Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin’s lymphoma are limited. We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin’s lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt’s lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab–chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab–chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P=0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab–chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab–chemotherapy group and 24.2% in the chemotherapy group (P=0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab–chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin’s lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.)

The surface molecule CD56 marks a category of malignant lymphoma of putative natural killer (NK) cell origin. We conducted a retrospective analysis of 24 cases of CD56⁺ NK lymphoma/leukaemia to define the clinicopathologic and prognostic features of this specific group of lymphomas. 56 cases of nasal lymphomas and 204 cases with an initial diagnosis of peripheral T‐cell lymphoma were retrospectively analysed. To specifically examine lymphomas of putative NK origin, only those that were negative for surface expression of CD3 but positive for CD56 were analysed. 24 cases were identified. The initial predominant sites of involvement were nasal (n =18), palate (n = 1), nodal (n = 1) and multi‐organ (n =4). Clinically, in patients with disease localized to one anatomical site (n = 20), most had symptoms confined to the nose, with a high percentage in early stage (I: 91%; IV: 9%). The marrow was not involved in any of these cases. However, patients with multi‐organ involvement at presentation (n = 4) behaved differently. All presented acutely with pancytopenia, hepatosplenomegaly, and marrow infiltration with haemophagocytosis. A leukaemic phase was observed in one case. Anthracycline containing combination chemotherapy resulted in complete remission in 75% of patients with localized disease, but only in 25% with multi‐organ involvement. The median survival of patients with localized disease was 12 months, compared with 2 months in the multi‐organ group (P =0.06); the disease‐free survival was significantly better in the former (P <0.01). The overall median survival of all patients was still poor at 11 months.We conclude that CD56⁺ NK lymphomas could be divided into two main patterns of disease presentations: localized (predominantly nasal), and multi‐organ involvement. Each has different clinicopathologic and prognostic features. Conventional chemotherapy appeared ineffective for the majority of patients, and innovative treatment modalities are needed to improve outcome.

Interferon gamma (IFN-γ) and interleukin 10 (IL-10) are believed to play opposing roles in host immunity against mycobacterial infection. IFN-γ activates macrophages, while IL-10 downregulates the expression of T helper type 1 cytokines, MHC class II antigens and costimulatory molecules on macrophages. Associations of IFN-γ −179 (G/T), +874 (A/T), +875 miscrosatellite CA repeats and +4766 (C/T), and IL-10 −1082 (A/G), −819 (C/T) and −592 (C/A) with tuberculosis (TB) were investigated in 385 HIV-negative patients and 451 controls in a Hong Kong Chinese population. The frequency of a low IFN-γ-producing +874 A/A genotype was significantly over-represented in the patient group (P<0.001, OR=3.79, 95% CI=1.93–7.45). We identified 10 alleles in the IFN-γ CA repeats and observed a significant difference in allele frequency distribution between patients and controls (P<0.001). By grouping alleles into 12 and non-12 CA repeats, the non-12/non-12 genotype yielded a similar significant result (P<0.001, OR=4.56, 95% CI=2.21–9.43) as observed in +874 A/A genotype. Weak associations of the IL-10 GCC/− genotype (P=0.04) and the low IFN-γ-producing A/A genotype (P=0.06) with TB relapse/extrapulmonary cases were found. This study suggests the possible role of interferon gamma in TB susceptibility.

Significance: Nasopharyngeal carcinoma (NPC) is a valuable cancer model to study the interaction of host genetics, viral infection, and environment in tumorigenesis. Little is known about the genetic basis for the remarkably distinct geographical distribution of NPC. We used a whole-exome sequencing approach to identify the genetic alterations associated with NPC susceptibility and revealed a strong link between macrophage-stimulating 1 receptor ( MST1R ) and NPC early-age onset (age of ≤20 y). MST1R is critical for innate immunity and plays an important role for host defense against viral infection. We further discovered that an interaction network involved in the MST1R/14-3-3 complex was frequently deregulated by genetic alterations in NPC. Our findings provide new insights in the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

A cohort of 138 children with 144 hematopoietic stem cell transplantation (HSCT) performed in 1997–2006 were analyzed to evaluate risk factors and mortality predictors of hepatic veno-occlusive disease (VOD). Nineteen patients (13.2%) developed VOD (nine boys, median age 3.5 years) at 1–21 days after HSCT (median 13 days). Age ⩽2 years at transplant (odds ratio (OR)=5.25, P=0.011), BU–CY conditioning (OR=5.16, P=0.001), thalassemia major (OR=3.97, P=0.015), platelet engraftment beyond day +21 (OR=8.67, P=0.025) were univariate risk factors for VOD. The first two remained significant in multivariate regression. Seven patients (36.8%) with VOD died, at a median of 44 days post transplant (range, 30–421 days). The 5-year survival was 62%. All surviving patients had normal liver function on follow-up at 0.5–9 years. Patients with VOD had higher 100-day mortality (16.3 vs 9.6%, P=0.024). Mortality predictors included donors other than autologous or matched sibling (hazard ratio (HR)=23.6, P=0.006), hepatic and cutaneous GVHD (HR=8.15, P=0.038), maximal weight gain >9% (HR=6.81, P=0.023), pleural effusion, intensive care unit admission, peak bilirubin >300 μmol l⁻¹ (HR=13.6, P=0.016), day +21 bilirubin >200 μmol l⁻¹ (HR=33.9, P=0.001), and rise of bilirubin >15 μmol l⁻¹ per day within the first week (HR=19.8, P=0.006). Mortality was substantially higher if >3 predictors were present (HR=33.9, P=0.001). Meticulous monitoring in high-risk patients and early treatment should be considered before VOD progresses beyond salvage.

Undifferentiated nasopharyngeal carcinoma (NPC) has a 100% association with Epstein-Barr virus (EBV). However, only three EBV genomes isolated from NPC patients have been sequenced to date, and the role of EBV genomic variations in the pathogenesis of NPC is unclear. We sought to obtain the sequences of EBV genomes in multiple NPC biopsy specimens in the same geographic location in order to reveal their sequence diversity. Three published EBV (B95-8, C666-1, and HKNPC1) genomes were first resequenced using the sequencing workflow of target enrichment of EBV DNA by hybridization, followed by next-generation sequencing, de novo assembly, and joining of contigs by Sanger sequencing. The sequences of eight NPC biopsy specimen-derived EBV (NPC-EBV) genomes, designated HKNPC2 to HKNPC9, were then determined. They harbored 1,736 variations in total, including 1,601 substitutions, 64 insertions, and 71 deletions, compared to the reference EBV. Furthermore, genes encoding latent, early lytic, and tegument proteins and glycoproteins were found to contain nonsynonymous mutations of potential biological significance. Phylogenetic analysis showed that the HKNPC6 and -7 genomes, which were isolated from tumor biopsy specimens of advanced metastatic NPC cases, were distinct from the other six NPC-EBV genomes, suggesting the presence of at least two parental lineages of EBV among the NPC-EBV genomes. In conclusion, much greater sequence diversity among EBV isolates derived from NPC biopsy specimens is demonstrated on a whole-genome level through a complete sequencing workflow. Large-scale sequencing and comparison of EBV genomes isolated from NPC and normal subjects should be performed to assess whether EBV genomic variations contribute to NPC pathogenesis. IMPORTANCE This study established a sequencing workflow from EBV DNA capture and sequencing to de novo assembly and contig joining. We reported eight newly sequenced EBV genomes isolated from primary NPC biopsy specimens and revealed the sequence diversity on a whole-genome level among these EBV isolates. At least two lineages of EBV strains are observed, and recombination among these lineages is inferred. Our study has demonstrated the value of, and provided a platform for, genome sequencing of EBV.