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

Activation of Extrinsic Coagulation Pathway in Myeloproliferative Neoplasms – Preliminary Report

The aim of the study was to assess the activation of extrinsic blood coagulation pathway, based on the TF and TFPI measurements in patients with MPNs. The study group consisted of 17 patients with MPNs (mean age 59 years). The control group was made of 30 healthy volunteers (mean age 52 years). In blood samples tissue factor TF, tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complexes (TAT) concentration and antithrombin (AT) activity were determined. The present study showed a significantly higher level of tissue factor and decreased TFPI concentration in patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis. Conclusions: 1. The results showed that in all groups of patients with MPNs an extrinsic activation of coagulation, resulting in a high concentration of TF in the blood of these patients, occurs. 2. It seems that in patients with ET, PMF and PV, an extrinsic activation of coagulation is inhibited by TFPI inhibitor as evidenced by its reduced concentration observed in the blood of these patients (the result of extrinsic consumption in the track).Celem pracy była ocena aktywności krzepnięcia krwi drogą zewnątrzpochodną u chorych na przewlekłe nowotwory mieloproliferacyjne (PZM), na podstawie oceny stężenia czynnika tkankowego (TF) i inhibitora drogi zewnątrzpochodnej układu krzepnięcia (TFPI). Badaniami objęto grupę 17 chorych na PZM (kobiet i mężczyzn w średnim wieku 59 lat). Grupę kontrolną stanowiło 30 zdrowych ochotników, kobiet i mężczyzn w średnim wieku 52,4 lat. W cytrynianowej krwi żylnej oznaczono stężenie TF, całkowitej puli TFPI, stężenie kompleksów TAT oraz aktywności AT. Stwierdzono we krwi chorych na PZM istotnie podwyższone stężenie TF, a obniżone stężenie TFPI u chorych na CzP, NS i MF. Wnioski: 1. Przeprowadzone badania wykazały, że we wszystkich grupach chorych z PZM występuje aktywacja krzepnięcia drogą zewnątrzpochodną, czego wyrazem jest wysokie stężenie TF we krwi tych chorych. 2. Wydaje się, że u chorych na NS, MF i CzP aktywacja układu krzepnięcia drogą zewnątrzpochodną jest hamowana przez inhibitor TFPI, o czym może świadczyć obniżone jego stężenie obserwowane we krwi tych chorych (wynik zużycia w torze zewnątrzpochodnym)

Aktywacja układu krzepnięcia krwi drogą zewnątrzpochodną w nowotworach mieloproliferacyjnych- doniesienie wstępne

The aim of the study was to assess the activation of extrinsic blood coagulation pathway, based on the TF and TFPI measurements in patients with MPNs.The study group consisted of 17 patients with MPNs (mean age 59 years). The control group was made of 30 healthy volunteers (mean age 52 years). In blood samples tissue factor TF, tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complexes (TAT) concentration and antithrombin (AT) activity were determined.The present study showed a significantly higher level of tissue factor and decreased TFPI concentration in patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis.Conclusions:1. The results showed that in all groups of patients with MPNs an extrinsic activation of coagulation, resulting in a high concentration of TF in the blood of these patients, occurs.2. It seems that in patients with ET, PMF and PV, an extrinsic activation of coagulation is inhibited by TFPI inhibitor as evidenced by its reduced concentration observed in the blood of these patients (the result of extrinsic consumption in the track).Celem pracy była ocena aktywności krzepnięcia krwi drogą zewnątrzpochodną u chorych na przewlekłe nowotwory mieloproliferacyjne (PZM), na podstawie oceny stężenia czynnika tkankowego (TF) i inhibitora drogi zewnątrzpochodnej układu krzepnięcia (TFPI).Badaniami objęto grupę 17 chorych na PZM (kobiet i mężczyzn w średnim wieku 59 lat). Grupę kontrolną stanowiło 30 zdrowych ochotników, kobiet i mężczyzn w średnim wieku 52,4 lat. W cytrynianowej krwi żylnej oznaczono stężenie TF, całkowitej puli TFPI, stężenie kompleksów TAT oraz aktywności AT. Stwierdzono we krwi chorych na PZM istotnie podwyższone stężenie TF, a obniżone stężenie TFPI u chorych na CzP, NS i MF.Wnioski:1. Przeprowadzone badania wykazały, że we wszystkich grupach chorych z PZM występuje aktywacja krzepnięcia drogą zewnątrzpochodną, czego wyrazem jest wysokie stężenie TF we krwi tych chorych.2. Wydaje się, że u chorych na NS, MF i CzP aktywacja układu krzepnięcia drogą zewnątrzpochodną jest hamowana przez inhibitor TFPI, o czym może świadczyć obniżone jego stężenie obserwowane we krwi tych chorych (wynik zużycia w torze zewnątrzpochodnym)

Neutrophil gelatinase-associated lipocalin and Cathepsin L as early predictors of kidney dysfunction in children with type 1 diabetes

Wstęp: Celem pracy była ocena stężenia w surowicy i w moczu markerów wczesnego uszkodzenia nerek, to jest lipokainy związanej z żelatynazą neutrofilii (odpowiednio sNGAL i uNGAL) oraz wydalania z moczem katepsyny L (uCathL) u dzieci z cukrzycą typu 1 (DM1) wykazujących normoalbuminurię i filtrację kłębuszkową (eGFR) powyżej 90 ml/min/1,73 m2.Materiał i metody: Grupę badaną stanowiło 63 dzieci ze średnim czasem trwania DM1 wynoszącym 5,16 ± 3,39 roku. Albuminurię oceniano za pomocą wskaźnika albuminowo-kreatyninowego (ACR). eGFR obliczano na podstawie stężenia cystatyny C. Hiperfiltrację kłębuszkową (GH) definiowano jako wartość eGFR > 135 ml/min/1.73 m2.Wyniki: U dzieci z DM1 w porównaniu do grupy kontrolnej wykazano znamiennie wyższe stężenia uNGAL, niższe sNGAL i uCathL. Istotne zmiany stężeń uNGAL i uCathL stwierdzono już u dzieci bez GH i z optymalną kontrolą glikemii (HbA1c < 7,5%). Stwierdzono pozytywną zależność pomiędzy uNGAL, ACR i eGFR oraz pomiędzy uCathL i eGFR.Wnioski: Istotne zmiany w stężeniu markerów wczesnego uszkodzenia nerek to jest sNGAL, uNGAL i uCathL mogą wystąpić u dzieci z DM1 i normoalbuminurią. Zmiany uNGAL i uCathL mogą wystąpić nawet u chorych bez GH oraz wykazujących optymalną kontrolę glikemii. Pierwsze objawy zaburzenia czynności nerek w przebiegu DM1 wydają się wynikać z uszkodzenia cewek nerkowych. (Endokrynol Pol 2014; 65 (6): 479–484)Introduction: The aim of this study was to evaluate serum levels and urinary excretion of neutrophil-gelatinase associated lipocalin (respectively sNGAL and uNGAL) and urinary excretion of Cathepsin L (uCathL) in children with type 1 diabetes mellitus (DM1) who presented normoalbuminuria and the estimated glomerular filtration rate (eGFR) above 90 mL/min/1.73 m2.Material and methods: The study group consisted of 63 children with a diabetes duration of 5.16 ± 3.39 years. The degree of albuminuria was based on urine albumin-to-creatinine ratio (ACR), while eGFR was based on serum cystatin C. Glomerular hyperfiltration (GH) was defined as an eGFR value above 135 mL/min/1.73 m2.Results: Children with DM1 showed significantly higher concentrations of uNGAL, and lower sNGAL and uCathL. Significant changes of uNGAL and uCathL levels were even found in children without GH and with optimal glycaemic control (HbA1c < 7.5%). Positive correlations between uNGAL, ACR and eGFR were shown, as well as between uCathL and eGFR.Conclusions: Significant changes in the concentration of markers of early kidney injury: sNGAL, uNGAL, and uCathL, can occur in children with DM1 and normoalbuminuria. The changes of uNGAL and uCathL can be even found in children without GH and with optimal glycaemic control. The earliest signs of diabetic kidney dysfunction seem to result from tubular damage. (Endokrynol Pol 2014; 65 (6): 479–484)

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

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