Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.

• MeSH
• akutní lymfatická leukemie farmakoterapie   metabolismus   patologie   MeSH
• antitumorózní látky farmakologie   MeSH
• asparaginasa * farmakologie   metabolismus   MeSH
• citrátový cyklus účinky léků   MeSH
• glutamin metabolismus   MeSH
• glutathion * metabolismus   MeSH
• kyselina glutamová * metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Ganglioneurom je vzácný, benigní, terminálně diferencovaný a pomalu rostoucí nádor autonomního nervového systému, který obvykle vzniká ze sympatických gangliových buněk. Většina z nich je asymptomatická a nachází se náhodně. Uvádíme poměrně vzácný případ ganglioneuromu zadního mediastina, který byl souběžně diagnostikován při vstupním zobrazovacím vyšetření 11leté dívky s akutní lymfoblastickou leukemií (ALL). Histopatologické a histochemické vyšetření bioptických vzorků potvrdily diagnózu ganglioneuromu. Vzhledem k asymptomatickému průběhu, bez propagace nádoru do páteřního kanálu byl zvolen neoperativní management sledováním pomocí zobrazovacích metod. Dívka s akutní leukemií je v celkové remisi, na udržovací léčbě podle protokolu AIEOP-BFM ALL 2017. Kontrolní vyšetření MR hrudníku po 10 měsících potvrdilo stacionární charakter GN bez progrese.

Ganglioneuroma is a rare, benign, terminally differentiated and slow-growing tumour of the autonomic nervous system, usually arising from sympathetic ganglion cells. Most are asymptomatic and found incidentally. We report a relatively rare case of a ganglioneuroma of the posterior mediastinum that was diagnosed simultaneously on initial imaging in an 11-year-old girl with acute lymphoblastic leukemia (ALL). Histopathological and histochemical examination of biopsy speci­mens confirmed the diagnosis of ganglioneuroma. Because of an asymptomatic course, without tumor propagation into the spinal canal, a non-operative mana­gement by imaging follow-up was chosen. The girl with acute leukemia is in complete remission, on maintenance treatment according to the AIEOP-BFM ALL 2017 protocol. The control chest MRI after 10 months confirmed the stationary character of GN without progression.

• MeSH
• akutní lymfatická leukemie * diagnóza   farmakoterapie   MeSH
• diagnostické zobrazování metody   MeSH
• dítě MeSH
• ganglioneurom * diagnostické zobrazování   diagnóza   klasifikace   patologie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• management nemoci MeSH
• nádory mediastina diagnóza   klasifikace   MeSH
• souběh chronických nemocí klasifikace   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

Steroids are a mainstay in the treatment of acute lymphoblastic leukaemia (ALL) in children and adolescents; however, their use can cause clinically significant steroid-related neuropsychiatric symptoms (SRNS). As current knowledge on SRNS during ALL treatment is limited, we mapped the phenotypes, occurrence and treatment strategies using a database created by the international Ponte di Legno Neurotoxicity Working Group including data on toxicity in the central nervous system (CNS) in patients treated with frontline ALL protocols between 2000 and 2017. Ninety-four of 1813 patients in the CNS toxicity database (5.2%) experienced clinically significant SRNS with two peaks: one during induction and one during intensification phase. Dexamethasone was implicated in 86% of SRNS episodes. The most common symptoms were psychosis (52%), agitation (44%) and aggression (31%). Pharmacological treatment, mainly antipsychotics and benzodiazepines, was given to 87% of patients while 38% were hospitalised due to their symptoms. Recurrence of symptoms was reported in 29% of patients and two previously healthy patients required ongoing pharmacological treatment at the last follow up. Awareness of SRNS during ALL treatment and recommendation on treatment strategies merit further studies and consensus.

• MeSH
• akutní lymfatická leukemie * farmakoterapie   MeSH
• dexamethason škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• neurotoxické syndromy etiologie   MeSH
• předškolní dítě MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• steroidy terapeutické užití   škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

Pyogenní granulom (lobulární kapilární hemangiom) se vyznačuje rychle rostoucí lézí podobnou moruši, která může být přisedlá nebo stopkatá. Krvácení, i při lehkém doteku (traumatu), je obvykle jeho prvním klinickým projevem. Na rozdíl od infantilního hemangiomu se může vyskytovat v každém věkovém období včetně dospělosti. Uvádíme kazuistiku 4leté dívky s pyogenním granulomem (PG) levé tváře, který matka pozorovala 3 měsíce po ukončení léčby akutní lymfoblastické leukemie (ALL). V celkové anestezii byla provedena exstirpace parciálně stopkatého PG současně s excizí jeho spodiny. Histologický nález prokázal fokálně prokrvácený lobulární kapilární hemangiom.

Pyogenic granuloma (lobular capillary hemangioma) is characterized by a rapidly growing mulberry-like lesion that may be sessile or pedunculated. Bleeding even with light touch (trauma) is usually its first clinical manifestation. Unlike infantile haemangioma, it can occur at any age, including adulthood. We present a case report of a 4-year-old girl with pyogenic granuloma (PG) of the left cheek, observed by her mother 3 months after treatment for acute lymphoblastic leukemia (ALL). Under general anesthesia, extirpation of the partially pedunculated PG was performed simultaneously with excision of its base. Histological findings showed a focally hemorrhaged lobar capillary hemangioma.

• MeSH
• akutní lymfatická leukemie farmakoterapie   MeSH
• antitumorózní látky škodlivé účinky   MeSH
• lidé MeSH
• předškolní dítě MeSH
• pyogenní granulom * chirurgie   diagnóza   etiologie   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Recent trials show 5-year survival rates >95% for ETV6::RUNX1 Acute Lymphoblastic Leukemia (ALL). Since treatment has many side effects, an overview of cumulative drug doses and intensities between eight international trials is presented to characterize therapy needed for cure. A meta-analysis was performed as a comprehensive summary of survival outcomes at 5 and 10 years. For drug dose comparison in non-high risk trial arms, risk group distribution was applied to split the trials into two groups: trial group A with ~70% (range: 63.5-75%) of patients in low risk (LR) (CCLSG ALL2004, CoALL 07-03, NOPHO ALL2008, UKALL2003) and trial group B with ~45% (range: 38.7-52.7%) in LR (AIEOP-BFM ALL 2000, ALL-IC BFM ALL 2002, DCOG ALL10, JACLS ALL-02). Meta-analysis did not show evidence of heterogeneity between studies in trial group A LR and medium risk (MR) despite differences in treatment intensity. Statistical heterogeneity was present in trial group B LR and MR. Trials using higher cumulative dose and intensity of asparaginase and pulses of glucocorticoids and vincristine showed better 5-year event-free survival but similar overall survival. Based on similar outcomes between trials despite differences in therapy intensity, future trials should investigate, to what extent de-escalation is feasible for ETV6::RUNX1 ALL.

• MeSH
• akutní lymfatická leukemie * genetika   farmakoterapie   mortalita   terapie   MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• lidé MeSH
• míra přežití MeSH
• protein ETS, translokační varianta 6 * MeSH
• protein PEBP2A2 * genetika   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny c-ets * genetika   MeSH
• represorové proteiny * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

• MeSH
• akutní lymfatická leukemie diagnóza   farmakoterapie   MeSH
• diferenciální diagnóza MeSH
• dítě * MeSH
• germinální a embryonální nádory diagnóza   terapie   MeSH
• hepatoblastom chirurgie   diagnóza   terapie   MeSH
• lidé MeSH
• lymfom diagnóza   farmakoterapie   terapie   MeSH
• nádory centrálního nervového systému chirurgie   diagnóza   terapie   MeSH
• nádory * chirurgie   diagnóza   terapie   MeSH
• neuroblastom diagnóza   terapie   MeSH
• sarkom chirurgie   diagnóza   terapie   MeSH
• Wilmsův nádor diagnóza   terapie   MeSH
• Check Tag
• dítě * MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P < 0.0001 each). Proven/probable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for proven/probable IFD, age ≥12 years, and insufficient response to therapy (P < 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis.

• MeSH
• akutní lymfatická leukemie * komplikace   farmakoterapie   MeSH
• antifungální látky terapeutické užití   MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mykózy * farmakoterapie   etiologie   MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).

• MeSH
• akutní lymfatická leukemie * komplikace   farmakoterapie   MeSH
• dítě MeSH
• indukční chemoterapie škodlivé účinky   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• methotrexát * terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The aim of this study was to compare two immunosuppressive strategies, based on the use of either rabbit antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY), as a prophylaxis of graft-versus-host disease (GVHD) for patients with acute lymphoblastic leukemia (ALL) in first complete remission who underwent hematopoietic cells transplantation from matched unrelated donors. METHODS: Overall, 117 and 779 adult patients who received PTCY and ATG, respectively, between the years 2015 and 2020 were included in this retrospective study. The median patient age was 40 and 43 years in the PTCY and ATG groups, respectively, and 37% and 35% of patients, respectively, had Philadelphia chromosome-positive ALL. RESULTS: In univariate analysis, the cumulative incidence of acute and chronic GVHD did not differ significantly between the study groups. The cumulative incidence of relapse at 2 years was reduced in the PTCY group (18% vs. 25%; p = .046) without a significant impact on nonrelapse mortality (11% vs. 16% in the ATG group; p = .29). The rates of leukemia-free survival (LFS) and overall survival were 71% versus 59%, respectively (p = .01), and 82% versus 74%, respectively (p = .08). In multivariate analysis, the receipt of ATG compared with PTCY was associated with a reduced risk of extensive chronic GVHD (hazard ratio, 0.54; 95% confidence interval, 0.3-0.98; p = .04) and an increased risk of low LFS (hazard ratio, 1.57; 95% confidence interval, 1.01-2.45; p = .045). CONCLUSIONS: The receipt of ATG compared with PTCY, despite the reduced risk of extensive chronic GVHD, is associated with inferior LFS in adults with ALL who undergo hematopoietic cell transplantation from 10/10 human leukocyte antigen-matched unrelated donors. These findings warrant verification in prospective trials.

• MeSH
• akutní lymfatická leukemie * farmakoterapie   MeSH
• akutní myeloidní leukemie * farmakoterapie   MeSH
• akutní nemoc MeSH
• antilymfocytární sérum terapeutické užití   MeSH
• cyklofosfamid terapeutické užití   MeSH
• dospělí MeSH
• kostní dřeň MeSH
• lidé MeSH
• nemoc štěpu proti hostiteli * etiologie   prevence a kontrola   MeSH
• nepříbuzný dárce MeSH
• příprava pacienta k transplantaci MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1). METHODS: Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018. RESULTS: With a median follow-up period of 6.4 years (range, 0.3-17.9 years), the 10-year overall survival (OS) was 54.7% (SE = 2.9), which is significantly higher than the 27.6% (SE = 2.9) observed in the historical cohort from 1985 to 2000. There was no significant impact of sex, age, white blood cell count, central nervous system disease status, T-cell maturity, or BM disease burden at EOI on OS. Postinduction complete remission (CR) was achieved in 93% of patients with 10-year OS of 59.6% (SE = 3.1%) and disease-free survival (DFS) of 56.3% (SE = 3.1%). Among the patients who achieved CR, 72% underwent HSCT and their 10-year DFS (with a 190-day landmark) was significantly better than nontransplanted patients (63.8% [SE = 3.6] v 45.5% [SE = 7.1]; P = .005), with OS of 66.2% (SE = 3.6) versus 50.8% (SE = 6.8); P = .10, respectively. CONCLUSION: Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.

• MeSH
• akutní lymfatická leukemie * farmakoterapie   MeSH
• dítě MeSH
• dospělí MeSH
• indukce remise MeSH
• lidé MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk * terapie   MeSH
• mladý dospělý MeSH
• přežití po terapii bez příznaků nemoci MeSH
• retrospektivní studie MeSH
• T-lymfocyty MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH