TP53 mutation in children with therapy-related myelodysplastic syndrome/acute myeloid leukemia after rhabdomyosarcoma treatment

After successful treatment of childhood malignancy, development of second malignancy (SM) is the mostdevastating and potentially life-threatening sequelae of it. In the past 12 years there have been no casesof therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) among 80 childrentreated for soft tissue sarcomas (STS) in the Department of Paediatric Oncology, Haematology, and BoneMarrow Transplantation. Given the rarity of recognition of t-MDS/AML in children after treatment ofcancers, it was decided to analyse in detail the therapy and cytogenetic and molecular results in two boysaged 9 and 10 years old, diagnosed with t-MDS/AML secondary to rhabdomyosarcoma. In both of themTP53 mutation was found. Palliat Med Pract 2020; 14, 1: 58–6

Gastrointestinal autonomic nerve tumour — report of a case of GANT that developed as a secondary cancer in a neuroblastoma survivor

Gastrointestinal autonomic nerve tumours (GANT) are rare stromal tumours of the gastrointestinal tractand retroperitoneum in adults; they are very uncommon among children. In the literature there are nodata about the occurrence of GANTs after neuroblastoma. The authors report a case of 12-year-old girl,previously treated for neuroblastoma, who presented to the emergency room with symptoms of acuteabdomen. She developed intussusception caused by a tumour, which was subsequently diagnosed asa GANT of the colon. No metastatic lesions were found. Surgery and subtotal resection of the colon wereperformed. During 30 months of follow-up she had no signs of recurrence. To conclude, in cancer survivorspresenting to the emergency room with acute symptoms, recurrent or new cancer should always beconsidered in the differential diagnosis

Repertoire sequencing of B cells elucidates the role of UNG and mismatch repair proteins in somatic hypermutation in humans

The generation of high-affinity antibodies depends on somatic hypermutation (SHM). SHM is initiated by the activation-induced cytidine deaminase (AID), which generates uracil (U) lesions in the B-cell receptor (BCR) encoding genes. Error-prone processing of U lesions creates a typical spectrum of point mutations during SHM. The aim of this study was to determine the molecular mechanism of SHM in humans; currently available knowledge is limited by the number of mutations analyzed per patient. We collected a unique cohort of 10 well-defined patients with bi-allelic mutations in genes involved in base excision repair (BER) (UNG) or mismatch repair (MMR) (MSH2, MSH6, or PMS2) and are the first to present next-generation sequencing (NGS) data of the BCR, allowing us to study SHM extensively in humans. Analysis using ARGalaxy revealed selective skewing of SHM mutation patterns specific for each genetic defect, which are in line with the five-pathway model of SHM that was recently proposed based on mice data. However, trans-species comparison revealed differences in the role of PMS2 and MSH2 in strand targeting between mice and man. In conclusion, our results indicate a role for UNG, MSH2, MSH6, and PMS2 in the generation of SHM in humans comparable to their function in mice. However, we observed differences in strand targeting between humans and mice, emphasizing the importance of studying molecular mechanisms in a human setting. The here developed method combining NGS and ARGalaxy analysis of BCR mutation data forms the basis for efficient SHM analyses of other immune deficiencies

Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005-2011 : experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)

AIM OF THE STUDY: Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011. MATERIAL AND METHODS: The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children. RESULTS: Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1. CONCLUSIONS: The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy

High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers

Introduction: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. Materials and methods: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. Results: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). Conclusions: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations. Keywords: constitutional mismatch repair deficiency; highly sensitive methodologies; lynch syndrome; microsatellite instability; next generation sequencing

Too young to be vaccinated: hospitalizations caused by varicella among children in the first year of life

Aim: The aim of this study was to analyse the causes of hospitalization in the course of varicella in children during the first year of life. Methods: An analysis was performed of the medical documentation of 359 children hospitalized for varicella on the infectious diseases ward at the Children’s Hospital in Poznan (Poland) between January 2007 and August 2015. Results: Of the 359 children in the study group, 96 were younger than 1 year old. The most common cause of hospitalization was respiratory infections, found in 31 (32%) children. A severe course of varicella was observed in 38 (14%) children, and 21 (22%) developed skin infections, while 11 (11%) exhibited more than one complication. Treatment with acyclovir was implemented in 90 cases and parenteral antibiotic therapy was applied in 49 children. Contact with siblings suffering from varicella was confirmed in 46 children; for 16, the source of the infection was the mother. Conclusions: The main source of varicella virus among hospitalized children in the first year of life is home contact. An infant may become infected from its mother suffering from zoster. Children who are exclusively breastfed and are born of mothers who have previously had varicella may develop varicella with a severe course during the first year of life