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We report about a female toddler congenitally deaf and diagnosed with a non-metastatic desmoplastic medulloblastoma (SHH activated, TP53-wt, variant in LDB1 gene). No tumor predisposition syndrome was found. After complete tumor resection the patient was treated according to I-HIT-MED-Guidance protocol. Five months later an asymptomatic localised relapse (same histology, PTEN frameshift deletion, TERT mutation, LDB1 mutation) detected by routine MRI was treated by complete resection, craniospinal irradiation and an antiangiogenic regimen adapted from the MEMMAT scheme including fenofibrate, thalidomide, celecoxib, topotecan, temozolomide, bevacizumab and intraventricular cytarabine. Before start of systemic treatment blood cell counts were normal. In the second cycle we had to interrupt chemotherapy due to a leukopenia while continuing the antiangiogenic treatment. In order to avoid relevant bone marrow toxicity chemotherapy doses were reduced. Nevertheless we had to stop the fourth cycle because of a severe pancytopenia. Same time the girl presented with fever, neck and leg pain. A full blood count showed: hemoglobin 6.92 g/dl, leukocytes 640/µl, platelets 8,000/µl. Suspecting an infection supported by the presence of a high CrP value of 230 mg/l the patient was treated with i.v. antibiotics. MRI showed an unspecific retropharyngeal soft tissue augmentation, a pleural effusion and high T2 signals in multiple vertebral bodies but no central tumor relapse. The bone marrow diagnostics revealed a diffuse medulloblastoma cell infiltration with the known PTEN frameshift deletion and LDB1 mutation. The liquor was tumor-cell free. We report on an extremely rare case of an early local relapse of desmoplastic medulloblastoma progressing to a diffuse bone marrow infiltration in a toddler. The girl died due to therapy resistance 9 weeks after bone marrow relapse. It remains unclear whether the fatal course was related to the hereditary deafness syndrome and the molecular alterations of the tumor.

Background Isolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation. Methods and Results We report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole‐exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents. Conclusion Therefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype., We present the finding of an infant with thoracic and intraspinal aleukemic myeloid sarcoma with a rare germline PALB2 variant (p.A1079S). The identified variant is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. A functional role of the variant is further supported by increased sensitivity towards irradiation and DNA intercalating agents observed in primary cells from the patient carrying PALB2 p.A1079S.

Acute lymphoblastic leukaemia (ALL) is the most common form of paediatric cancer and epigenetic aberrations are determinants of leukaemogenesis. The aim of this study was to investigate the methylation degree of a distinct phospholipase A2 receptor 1 (PLA2R1) promoter region in paediatric ALL patients and to evaluate its relevance as new biomarker for monitoring treatment response and burden of residual disease. The impact of PLA2R1 re-expression on proliferative parameters was assessed in vitro in Jurkat cells with PLA2R1 naturally silenced by DNA methylation. Genomic DNA was isolated from bone marrow (BM) and peripheral blood (PB) of 44 paediatric ALL patients. PLA2R1 methylation was analysed using digital PCR and compared to 20 healthy controls. Transfected Jurkat cells were investigated using cell growth curve analysis and flow cytometry. PLA2R1 was found hypermethylated in BM and PB from pre-B and common ALL patients, and in patients with the disease relapse. PLA2R1 methylation decreased along with leukaemic blast cell reduction during ALL induction treatment. In vitro analysis revealed an anti-proliferative phenotype associated with PLA2R1 re-expression, suggesting a tumour-suppressive function of PLA2R1. Collected data indicates that PLA2R1 promoter methylation quantitation can be used as biomarker for ALL induction treatment control, risk stratification, and early detection of ALL relapse.

A considerable proportion of patients with chronic myeloid leukaemia (CML) may present at diagnosis with high platelet counts. This may result in thrombosis or bleeding complications due to binding of von Willebrand factor (VWF) multimers to platelets. Paediatric CML is very rare and no systematic investigation on clinical complications of elevated platelets has been reported. Data on platelet count and associated haemostaseological complications were retrospectively analysed in a cohort of 156 children with CML. Fifty-one percent (81/156) patients presented with thrombocytosis (platelet count> 500 × 109 /l), and were extreme (>1 000 × 109 /l) in 23/156 (16%). There were no cases of thrombosis but mild bleeding signs were present in 12% (n = 9) children with thrombocytosis. Bleeding occurred without correlation to elevated platelet counts and was associated with reduced large VWF multimers, indicating a diagnosis of acquired von Willebrand syndrome (AVWS), which resolved after initiation of CML treatment. Patients with paediatric CML frequently exhibit high platelet counts not resulting in thrombosis. In patients with thrombocytosis mild bleeding signs due to a low percentage of large VWF multimers can be demonstrated. AVWS may be underdiagnosed in paediatric CML (Clinical-Trials.gov NCT00445822, 9 March 2007).

Antineoplastic treatment of osteoblastic osteosarcoma in a patient with cystic fibrosis (CF) may harbor a high risk of neutropenia-associated complications, and, to the best of our knowledge, has not been previously reported. Diagnosis of CF was confirmed in a 6-week-old boy following pathological newborn screening. The patient had a stable course of CF under standardized continuous therapy. At the age of 5 years, osteosarcoma of the left proximal humerus was diagnosed without evidence of metastases. Neoadjuvant chemotherapy, including doxorubicin, cisplatin and methotrexate, was administered for 10 weeks. The patient tolerated this therapy relatively well, with a continuous antibiotic prophylaxis of cefuroxime without experiencing major complications; in particular, no pulmonary exacerbations were observed as a consequence of immunosuppression or mucosal toxicity. The tumor responded well, and amputation of the limb was avoided via the use of 'clavicle per humerus' osteosynthesis. Postoperatively, compartmental syndrome occurred, requiring management by fasciotomy. Adjuvant chemotherapy was applied thereafter again, without major toxicity that would have required dose reduction. Under intensive physiotherapy, the mobility of the left arm and hand was deemed to be satisfactory. The coincidence of CF with osteosarcoma is extremely rare, and, to the best of our knowledge, has not been previously described. Under antibiotic prophylaxis, antineoplastic treatment was possible without major complications during neutropenia.

Background/aim DNA methylation plays an important role in the initiation and propagation of carcinogenesis; however, the role of heterogeneously methylated epialleles is currently not well studied, also due to the lack of sensitive, unbiased and high throughput methods. Here, a newly developed droplet digital PCR (ddPCR)-based method was evaluated regarding its ability to quantify such heterogeneously methylated epialleles with sufficient analytical sensitivity and specificity. Materials and methods Genomic DNA from blood leukocytes and bone marrow aspirate of an 8-year old male with B-cell acute lymphoblastic leukemia (B-ALL) and from normal and malignant prostate cell lines were analysed using ddPCR. Results By using these DNA samples, the specificity of an applied set of fluorescence-labeled probes was demonstrated as a proof of concept. Conclusion All individual heterogeneously-methylated epialleles were quantifiable by a set of fluorescence-labeled probes with complementary sequences to epialleles in a closed-tube and high-throughput manner. The new method named epiallele-sensitive droplet digital PCR (EAST-ddPCR) may give new insights in the generation and regulation of epialleles and may help in finding new biomarkers for the diagnosis of benign und malignant diseases.

Burkitt lymphoma (BL) in children often presents with abdominal localization. Intestinal perforations have been described mainly during treatment. We report on a three-year-old patient with abdominal BL who was diagnosed with a duodenocolonic fistula.A three-year-old boy presented with diarrhea, crampy abdominal pain, and a four-week history of loss of appetite and weight. Ultrasound and MRI detected a colonic tumor forming a duodenocolonic fistula which was verified by gastroduodenoscopy. A surgical biopsy revealed BL. The stage III BL with low LDH was treated with four courses of BFM-type short-pulse chemotherapy. After two courses of chemotherapy the patient developed a mechanic ileus. A segmental resection of a short segment of the colon at the right flexure carrying the residual tumor mass with cicatricial stenosis and fistula followed by colonic end to end anastomosis and covering of the fistula by omentum major were carried out without complication. 15 days after surgery, two additional courses of chemotherapy could be administrated and the boy is in ongoing remission and free of any symptoms with a follow-up interval of 18 months.Duodeonocolonic fistula at presentation in a child with abdominal BL is extremely rare. Delayed surgery after size of the tumor bulk has been reduced by chemotherapy might represent a risk adapted approach. However, due to limited experience with duodenocolonic fistulas even in larger pediatric lymphoma trials any decision has to be based on the problems to be faced in individual cases.Ein Burkitt-Lymphom (BL) im Kindesalter ist oft im Abdomen lokalisiert. Intestinale Perforationen wurden in der Literatur zumeist als während der Chemotherapie auftretende Komplikation beschrieben. Wir berichten über einen Patienten mit abdominellen BL, welcher bei Diagnosestellung eine duodenokolische Fistel aufwies.Ein 3jähriger Junge wurde vorgestellt mit rezidivierenden Diarrhoen, krampfartigen Bauchschmerzen, Appetitlosigkeit und Gewichtsverlust über einen 4wöchigen Zeitraum. Die radiologische Diagnostik mittels Abdomensonographie und MRT ergab das Bild eines Tumors, welcher eine duodenokolonische Fistel ausgebildet hatte, was mittels Ösophagogastroduodenoskopie bestätigt wurde. Die chirurgische Tumorbiopsie sicherte den Befund eines BL. Es handelte sich um das Stadium III mit einer leichten LDH-Erhöhung. Nach 2 Blöcken der Chemotherapie entwickelte der Patient einen mechanischen Ileus. Eine operative kurzstreckige Segementresektion des stenosierenden und fistelbildenden Tumors im Bereich des Colons ascendens wurde mit einer End-zu-End-Anastomose und Abdecken der Fistel durch Omentum majum ohne Komplikationen durchgeführt. Am 15. postoperativen Tag konnten anschließend 2 weitere Chemotherapie-Blöcke verabreicht werden. Der Patient befindet sich 16 Monaten später beschwerdefrei in Remission.Eine duodenokolonische Fistel als Komplikation eines abdominellen BL ist eine extreme Rarität. Die verzögerte Resektion nach Tumorverkleinerung durch Chemotherapie stellt möglicherweise eine risiko-adaptierte Vorgehensweise dar. Jedoch sollte jede Entscheidung zur Vorgehensweise bei duodenokolonischen Fisteln aufgrund der fehlenden Erfahrungen im Kindesalter auch innerhalb großer Lymphomstudien immer individuell angepasst sein.