incidence of TLS and anuria between period 3 and period 1 were more pronounced, reaching significance for anuria (15.4% vs 3.8%, p=0.03). Our results suggest that patients with the highest risk to develop a TLS might benefit from the prophylactic use of urate oxidase.

Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials

The spectrum of entities, the therapeutic strategy, and the outcome of mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) differs between children and adolescents on the one hand and adult patients on the other. Whereas adult maB-NHLs have been studied in detail, data on molecular profiling of pediatric maB-NHLs are hitherto lacking. We analyzed 65 cases of maB-NHL from patients up to 18 years of age by gene expression profiling, matrix comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and immunohistochemistry. The majority of the analyzed pediatric patients were treated within prospective trials (n = 49). We compared this group to a series of 182 previously published cases of adult maB-NHL. Gene expression profiling reclassified 31% of morphologically defined diffuse large B-cell lymphomas as molecular Burkitt lymphoma (mBL). The subgroups obtained by molecular reclassification did not show any difference in outcome in children treated with the NHL-Berlin-Frankfurt-Muenster (BFM) protocols. No differences were detectable between pediatric and adult mBL with regard to gene expression or chromosomal imbalances. This is the first report on molecular profiling of pediatric B-NHL showing mBL to be much more prominent in children than suggested by morphologic assessment. Based on molecular profiling mBL is a molecularly homogeneous disease across children and adults.

Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence.

Probability of event-free survival (pEFS) in pediatric T-cell lymphoblastic lymphoma is about 80%, whereas survival in relapsed patients is very poor. No stratification criteria have been established so far. Recently, activating NOTCH1 mutations were reported to be associated with favorable prognosis, and loss of heterozygosity at chromosome 6q (LOH6q) was reported to be associated with increased relapse risk. The current project was intended to evaluate the prognostic effect of these markers. Mutations in hot spots of NOTCH1 and FBXW7 were analyzed in 116 patients. Concerning LOH6q status, 118 patients were investigated, using microsatellite marker analysis, in addition to an earlier reported cohort of 99 available patients. Ninety-two cases were evaluable for both analyses. All patients were treated with T-cell lymphoblastic lymphoma-Berlin-Frankfurt-Münster group (BFM)-type treatment. LOH6q was observed in 12% of patients (25/217) and associated with unfavorable prognosis (pEFS 27% ± 9% vs 86% ± 3%; P < .0001). In 60% (70/116) of the patients, NOTCH1 mutations were detected and associated with favorable prognosis (pEFS 84% ± 5% vs 66% ± 7%; P = .021). Interestingly, NOTCH1 mutations were rarely observed in patients with LOH in 6q16. Both prognostic markers will be used as stratification criteria in coming Non-Hodgkin Lymphoma-BFM trials.

Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact

Deletions on chromosome 6q are frequently reported in hematological malignancies. However, their biological or prognostic impact has not yet been clarified. This study analyzed loss of heterozygosity (LOH) at chromosome 6q and compared the LOH findings in pediatric precursor T lymphoblastic lymphoma (T-LBL) with the LOH findings in precursor-T lymphoblastic leukemia (T-ALL). For LOH analyses, a set of 25 microsatellite-markers on 6q14-q24 were examined. All patients were treated uniformly according to ALL-BFM-type treatment-strategy. A total of 1671 markers were successfully analyzed from 108 T-LBL patients. LOH was detected in 21 T-LBL patients. There was clear association between LOH at 6q and an increased risk of relapse. In comparison, 3109 markers were successfully analyzed from 127 T-ALL-patients. LOH was detected in 16 patients, but was not associated with increased relapse-rate. The localization of the common LOH regions identified for T-LBL and T-ALL samples did not overlap. Therefore patterns of LOH at 6q and the prognostic impact of LOH differ between T-ALL and T-LBL. These results hint at biologic differences between the two diseases.

Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey.

Children with chromosomal instability syndromes have an increased risk of developing lymphoma and leukaemia. The treatment of these malignancies is hampered by therapy‐associated toxicity and infectious complications. This retrospective analysis evaluated the therapy outcome of 38 children with Ataxia teleangiectasia or Nijmegen‐breakage syndrome with acute lymphoblastic leukaemia (ALL, nu2003=u20039), Non‐Hodgkin lymphoma (NHL, nu2003=u200328) and Hodgkin lymphoma (HL, nu2003=u20031). All patients with NHL or ALL were treated in accordance to Berlin‐Frankfurt‐Münster (BFM)‐ or Co‐operative study group for childhood ALL (CoALL)‐oriented chemotherapy schedules. 22 patients received significantly reduced‐intensity chemotherapy. After a median follow‐up of 3·7u2003years the 10‐year overall survival was 58%. Dosage‐reduction of chemotherapeutic drugs seemed to have no disadvantages and reduced toxic side effects. On the other hand, reduced‐intensity chemotherapy did not prevent second malignancies, which occurred in ten patients with a 10‐year incidence of 25%. After individual treatment approaches three of these patients with second malignancies were in complete clinical remission for more than 5u2003years. We conclude that BFM‐ or CoALL‐oriented chemotherapy is effective and can be administered in children with AT or NBS. Moreover, we show that even second lymphoid malignancies can successfully be treated in these patients.

Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK–positive anaplastic large-cell lymphoma

Detection of minimal disseminated disease (MDD) at diagnosis correlates with relapse risk in children with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL). We investigated whether minimal residual disease (MRD) positivity by qualitative reverse-transcriptase polymerase chain reaction (RT-PCR) for Nucleophosmin (NPM)-ALK during treatment identifies patients at the highest relapse risk. Blood and/or bone marrow of 180 patients with NPM-ALK-positive ALCL treated with Berlin-Frankfurt-Münster-type protocols were screened for NPM-ALK transcripts at diagnosis; 103 were found to be MDD-positive. MRD before the second therapy course could be evaluated in 52 MDD-positive patients. MRD positivity correlated with uncommon histology. The cumulative incidence of relapses (CIR) of 26 MDD-positive/MRD-positive patients (81% ± 8%) was significantly higher than the CIR of 26 MDD-positive/MRD-negative (31% ± 9%) and 77 MDD-negative patients (15% ± 5%) (P < .001). Five-year survival of MDD-negative and MDD-positive/MRD-negative patients was 91% ± 3% and 92% ± 5%, respectively, compared with 65% ± 9% of MDD-positive/MRD-positive patients (P < .001). Early evaluation of MRD in NPM-ALK-positive ALCL identifies patients with a very high relapse risk and inferior survival.

Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma.

Non‐Hodgkin lymphoma (NHL) is rarely observed during infancy and data on its incidence, characteristics and outcome are scarce. The present study aimed to assess the prevalence, clinical presentation and treatment results of all infants who were diagnosed with NHL between October 1986 and December 2002 among 2084 patients treated according to the NHL‐BFM (Berlin‐Frankfurt‐Münster) multicentre trials 86, 90 and 95. We identified 20 (1%) infants with NHL including five with T‐cell lymphoblastic lymphoma (T‐cell LBL), seven with precursor B‐cell LBL (pB‐cell LBL), two with a mature Burkitt neoplasm, five with anaplastic large cell lymphoma (ALCL) and one with peripheral T‐cell lymphoma (PTCL). The PTCL patient, 3/7u2003pB‐cell LBL and 1/5 ALCL patients relapsed. One patient each from the T‐cell LBL and Burkitt lymphoma groups suffered from a second malignancy and one patient each with ALCL and Burkitt leukaemia died from treatment‐related toxicity. The 5‐year event‐free survival rate was 53u2003±u200312% for the 20 cases. This study has provided preliminary evidence that infants with NHL have a dismal prognosis and showed that infant NHL differed to lymphomas in older patients with respect to the distribution of gender, histopathologic subtypes as well as the ratio of T‐ to pB‐cell LBL and the frequency of relapses of pB‐cell LBL.

Photo recombination on highly charged few-electron uranium ions

The theory of photo recombination is reviewed and cross sections for radiative and dielectronic recombination and for interference between both processes are derived by an expansion of the T-matrix in low order. In order to demonstrate the interference effects, KLL-photo recombination cross sections are calculated for hydrogen- and helium-like uranium ions. The radiative recombination cross sections are obtained with a multipole expansion for the radiation field leading to an increase of the cross sections by a factor of 2 compared with calculations in the dipole approximation. The effect of interference is found to be strongest in hydrogen-like very heavy ions.

Trajectory method for the time-dependent Schrödinger and Thomas-Fermi equations☆

Abstract A trajectory method for the solution of the one-electron Schrodinger equation and the time-dependent Thomas-Fermi equation is presented. The method is based on the fluid dynamical interpretation of the quantum mechanical one-particle density. The time evolution is described by trajectories of test particles which represent the electron density. The trajectories are calculated by solving classical equations of motion with forces derived from a density-dependent effective potential. Applications of the trajectory method to the proton-hydrogen scattering and the photo-absorption of argon atoms are given.

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 3·9u2003years (range 2–11·7). The median age at diagnosis of NHL was 7·6u2003years (range 4·7–18). Only lymphoblastic (nu2003=u20037) and diffuse large B‐cell (nu2003=u20034) 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.