BackgroundWhile TNFα-inhibitors improved outcome of JIA markedly, concerns have been raised about an increased risk for malignancies especially lymphoma, probably already due to the disease itself.MethodsThe BIKER data base was used to identify cases of suspected and confirmed malignanciesResultsUntil 2015, 3695 pts treated with MTX and /or TNFα inhibitors were prospectively followed with 13198 observation years (OY). 12 cases of suspected malignancies, including 7 lymphoid neoplasms, have been reported. 11 pts had received MTX, 2 CSA, single patients received Sulfasalazine, Azathioprine or Leflunomide. 9 pts received Etanercept (ETA), 2 Adalimumab, and 1 case consecutively ETA, Infliximab and Abatacept. A case of myelodysplasia, with spontaneous recovery and a cervical dysplasia were labelled as suspected. Confirmed cases included 2 Hodgkin's lymphoma, 1 non-Hodgkin's lymphoma, 2 ALL and 2 lymphoproliferative disorders, who recovered after discontinuation of immunosuppressive therapy. Singular confirmed cases were thyroid carcinoma, yolk sac carcinoma, cervical dysplasia and anaplastic ependymoma. The total rate of malignancies observed in the registry (0.91/1000Y) exceeds the rate expected according to data of the German cancer registry (0.16/1000Y, p<0.001). The calculated risk-ratio in the MTX cohort (n=3: 1 lymphoma, 2 acute lymphatic leukaemias) was significantly increased for both all malignancies (RR 4.5; 95% CI1.5–14.0) and for haemato-lymphatic malignancies (RR 10.1; 95% CI 3.2–31.2). The risk ratio in the ETA cohort also was significantly increased (RR for all malignancies 8.1; 95% CI 4.2–15.5; RR for leukaemia/lymphoma 10.4 (3.9–27.7). No difference was found between the incidence rate of malignancies within the ETA cohort compared to the MTX cohort (p=0.39). Rates did not markedly differ if suspected malignancies (cervical dysplasia, myelodysplasia) were excluded. 6 of the 7 haemato-lymphatic malignancies occurred in ps <15 y of age. There was a higher rate within MTX (0.93/1000Y; 95%CI 0.30–2.89) than with ETA (0.56/1000Y; 95%CI 0.18–1.74). 4 of 5 solid tumours occurred after the age of 15, all in the ETA cohort. One patient never exposed to biologics but to MTX died of ALL, all other recovered.Table 1.Risk ratios (RR) and 95% CI compared to the German Childhood Cancer Registry report 2015 (1657/2056 cancers in children <15/<18 years of age in 10.5/12.9×106 children)MalignanciesNRR (95% CI)*P(Incidence/1000 PY)(Wald test)MTX <15 y (3224 PY)All3 (0.93)5.90 (1.90–18.3)0.002Lymphoma & leukemia3 (0.93)13.74 (4.42–42.71)<0.0001ETA <15 (5333 PY)All3 (0.56)3.56 (1.15–11.1)0.028Lymphoma & leukemia3 (0.56)8.31 (2.67–25.82)0.0003MTX <18 y (4182 PY)All3 (0.72)4.50 (1.45–13.97)0.009Lymphoma & leukemia3 (0.72)10.05 (3.23–31.21)<0.0001ETA <18 Y (6998 PY)All9 (1.29)8.07 (4.19–15.53)<0.0001Lymphoma & leukemia4 (0.57)8.01 (3.00–21.38)<0.0001ConclusionsMalignancies were more frequent than expected. Whether the increased risk is through the rheumatic disease or through treatment remains unclear. Treatment with ETA seem...

10017 Background: The prognosis for children with recurrent or refractory neuroblastoma (rNB) remains dismal. Novel therapeutic approaches are urgently needed. Methods: Based on promising in vitro data unselected patients with rNB were treated as compassionate use according to a multimodal approach (RIST design). The treatment consisted of metronomic courses of Rapamycin/Dasatinib (R/S) for 4 days followed by 5 days of Irinotecan and Temozolomide (I/T). Twenty-one patients (median age: 38 months) with stage IV (n=19) and stage III (n=2) disease, 5 with refractory disease, 8 with 1st and 8 with 2nd and 3rd relapses were included. Seven patients presented within 18 months after diagnosis (median age: 28 months). 18 patients were MIBG positive, 4 MYCN amplified. Dissemination was present in the bone in 15, bone marrow in 11 and lymph nodes in 6 patients, respectively. Results: The patients received a median of 16 courses of R/S (4 to 72) and 7 courses of I/T (4 to 65). 19 patients (90%) showed an initial response according to imaging criteria after a median of 7 R/S and 4 I/T courses (median treatment duration 12 weeks): CR in 12 (57%), a PR in 3 (14%) and a SD in 4 (19%). The median PFS was 90 weeks. The OS after a median of 148 weeks was 43% with 7 patients in CR, 1 VGPR and 1 in PR. There were no toxic deaths in this highly pretreated population. Grade III and IV toxicities (CTC 3.0) were thrombocytopenia in 81%, leukopenia in 76%, anemia in 71%, and diarrhea in 71% respectively. Conclusions: This RIST treatment design applied as a multimodal approach in a compassionate use setting exhibited very promising results considering the adequately long follow-up period of 3 years. This molecular targeted therapy design for rNB warrants confirmation in a prospective clinical trial.

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Three-dimensional echocardiography (3DE) improves the accuracy of left ventricle (LV) volumetry compared with the two-dimensional echocardiography (2DE) approach because geometric assumptions in the algorithms may be eliminated. The relationship between accuracy of mode (short- versus long-axis planimetry) and the number of component images versus time required for analysis remains to be determined. Sixteen latex models simulating heterogeneously distorted (aneurysmatic) human LVs (56–303 ml; mean 182 ± 82 ml) were scanned from an ‘apical’ position (simultaneous 2DE and 3DE). For 3DE volumetry, the slice thickness was varied for the short (C-scan) and long axes (B-scan) in 5-mm steps between 1 and 25 mm. The mean differences (true-echocardiographic volumes) were 16.5 ± 44.3 ml in the 2DE approach (95% confidence intervals –27.8 to +60.8) and 0.6 ± 4.0 ml (short axis; 95% confidence intervals –3.4 to +4.6) as well as 2.1 ± 9.9 ml (long axis; 95% confidence intervals –7.8 to +12.0) in the 3DE approach (in both cases, the slice thickness was 1 mm). Above a slice thickness of 15 mm, the 95% confidence intervals increased steeply; in the short versus long axes, these were –6.5 to +8.5 versus –7.0 to +10.6 at 15 mm and –10.1 to +15.7 versus –11.3 to +10.9 at 20 mm. The intra-observer variance differed significantly (p < 0.001) only above 15 mm (short axis). Time required for analysis derived by measuring short-axis slice thicknesses of 1, 15, and 25 mm was 58 ± 16, 7 ± 2 and 3 ± 1 min, respectively. The most rational component image analysis for 3DE volumetry in the in vitro model uses short-axis slices with a thickness of 15 mm.