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1.
Epilepsy Behav ; 102: 106717, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31785481

RESUMO

BACKGROUND: The health management of patients with epilepsy could be improved by wearing devices that reliably detect when epileptic seizures happen. For the devices to be widely adopted, they must be acceptable and easy to use for patients, and their views are very important. Previous studies have collected feedback from patients on hypothetical devices, but very few have examined experience of wearing actual devices. PURPOSE: This study assessed the first-hand experiences of people with epilepsy using wearable devices, continuously over a period of time. The aim was to understand how acceptable and easy they were to use, and whether it is reasonable to expect that people will use them. MATERIALS AND METHODS: Adults with a diagnosis of epilepsy admitted routinely to a hospital epilepsy monitoring unit were asked to wear one, or more, wearable biosensor devices, tested for seizure detection. The devices are designed to continuously monitor and record signals from the body (biosignals). Participants completed semistructured interviews about their experiences of wearing the device(s). A systematic thematic analysis extracted themes from the interviews, focusing on acceptability and usability. Feedback was organized into (1) participants' experiences of the devices, any support they required and reasons for stopping wearing them; (2) their thoughts about using this technology outside a hospital setting. RESULTS: Twenty-one people with epilepsy wore one, or more, wearable devices for an average of 112.81 (SD = 71.83) hours. Participants found the devices convenient, and had no problem wearing them in hospital or sharing the data collected from them with the researchers and medical professionals. However, the presence of wires, bulky size, discomfort, and need for support, moderated experience. Participants' thoughts about wearing them in everyday life were strongly influenced by how visible and perceived accuracy. Willingness to use a smartphone app to complete questionnaires depended on the frequency, number of questions, and support. CONCLUSIONS: Overall, this work provides evidence about the feasibility and acceptability of using wearable devices to monitor seizure activity in people with epilepsy. Key barriers and facilitators to use while in hospital and hypothetical use in everyday life were identified and will be helpful for guiding future implementation.

2.
J Allergy Clin Immunol Pract ; 8(1): 273-282, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31377437

RESUMO

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients.

3.
Pharmacogenomics J ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31792371

RESUMO

The aim of the study was to validate the impact of the single-nucleotide polymorphism rs2413739 (T > C) in the PACSIN2 gene on thiopurines pharmacological parameters and clinical response in an Italian cohort of pediatric patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD). In ALL, PACSIN2 rs2413739 T allele was associated with a significant reduction of TPMT activity in erythrocytes (p = 0.0094, linear mixed-effect model, multivariate analysis considering TPMT genotype) and increased severe gastrointestinal toxicity during consolidation therapy (p = 0.049). A similar trend was present also for severe hematological toxicity during maintenance. In IBD, no significant effect of rs2413739 could be found on TPMT activity, however azathioprine effectiveness was reduced in patients carrying the T allele (linear mixed effect, p = 0.0058). In PBMC from healthy donors, a positive correlation between PACSIN2 and TPMT protein concentration could be detected (linear mixed effect, p = 0.045). These results support the role of PACSIN2 polymorphism on TPMT activity and mercaptopurine adverse effects in patients with ALL. Further evidence on PBMC and pediatric patients with IBD supports an association between PACSIN2 variants, TPMT activity, and thiopurines effects, even if more studies are needed since some of these effects may be tissue specific.

5.
Neuropsychol Rehabil ; : 1-21, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31833819

RESUMO

Mental health disturbances are common after stroke and linked to a slower recovery. Current face-to-face treatment options are costly and often inaccessible. Technology advances have made it possible to overcome some of these barriers to deliver technology-based mental health interventions remotely, but we do not know how acceptable and feasible they are. This systematic review aims to provide an examination of the acceptability and feasibility of technology-based mental health interventions provided to stroke patients and evaluate any barriers to their adoption. A total of 13 studies were included investigating interventions targeting non-specific mental health, depression or anxiety. The delivery technologies were: video conferencing, computer programmes, telephones, DVDs, CDs, robot-assisted devices, and personal digital assistants. Rates of refusal to participate were low (7.9-25%). Where satisfaction was reported, this was generally high. Many studies achieved high levels of adherence (up to 89.6%). This was lower for some technologies (e.g., robotic assistive devices). Where dropout occurred, this was for reasons including a decline in health as well as technical difficulties. Overall, the literature displays early evidence of using technology to deliver mental health interventions to patients with stroke. This review has identified factors that the design of future studies should take into consideration.

6.
Hemasphere ; 3(3): e250, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31723839

RESUMO

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.

7.
Eur J Cancer ; 122: 61-71, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629941

RESUMO

BACKGROUND: Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. METHODS: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years. FINDINGS: Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. INTERPRETATION: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

8.
Haematologica ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601692

RESUMO

ABL-class fusions other than BCR-ABL1 characterize about 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of >5x10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality 20.8+6.8%. One out of 13 cases with tyrosine kinase inhibitor added to chemotherapy relapsed while eight of 33 cases without tyrosine kinase inhibitor treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high treatment-related mortality (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of tyrosine kinase inhibitors, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (ClinicalTrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

10.
BMC Oral Health ; 19(1): 161, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340803

RESUMO

BACKGROUND: Aim of the study was to evaluate the gelatinolytic activity in the saliva and gingival crevicular fluid from a sample group of subjects with Marfan syndrome. METHODS: Two groups were analyzed in this case-control study. A group of 28 subjects with Marfan syndrome (MG) was recruited from the Centre for Rare Disease, Marfan Clinic of Tor Vergata University Hospital. The second sample, 23 subjects, with the same characteristics and without any syndrome, was the control group (CG). Saliva and gingival crevicular fluid were collected and transferred to a sterile test tube and stored frozen at - 20 °C until analysis at the Medical Chemistry Laboratory. Gelatin substrate zymography was used for the evaluation and characterization of saliva and crevicular fluid proteinases. Correlation test and Student's t-test have been used to analyze data. RESULTS: In all samples different gelatin-degrading activities were observed. Two bands, which are related to the molecular weights of pro-MMP-9 and active MMP-9, respectively, were detectable in 100% of Marfan and control samples. MMP-2 activity was higher in Marfan group. Additional bands (55/48 kDa), corresponding to the activated forms of collagenase (MMP-13), were observed in saliva samples of both groups. CONCLUSIONS: The association of an enhanced activity by MMP-13 with an increased amount of active MMP-9 might be an important biomarker for the diagnosis of Marfan syndrome.


Assuntos
Líquido do Sulco Gengival/enzimologia , Síndrome de Marfan/enzimologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Saliva/enzimologia , Estudos de Casos e Controles , Criança , Feminino , Gelatina/metabolismo , Humanos , Masculino , Síndrome de Marfan/complicações
11.
J Clin Oncol ; 37(25): 2246-2256, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283407

RESUMO

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS: Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS: A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION: Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.

12.
Epilepsy Behav ; 97: 123-129, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31247523

RESUMO

BACKGROUND: Innovative uses of mobile health (mHealth) technology for real-time measurement and management of epilepsy may improve the care provided to patients. For instance, seizure detection and quantifying related problems will have an impact on quality of life and improve clinical management for people experiencing frequent and uncontrolled seizures. Engaging patients with mHealth technology is essential, but little is known about patient perspectives on their acceptability. The aim of this study was to conduct an in-depth qualitative analysis of what people with uncontrolled epilepsy think could be the potential uses of mHealth technology and to identify early potential barriers and facilitators to engagement in three European countries. METHOD: Twenty people currently experiencing epileptic seizures took part in five focus groups held across the UK, Italy, and Spain. Participants all completed written consent and a demographic questionnaire prior to the focus group commencing, and each group discussion lasted 60-120 min. A coding frame, developed from a systematic review of the previous literature, was used to structure a thematic analysis. We extracted themes and subthemes from the discussions, focusing first on possible uses of mHealth and then the barriers and facilitators to engagement. RESULTS: Participants were interested in mHealth technology as a clinical detection tool, e.g., to aid communication about seizure occurrence with their doctors. Other suggested uses included being able to predict or prevent seizures, and to improve self-management. Key facilitators to engagement were the ability to raise awareness, plan activities better, and improve safety. Key barriers were the potential for increased stigma and anxiety. Using familiar and customizable products could be important moderators of engagement. CONCLUSION: People with uncontrolled epilepsy think that there is a scope for mHealth technology to be useful in healthcare as a detection or prediction tool. The costs will be compared with the benefits when it comes to engagement, and ongoing work with patients and other stakeholders is needed to design practical resources.

13.
Br J Haematol ; 186(3): 420-430, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31044436

RESUMO

Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti-leukaemic effect of L-asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML-LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+ CD38+ and CD34+ CD38- LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French-American-British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.

14.
Int J Cardiol ; 292: 62-67, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31130281

RESUMO

BACKGROUND: To assess early and late mortality in patients with isolated acute tricuspid valve infective endocarditis (TVIE) using data from a multicenter registry. METHODS: From 1983 to 2018, isolated acute TVIE was surgically treated in 157 (3.8%) patients [mean age 47 ±â€¯16 years (range 15-86 years), 25% females]. Of these, 142 (90%) had native tricuspid regurgitation, 7 (5%) native tricuspid valve (TV) steno-regurgitation, and 8 (5%) prosthetic TVIE. Intravenous drug use (IVDU) was recorded in 38% of patients, infection involved cardiac implantable electronic device leads in 21%, and vascular catheters for dialysis in 1%; in the remaining cases, the cause was unknown. The primary endpoint was in-hospital outcome, long-term freedom from recurrence and overall survival. RESULTS: Overall, 77 (49%) patients underwent TV repair, 72 (46%) TV replacement, and 8 (5%) prosthetic TV replacement. Early mortality was 11% (n = 17). Expected early mortality according to EndoSCORE was 12%, with age (odds ratio 1.06) and redo (odds ratio 6.64) as risk factors. Late deaths occurred in 31 patients and TVIE recurrences in 4. Survival rates at 10, 20, and 25 years were 66%, 60%, and 44%, respectively. Risk factors were age [hazard ratio (HR) 1.06], mycotic TVIE (HR 4.2), IVDU (HR 4.90), infected prosthesis replacement (HR 4.4), and presence of cardiac implantable electronic device leads (HR 3.0). No significant difference was found in valve repair vs. replacement and in IVDUs vs. non-IVDUs. CONCLUSIONS: Patients with isolated acute TVIE undergoing surgical treatment show acceptable early and late outcomes. TVIE recurrence was low, and repair of the affected valve does not seem to confer any advantage either at early or long term up to 25 years.

15.
J Clin Pathol ; 72(8): 558-561, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30948435

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.


Assuntos
Síndrome de Lange/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas/genética , Proteínas de Ciclo Celular , Pré-Escolar , Análise Mutacional de DNA , Síndrome de Lange/diagnóstico , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva
16.
Ital J Pediatr ; 45(1): 29, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832712

RESUMO

Globalization caused a shift in trial locations towards low-middle income countries, raising ethical concerns. These include the risk that conditions primarily affecting children in these countries will be neglected in favor of those affecting developed countries. We analyzed 253 published and 69 ongoing pharmacological RCTs performed in Latin America between 2000 and 2015 involving exclusively children. While over 50% of the previously highly investigated diseases were no longer priorities, other diseases acquired greater attention in recent years. Brazil and Mexico resulted as the most active countries. A large gap remains between the real needs of children in these countries and scientific research.


Assuntos
Internacionalidade , Pediatria , Preparações Farmacêuticas , Criança , Pré-Escolar , Países em Desenvolvimento , Feminino , Humanos , Lactente , América Latina , Masculino , Pobreza , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
17.
Exp Hematol ; 73: 7-12.e4, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30825516

RESUMO

The TEL-AML1 fusion gene, generated by the t(12;21) chromosome translocation, arises in a progenitor/stem cell and could induce clonal expansion of a persistent preleukemic B-cell clone which, on acquisition of secondary alterations, may turn into full-blown leukemia. During infections, deregulated cytokine signaling, including transforming growth factor ß (TGF-ß), can further accelerate this process by creating a protumoral bone marrow (BM) microenvironment. Here, we show that activin A, a member of the TGF-ß family induced under inflammatory conditions, inhibits the proliferation of normal progenitor B cells but not that of preleukemic TEL-AML1-positive clones, thereby providing a selective advantage to the latter. Finally, we find that activin A inhibits BM-derived mesenchymal stromal cell-mediated secretion of CXCL12, a major chemoattractant in the BM compartment, thereby contributing to shape a leukemia-promoting environment. Overall, our findings indicate that activin A, in concert with TGF-ß, could play an important role in the creation of a pro-oncogenic BM microenvironment and provide novel mechanistic insights into TEL-AML1-associated leukemogenesis.

18.
Haematologica ; 104(9): 1812-1821, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30705097

RESUMO

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 µmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 µmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 µmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.

19.
Eur J Cancer ; 110: 86-97, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30772657

RESUMO

INTRODUCTION: Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. MATERIALS AND METHODS: CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS: Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86-88) and at 45 years was 81% (95% CI: 77-84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7-12), corresponding to an AER of 48 (95% CI: 45-51). Mortality decreased by 60% for survivors treated most recently (1990-1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. CONCLUSIONS: This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

20.
Eur J Cancer ; 110: 120-126, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30785015

RESUMO

Although all tumours are rare in childhood, there are some particularly rare paediatric cancers which have not benefited from advances made by the international paediatric oncology network. To establish a shared definition and produce a list of these entities, the European Union Joint Action on Rare Cancers (JARC) promoted a consensus effort. The definition was based on the incidence rates estimated using the information network on rare cancers (RARECAREnet) database, pooling data from 94 population-based cancer registries and 27 countries. The RARECAREnet list of cancers was used to estimate the incidence rates. This list groups cancers by combining the International Classification of Diseases for Oncology, third edition, morphology and topography codes. According to the consensus, very rare paediatric cancers were identified as those with an annual incidence <2/1000000 and corresponded to 11% of all cancers in patients aged 0-14 years. Two subgroups were identified: tumour types typical of childhood (i.e. hepatoblastoma, pleuropulmonary blastoma, pancreatoblastoma) and those typical of adult age (i.e. carcinomas, melanoma). The threshold of 2/1000000 could also be adopted in populations aged 0-19 years: in this case, three tumour types had an incidence rate which was >2/1000000 (i.e. thyroid and testicular cancers and skin melanoma), but the consensus experts considered them as 'very rare' according to their clinical needs (e.g. shortage of knowledge and clinical expertise as the other rare paediatric cancers). The JARC consensus produced a definition and a list of very rare paediatric cancers which may represent a starting point for prioritising research on these tumours, based on data and patients' clinical needs.

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