RESUMO
Venous thromboembolism (VTE) is a well-known complication of the treatment of pediatric acute lymphoblastic leukemia (ALL). We analyzed 1026 ALL patients 1-18-years-old, who were enrolled into the AIEOP-BFM ALL 2000 or 2009 studies in Austria, with regard to the incidence and risk factors of VTE. The 2.5-year cumulative incidence (CI) of VTE ≥ grade 2 was 4%±1% (n = 36/1026). Twenty VTE (56%) were found in the central nervous system (19 cerebral venous sinus and 1 cortical vein thrombosis), and 16 (44%) at other sites (7 deep vein thromboses (DVT) of the lower extremity, 4 DVT of the upper extremity, 4 central venous line-thromboses, 1 pulmonary embolism). Most VTE occurred during induction and early consolidation therapy (81%) and were associated with L-asparaginase within 4 and corticosteroids withing 1 week(s) preceding the event (89 and 86%, respectively). In multivariable analysis, two independent risk factors were found. Patients 10-18-years-old had an increased (hazard-ratio: 2.156, p = 0.0389), whereas treatments in trial AIEOP-BFM ALL 2009 had a lower risk for VTE (hazard-ratio: 0.349, p = 0.0270). In conclusion, the 2.5-year CI of VTE among our pediatric patient cohort was <5% and adolescent age was the main patient-related risk factor. This older age group might benefit from primary prophylactic measures.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Trombose Venosa Profunda de Membros Superiores , Tromboembolia Venosa , Adolescente , Criança , Humanos , Idoso , Lactente , Pré-Escolar , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Incidência , Áustria/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Near-tetraploidy-defined by DNA index 1.79-2.28 or 81-103 chromosomes-is a rare cytogenetic abnormality observed both in children and adults with T-cell acute lymphoblastic leukaemia (T-ALL) and its prognostic value is not yet determined. PATIENTS AND METHODS: We report a retrospective study conducted in paediatric patients with newly diagnosed T-ALL treated in AIEOP-BFM ALL 2000 and 2009 studies. 31 near-tetraploid T-ALL patients (1.4%) are compared to T-ALL patients without near-tetraploidy. RESULTS: Near-tetraploid karyotype was associated with lower frequency of high-risk features: white blood cells count at diagnosis ≥100,000/µL (19.3% versus 41.0%, p-value < 0.001), PPR (13.3% versus 35.8%, p-value = 0.01) and minimal residual disease high-risk at the end of consolidation phase Induction B (4.03% versus 14.6%, p-value = 0.001). Complete remission was achieved at the end of induction phase (day 33) in 100% near-tetraploid T-ALL patients, compared to 93.2% T-ALL without near-tetraploidy. CONCLUSION: Overall, we found that near-tetraploid T-ALL in newly diagnosed paediatric patients is associated with low-risk presenting features, with favourable treatment response and outcome.
Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , DNA , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Estudos Retrospectivos , Linfócitos T , Tetraploidia , Resultado do TratamentoRESUMO
Second malignant neoplasms (SMN) after primary childhood acute lymphoblastic leukemia (ALL) are rare. Among 1487 ALL patients diagnosed between 1981 and 2010 in Austria, the 10-year cumulative incidence of an SMN was 1.1% ± 0.3%. There was no difference in the 10-year incidence of SMNs with regard to diagnostic-, response- and therapy-related ALL characteristics except for a significantly higher incidence in patients with leukocytes ≥50.0 G/L at ALL diagnosis (2.1% ± 1.0% vs. 0% for 20.0-50.0 G/L, and 1.0% ± 0.3% for < 20.0 G/L; p = 0.033). Notably, there was no significant difference in the incidence of SMNs between patients with or without cranial radiotherapy (1.2% ± 0.5% vs. 0.8% ± 0.3%; p = 0.295). Future strategies must decrease the incidence of SMNs, as this event still leads to death in one-third (7/19) of the patients.
RESUMO
We report the case of a male Pakistani patient with a pathogenic homozygous loss of function variant in the non-homologous end-joining factor 1 (NHEJ1) gene. The growth retarded and microcephalic boy with clinodactyly of both hands and hyperpigmentation of the skin suffered from recurrent respiratory infections. He was five and a half years old when he came to our attention with refractory cytopenia and monosomy 7. Hematopoietic stem cell transplantation was considered but not feasible because there was no suitable donor available. Monosomy 7 was not detected anymore in subsequent bone marrow biopsies that were repeated in yearly intervals. Instead, seven and a half years later, a novel clone with a del(20q) appeared and steadily increased thereafter. In parallel, the patient's blood count, which had remained stable for over 20 years without necessitating any specific therapeutic interventions, improved gradually and the erythropoiesis-associated dysplasia resolved.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 7 , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Síndromes Mielodisplásicas/genética , SobreviventesRESUMO
While survival rates in paediatric acute lymphoblastic leukaemia (ALL) nowadays exceed 90%, systemic ALL relapse, especially after haemopoietic stem cell transplantation (HSCT), is associated with a poor outcome. As there is currently no standardized treatment for this situation, individualized treatment is often pursued. Exemplified by two clinical scenarios, the aim of this article is to highlight the challenge for treating physicians to find a customized treatment strategy integrating the role of conventional chemotherapy, immunotherapeutic approaches and second allogeneic HSCT. Case 1 describes a 2-year-old girl with an early isolated bone marrow relapse of an infant KMT2A-rearranged B-cell precursor ALL after allogeneic HSCT. After bridging chemotherapy and lymphodepleting chemotherapy, chimeric antigen receptor (CAR) T-cells (tisagenlecleucel) were administered for remission induction, followed by a second HSCT from the 9/10 human leukocyte antigen (HLA)-matched mother. Case 2 describes a 16-year-old girl with a late, isolated bone marrow relapse of B-cell precursor ALL after allogeneic HSCT who experienced severe treatment toxicities including stage IV renal insufficiency. After dose-reduced bridging chemotherapy, CAR T-cells (tisagenlecleucel) were administered for remission induction despite a CD19- clone without prior lymphodepletion due to enhanced persisting toxicity. This was followed by a second allogeneic HSCT from the haploidentical mother. While patient 2 relapsed around Day + 180 after the second HSCT, patient 1 is still in complete remission >360 days after the second HSCT. Both cases demonstrate the challenges associated with systemic ALL relapse after first allogeneic HSCT, including chemotherapy-resistant disease and persisting organ damage inflicted by previous therapy. Immunotherapeutic approaches, such as CAR T-cells, can induce remission and enable a second allogeneic HSCT. However, optimal therapy for systemic ALL relapse after first HSCT remains to be defined.
RESUMO
Acute appendicitis is a rare gastrointestinal complication of anti-cancer chemotherapy and hematopoietic stem cell transplantation. Among a cohort of 2341 hemato-oncologic patients at a pediatric tertiary care cancer center, we identified 21 patients (0.9%) with 23 episodes of acute appendicitis, based on pathological imaging of the appendix and clinical findings. Median age at diagnosis was 10.21 years. Types of underlying disease included acute leukemias (n = 15), solid tumors (n = 4), and aplastic anemia (n = 2). Clinical symptoms seen in > 1 case were recorded for all 23 episodes as follows: abdominal pain, n = 22; abdominal tenderness, n = 4; fever, n = 7; nausea, n = 2; emesis; n = 2; diarrhea, n = 5; and constipation, n = 2. Median leukocyte count at diagnosis was 0.5 × 109/L, with a median of 0.1 × 109/L for the absolute neutrophil count (ANC). All patients received broad-spectrum antibiotics and 18/23 (78%) patients underwent uneventful appendectomy after a median of 5 days and with a median ANC of 0.7 × 109/L. Median duration until continuation of chemotherapy was 17 days for the 20 cases of appendicitis occurring during the patients' disease course. Overall, 5/21 (19%) patients died including one related to the appendicitis itself which progressed to a typhlitis and was due to a fungal infection. The other fatalities were transplant- (n = 2) and leukemia-related (n = 2). Acute appendicitis is a rare and usually not life-threatening event in pediatric hemato-oncologic patients, which, if managed by prompt administration of broad-spectrum antibiotics (and antimycotics), can be safely followed by an elective (delayed) appendectomy, even before complete recovery of the neutrophils is achieved.
Assuntos
Antibacterianos/uso terapêutico , Apendicectomia/métodos , Apendicite/diagnóstico , Apendicite/terapia , Neoplasias Hematológicas/complicações , Atenção Terciária à Saúde/estatística & dados numéricos , Adolescente , Apendicite/etiologia , Criança , Pré-Escolar , Terapia Combinada , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Lactente , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
Immunocompromised children and adolescents receiving treatment for cancer have an increased risk for potentially life-threatening infectious complications such as blood stream infections with Gram-positive and Gram-negative pathogens. Therefore, several centers for Pediatric Hematology and Oncology administer antibacterial prophylaxis to these patients to lower morbidity and mortality. Two pediatric specific guidelines on antibacterial prophylaxis were recently published. One of these guidelines was drawn up by an international group of pediatric experts of Europe, North and South America and Australia. The other guideline was prepared by an European group convened at the Eighth European Conference on Infections in Leukaemia (ECIL-8). In this review article, the working groups "Infections" of the Society of Pediatric Oncology and Hematology (GPOH) and "Fever in the neutropenic host" of the German Society for Pediatric Infectious Diseases" (DGPI) summarize the available data from randomized studies, systematic reviews and meta-analyses on antibacterial prophylaxis as well of current data on the emergence of resistance and discuss methodological aspects and the recommendations of the two guidelines.
Assuntos
Doenças Transmissíveis , Hematologia , Neoplasias , Adolescente , Antibacterianos/efeitos adversos , Criança , Doenças Transmissíveis/tratamento farmacológico , Europa (Continente) , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Invasive mold disease (IMD) of the central nervous system (CNS) is a severe infectious complication in immunocompromised patients, but early microbiological diagnosis is difficult. As data on the value of biomarkers in the CNS are scarce, in particular in children, we retrospectively analyzed the performance of galactomannan (GM) and PCR assays in CNS samples of 15 children with proven and probable CNS IMD and of 32 immunocompromised children without fungal infection. Galactomannan in the cerebrospinal fluid (CSF) was assessed in nine of the 15 pediatric patients and was positive in five of them. Polymerase chain reaction (PCR) was performed in eight of the 15 patients and detected nucleic acids from molds in six patients. Galactomannan and PCR in CNS samples were the only positive microbiologic parameter in the CNS in three and two patients, respectively. In four patients, PCR specified the pathogen detected in microscopy. Galactomannan and PCR results remained negative in the CSF of all immunocompromised children without evidence for CNS IMD. Our data suggest that GM and PCR in CNS specimens are valuable additional tools in diagnosing CNS IMD and should be included in the work up of all pediatric patients with suspected mold disease of the CNS.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , DNA Fúngico/análise , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/diagnóstico , Mananas/análise , Reação em Cadeia da Polimerase/métodos , Adolescente , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Galactose/análogos & derivados , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Infecções Fúngicas Invasivas/etiologia , Infecções Fúngicas Invasivas/metabolismo , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Invasive mold disease (IMD) is a severe infectious complication in immunocompromised patients. The outcome of central nervous system (CNS) IMD is poor, but contemporary data, in particular in the pediatric setting, are lacking. PROCEDURE: For this retrospective multicenter analysis, pediatric patients < 18 years with proven or probable CNS IMD receiving chemotherapy or undergoing allogeneic HSCT were reported by the local investigator. CNS IMD had to be diagnosed between 2007 and 2016. Proven CNS IMD was defined as compatible CNS imaging or macroscopic autopsy findings in conjunction with a positive microscopic or microbiological result in the brain tissue or cerebrospinal fluid. Probable CNS IMD was defined as compatible CNS imaging findings in combination with proven or probable IMD at a site outside the CNS. RESULTS AND CONCLUSIONS: A total of 29 patients (median age, 14 years; 14 allogeneic HSCT recipients) were diagnosed with proven (n = 12) or probable (n = 17) CNS IMD. Aspergillus spp. was the most common fungal pathogen. All but one patient had IMD sites outside the CNS and eight patients (27.6%) were neurologically asymptomatic at diagnosis of CNS IMD. Forty-nine percent of the patients survived CNS IMD; however, 46.7% of the survivors suffered from severe long-term neurological sequelae. Our data suggest that (1) outcome of CNS IMD has improved in children as compared with previous series, (2) half of surviving patients suffer from severe neurological sequelae, and (3) imaging of the CNS should be performed in all children with IMD irrespective of neurological symptoms.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Nervoso Central/terapia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções Fúngicas Invasivas/epidemiologia , Adolescente , Doenças do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Alemanha/epidemiologia , Neoplasias Hematológicas/patologia , Humanos , Incidência , Lactente , Infecções Fúngicas Invasivas/etiologia , Infecções Fúngicas Invasivas/microbiologia , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Available data on the incidence and outcome of invasive fungal diseases (IFD) in children with hematological malignancies or after allogeneic hematopoietic stem cell transplantation (HSCT) are mostly based on monocenter, retrospective studies or on studies performed prior to the availability of newer triazoles or echinocandins. PROCEDURE: We prospectively collected clinical data on incidence, diagnostic procedures, management and outcome of IFD in children treated for hematological malignancies or undergoing HSCT in three major European pediatric cancer centers. RESULTS: A total of 304 children (median age 6.0 years) who underwent 360 therapies (211 chemotherapy treatments, 138 allogeneic HSCTs and/or 11 investigational chemotherapeutic treatments) were included in the analysis. Nineteen children developed proven/probable IFD, mostly due to Aspergillus (n = 10) and Candida spp. (n = 5), respectively. In patients receiving chemotherapy, 11 IFDs occurred, all during induction or re-induction therapy. None of these patients died due to IFD, whereas IFD was lethal in 3 of the 8 HSCT recipients with IFD. Significant differences among centers were observed with regard to the use of imaging diagnostics and the choice, initiation and duration of antifungal prophylaxis. CONCLUSION: This prospective multicenter study provides information on the current incidence and outcome of IFD in the real life setting. Practice variation between the centers may help to ultimately improve antifungal management in children at highest risk for IFDs.
RESUMO
Rothia mucilaginosa is part of the oral and upper respiratory tract flora. Usually, this gram-positive coccus is not pathogenic; however, in the setting of immunosuppressed hosts, it can cause life-threatening infections as an opportunistic pathogen. Among a cohort of 1511 hematologic-oncologic patients at a pediatric tertiary care cancer center, we identified five cancer patients (0.35%) within a period of 10 years having a proven Rothia mucilaginosa bacteremia (1 culture positive: n = 3/5; > 1 culture positive: n = 2/5). With prompt and adequate antibiotic treatment, infection resolved rapidly before recovery of neutrophils and without any sequelae, suggesting that Rothia mucilaginosa bacteremia without organ involvement is not exceptionally problematic in pediatric cancer patients.
Assuntos
Bacteriemia/terapia , Institutos de Câncer , Micrococcaceae , Centros de Atenção Terciária , Bacteriemia/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos RetrospectivosRESUMO
Maintaining dendritic cells (DC) in a state of dysfunction represents a key mechanism by which tumour cells evade recognition and elimination by the immune system. Limited knowledge about the intracellular mediators of DC dysfunction restricts success of therapies aimed at reactivating a DC-driven anti-tumour immune response. Using a cell type-specific murine knock-out model, we have identified MAPK-activated protein kinase 2 (MK2) as a major guardian of a suppressive DC phenotype in the melanoma tumour microenvironment. MK2 deletion in CD11c+ cells led to an expansion of stimulatory CD103+ DCs, mounting a potent CD8+ T cell response that resulted in elimination of highly aggressive B16-F10 tumours upon toll-like receptor (TLR) activation in the presence of tumour antigen. Moreover, tumour infiltration by suppressive myeloid cells was strongly diminished. These insights into the regulation of DC functionality reveal MK2 as a targetable pathway for DC-centred immunomodulatory cancer therapies.