Publications by authors named "Marta Pillon"

139 Publications

Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

Department of Pediatric Hematology, Oncology and BMT, University Hospital Muenster, 48149 Münster, Germany.

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.
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http://dx.doi.org/10.3390/cancers13092075DOI Listing
April 2021

Minimal Disease Monitoring in Pediatric Non-Hodgkin's Lymphoma: Current Clinical Application and Future Challenges.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Minimal residual disease (MRD) detection is established routine practice for treatment stratification in leukemia and used for treatment optimization in adult lymphomas. Minimal disease studies in childhood non-Hodgkin lymphomas are challenged by stratified treatment in different subtypes, high cure rates, low patient numbers, limited initial tumor material, and early progression. Current clinical applications differ between the subtypes. A prognostic value of minimal disseminated disease (MDD) could not yet be clearly established for lymphoblastic lymphoma using flow cytometry and PCR-based methods for T-cell receptor (TCR) or immunoglobulin (IG) rearrangements. fusion sequences or IG rearrangements enable minimal disease detection in Burkitt lymphoma and -leukemia. An additional prognostic value of MDD in Burkitt lymphoma and early MRD in Burkitt leukemia is implicated by single studies with risk-adapted therapy. MDD and MRD determined by PCR for ALK-fusion transcripts are independent prognostic parameters for patients with ALK-positive anaplastic large cell lymphoma (ALCL). They are introduced in routine clinical practice and used for patient stratification in clinical studies. Early MRD might serve as an endpoint for clinical trials and for guiding individual therapy. Validation of MDD and MRD as prognostic parameters is required for all subtypes but ALCL. Next-generation sequencing-based methods may provide new options and applications for minimal disease evaluation in childhood lymphomas.
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http://dx.doi.org/10.3390/cancers13081907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071445PMC
April 2021

Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Diagnostics (Basel) 2021 Feb 6;11(2). Epub 2021 Feb 6.

Maternal and Child Health Department, Padova University, 35128 Padova, Italy.

Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring.
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http://dx.doi.org/10.3390/diagnostics11020253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915848PMC
February 2021

MiR-26a-5p as a Reference to Normalize MicroRNA qRT-PCR Levels in Plasma Exosomes of Pediatric Hematological Malignancies.

Cells 2021 Jan 8;10(1). Epub 2021 Jan 8.

Maternal and Child Health Department, Padova University, 35128 Padova, Italy.

Plasma exosomal microRNAs (miRNAs) are considered as valid circulating biomarkers for cancer diagnosis and prognosis. Quantitative real-time polymerase chain reaction (qRT-PCR), the most commonly used technique to assess circulating miRNA levels, requires a normalization step involving uniformly expressed endogenous miRNAs. However, there is still no consensus on reference miRNAs for plasma exosomal miRNA abundance normalization. In this study, we identified a panel of miRNAs with stable abundance by analyzing public plasma exosome RNA-seq data and selected miR-486-5p, miR-26a-5p, miR-423-5p and miR191-5p as candidate normalizers. Next, we tested the abundance variation of these miRNAs by qRT-PCR in plasma exosomes of healthy donors and pediatric patients with anaplastic large cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia. MiR-486-5p and miR-26a-5p showed the most stable levels, both between healthy controls and patients and among the malignancies analyzed. In light of previous reports on miRNA stability in different exosome isolation methods, our data indicated that miR-26a-5p is a bona fide reference miRNA for qRT-PCR normalization to evaluate miRNA abundance from circulating plasma exosomes in studies of hematological malignancies.
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http://dx.doi.org/10.3390/cells10010101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827902PMC
January 2021

Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry.

Blood Adv 2020 11;4(22):5644-5649

Hematology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)-Istituto Giannina Gaslini, Genoa, Italy.

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.
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http://dx.doi.org/10.1182/bloodadvances.2020002793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686904PMC
November 2020

Systemic Fusariosis: A Rare Complication in Children with Acute Lymphoblastic Leukemia.

J Fungi (Basel) 2020 Oct 9;6(4). Epub 2020 Oct 9.

Maternal and Child Health Department, Pediatric Hematology, Oncology and Stem Cell Transplantation Division, Padua University Hospital, 35128 Padua, Italy.

species are ubiquitous pathogens causing opportunistic infections in immunocompromised patients. Clinical presentation depends on a host's immunity and can be localized or disseminated. Since there are few reports of disseminated fusariosis in children, we described an unusual case of infection in a 9-year-old child with acute lymphoblastic leukemia (ALL). This patient presented a deep wound in the elbow at diagnosis. During the induction phase of chemotherapy, he developed multiple skin lesions and severe pneumonia; was cultured from the skin lesions. He was treated with a high dose of liposomal amphotericin B, followed by voriconazole. Starting from this peculiar case, we collected all patients with acute leukemia affected by infection, treated in the pediatric Onco-Hematology Division of Padua University Hospital during the last 20 years. We identified another six cases: all these patients were affected by acute myeloid leukemia (AML) and five of them presented a relapsed/refractory disease. Two out of seven patients died because of infection; five patients recovered from infection, but three out of seven died because of leukemia. Skin lesions in immunocompromised patients should rise the suspicion of disseminated fusariosis. Furthermore, considering the emergence of filamentous fungi in immunocompromised patients, we all should be aware of infection, reminding us that the diagnosis is important to cure the infection.
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http://dx.doi.org/10.3390/jof6040212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712314PMC
October 2020

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively ( < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.
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http://dx.doi.org/10.3390/cancers12102747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598675PMC
September 2020

A mixed-methods study of the disease experience in hematopoietic stem cell transplantation survivors: the contribution of text analysis.

J Psychosoc Oncol 2020 Nov-Dec;38(6):728-745. Epub 2020 Sep 10.

Haematology-Oncology Division, Department of Woman's and Child's Health, University Hospital of Padua, Padua, Italy.

Objectives: Few studies have detected qualitative and quantitative aspects of patients who underwent HSCT during childhood. The aims of this study are to explore the most recurrent narrative themes of HSCT experience in families five years after the procedure, and to observe statistical correlations between meaning attributed to the experience and defined variables.

Methods: Thirty-five families of pediatric HSCT survivors participated in the research. Both survivors and their families were asked to write a brief composition about their disease experiences. Qualitative analysis of the texts was performed using the T-LAB software. Information about medical aspects and psychological problems in HSCT survivors were collected with interviews and administering the Child Behavior Checklist 6-18.

Results: HSCT survivor families that reported the presence of externalizing and internalizing symptoms focused on thematic areas concerning broken families with separation between parents and the affected child versus healthy children.

Conclusions: Long term psychological problems seem to be connected to the perception of family disruption. Specifically, family relationships seem to be the factor that protects from or enhances the risk of psychopathology in HSCT survivors. Moreover, the use of metaphoric terms to refer to HSCT presents higher associations with psychopathology. On the contrary, the possibility of referring directly to the transplantation is associated with psychological well-being. It is important to consider the family as a group in order to improve care.
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http://dx.doi.org/10.1080/07347332.2020.1814932DOI Listing
September 2020

Stem Cell Transplantation and Vinblastine Monotherapy for Relapsed Pediatric Anaplastic Large Cell Lymphoma: Results of the International, Prospective ALCL-Relapse Trial.

J Clin Oncol 2020 12 30;38(34):3999-4009. Epub 2020 Jul 30.

Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Germany.

Purpose: To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408) stratified patients according to the time of relapse and CD3 expression to prospectively test reinduction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy.

Patients And Methods: Patients with progression during frontline therapy (very high risk) or a CD3-positive relapse (high risk) were scheduled for allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine-etoposide-cytarabine-melphalan. This arm was terminated prematurely, and subsequent patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse > 1 year after initial diagnosis (low risk) received vinblastine monotherapy.

Results: One hundred sixteen patients met the inclusion criteria; 105 evaluable patients with CNS-negative disease had a 5-year event-free survival (EFS) of 53% ± 5% and a 5-year overall survival (OS) of 78% ± 4%. Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% ± 12%, 62% ± 10%, 44% ± 9%, and 81% ± 9%; the respective OS rates were 59% ± 12%, 73% ± 9%, 78% ± 7%, and 90% ± 6%. Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% ± 10% and 78% ± 9%, respectively. All 5 patients with intermediate risk receiving vinblastine monotherapy after the amendment experienced relapse again.

Conclusion: Shorter time to relapse was the strongest predictor of subsequent relapse. Allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. For early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy achieved cure in patients with late relapse; however, it was not effective for early relapses.
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http://dx.doi.org/10.1200/JCO.20.00157DOI Listing
December 2020

Neuro-meningeal relapse in anaplastic large-cell lymphoma: incidence, risk factors and prognosis - a report from the European intergroup for childhood non-Hodgkin lymphoma.

Br J Haematol 2021 Mar 9;192(6):1039-1048. Epub 2020 Jul 9.

Department of Children and Adolescents Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France.

Relapses involving the central nervous system (CNS) are rare in children and adolescents with ALK+ anaplastic large cell lymphoma (ALCL) treated with regimens including CNS prophylaxis. Early identification of patients at high-risk for CNS relapse would enable stratification and better adaptation of initial treatment especially in the light of the upcoming targeted therapies with limited CNS penetration. We analyzed clinical and histological data of all ALK+ALCL patients with CNS relapse registered in ALCL99-database with the aim to describe risk factors and outcome. Characteristics of patients with no relapse, relapse without CNS involvement and CNS relapse were compared. At a median follow-up of 8 years (0.05-18 years), a CNS involvement was reported at first or subsequent relapse in 26/618 patients. Median interval between initial diagnosis and first CNS relapse was 8 months (IQR 5.55-10.61/range 1.31-130.69). The 5-year cumulative risk of CNS relapse was 4% (95% CI 2.9-5.5). Bone marrow involvement, peripheral blasts and CNS involvement at diagnosis were more frequent in patients with CNS relapse than in patients with no relapse or with relapse with no CNS involvement. The treatment of CNS relapse was heterogeneous. The median survival after CNS relapse was 23.7 months. Eleven patients were alive at last follow-up. Three-year overall survival after CNS relapse was 48.70% (95% CI 30.52-67.23).
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http://dx.doi.org/10.1111/bjh.16755DOI Listing
March 2021

Pediatric Patients Treated for Leukemia Back to School: A Mixed-Method Analysis of Narratives about Daily Life and Illness Experience.

Behav Sci (Basel) 2020 Jul 1;10(7). Epub 2020 Jul 1.

Pediatric Hematology, Oncology and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padua, 35128 Padua, Italy.

In the last few years, more children and adolescents healed from leukemia go back to their daily life, even if they can show some psycho-social difficulties. The study adopted semi-structured interviews and a mixed-method approach to examine the narratives of 75 children and adolescents about their return to school post 2-years treatment for leukemia. The aims are to collect their illness experiences, to understand how they feel about school and daily routines and to identify the best socio-demographic and illness predictors of a good re-adaptation to school and daily life. The results show that by increasing age and when the pediatric patient have received a hematopoietic stem cell transplantation, at the stop-therapy time, her/his perception about relationships at school and academic performance decrease, especially if his/her feelings about the disease and follow-up visits are negative.
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http://dx.doi.org/10.3390/bs10070107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407376PMC
July 2020

Comparison of Hodgkin's Lymphoma in Children and Adolescents. A Twenty Year Experience with MH'96 and LH2004 AIEOP (Italian Association of Pediatric Hematology and Oncology) Protocols.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Pediatric Hematology Oncology Unit, Azienda Ospedaliero Universitaria of Parma, 43126 Parma, Italy.

Adolescents and young adults (AYAs) represent a distinct group of patients. The objectives of this study were: To compare adolescent prognosis to that of younger children; to compare the results achieved with the two consecutive protocols in both age groups; to analyze clinical characteristics of children and adolescents. Between 1996 and 2017, 1759 patients aged <18 years were evaluable for the study. Five hundred and sixty patients were treated with the MH'96 protocol and 1199 with the LH2004 protocol. Four hundred and eighty-two were adolescents aged ≥15 years. Patients in both age groups showed very favorable prognoses. In particular, OS improved with the LH2004 protocol, especially in the adolescent group and in the low risk group, where radiation therapy was spared. Adolescent characteristics differed significantly from the children's according to sex, histology, and the presence of symptoms. Remarkable is the decrease both in mixed cellularity in the children and in low stages in both age groups in the LH2004 protocol with respect to MH'96 protocol. Based on our experience, adopting pediatric protocols for AYA does not compromise patient outcomes.
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http://dx.doi.org/10.3390/cancers12061620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352443PMC
June 2020

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.

N Engl J Med 2020 06;382(23):2207-2219

From the Departments of Pediatric and Adolescent Oncology (V.M.-C., C.P.) and Clinical Research (G.V.), INSERM Unité 1015 (V.M.-C.), and the Unit of Biostatistics and Epidemiology and INSERM Unité 1018 (A.A.), Gustave Roussy, Université Paris-Saclay, Villejuif, France; the Department of Pediatric Hematology and Oncology, University of Padua, Padua, Italy (M.P.); the Department of Paediatric Haematology, Oncology, and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge (G.A.A.B.), Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham (K.W.), and the Department of Histopathology, Royal Marsden NHS Foundation Trust, London (A.W.) - all in the United Kingdom; the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (D.A.B.); the Department of Pediatric Hematology and Oncology, University of Valencia, Valencia, Spain (R.F.D.); the Division of Haematology-Oncology, Hospital for Sick Children, Toronto (S.A.); the Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium (A.U.); the Center for Cancer and Immunology Research, Children's National Health System and George Washington University, Washington, DC (C.M.B.); Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (J.Z.); the Department of Pediatric Hematology and Oncology, Semmelweis University, Budapest, Hungary (M.C.); the Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland (B.K.); the Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong (A.K.C.); the Department of Pathology, University of Utah, Salt Lake City (R.R.M.); Children's Hospital of Philadelphia, Philadelphia (P.C.A.); and the National Cancer Institute, Center for Global Health, Rockville, MD (T.G.G.).

Background: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited.

Methods: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed.

Results: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion.

Conclusions: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).
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http://dx.doi.org/10.1056/NEJMoa1915315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720281PMC
June 2020

Rare non-Hodgkin lymphoma of childhood and adolescence: A consensus diagnostic and therapeutic approach to pediatric-type follicular lymphoma, marginal zone lymphoma, and nonanaplastic peripheral T-cell lymphoma.

Pediatr Blood Cancer 2020 08 26;67(8):e28416. Epub 2020 May 26.

Department of Pediatric Hematology and Oncology, The Queen Silvia's Hospital for Children and Adolescents, University of Gothenburg, Gothenburg, Sweden.

Pediatric-type follicular (PTFL), marginal zone (MZL), and peripheral T-cell lymphoma (PTCL) account each for <2% of childhood non-Hodgkin lymphoma. We present clinical and histopathological features of PTFL, MZL, and few subtypes of PTCL and provide treatment recommendations. For localized PTFL and MZL, watchful waiting after complete resection is the therapy of choice. For PTCL, therapy is subtype-dependent and ranges from a block-like anaplastic large cell lymphoma (ALCL)-derived and, alternatively, leukemia-derived therapy in PTCL not otherwise specified and subcutaneous panniculitis-like T-cell lymphoma to a block-like mature B-NHL-derived or, preferentially, ALCL-derived treatment followed by hematopoietic stem cell transplantation in first remission in hepatosplenic and angioimmunoblastic T-cell lymphoma.
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http://dx.doi.org/10.1002/pbc.28416DOI Listing
August 2020

Second malignant neoplasms after treatment of non-Hodgkin's lymphoma-a retrospective multinational study of 189 children and adolescents.

Leukemia 2021 02 11;35(2):534-549. Epub 2020 May 11.

Department of Pediatric Hematology and Oncology, University of Padova, Padova, Italy.

Data on the spectrum of second malignant neoplasms (SMNs) after primary childhood non-Hodgkin's lymphoma (NHL) are scarce. One-hundred-and-eighty-nine NHL patients diagnosed in a 30 years period of 1980-2010 developing an SMN were retrieved from 19 members of the European Intergroup for Childhood NHL and/or the international Berlin-Frankfurt-Münster Study Group. Five subgroups of SMNs were identified: (1) myeloid neoplasms (n = 43; 23%), (2) lymphoid neoplasms (n = 51; 27%), (3) carcinomas (n = 48; 25%), (4) central nervous system (CNS) tumors (n = 19; 10%), and (5) "other" SMNs (n = 28; 15%). In 37 patients (20%) preexisting disorders were reported with 90% having any kind of cancer predisposition syndrome (CPS). For the 189 primary NHL patients, 5-year overall survival (OS) after diagnosis of an SMN was 56 ± 4%, being worst for patients with preexisting disorders at 28 ± 8%. Five-year OS rates were 38 ± 8%, 59 ± 7%, 79 ± 8%, 34 ± 12%, and 62 ± 11%, respectively, for patients with myeloid and lymphoid neoplasms, carcinomas, CNS tumors, and "other" SMNs (p < 0.0001). Patients with SMNs after childhood NHL having a reported CPS, mostly mismatch repair disorders, carried a very poor prognosis. Moreover, although outcome was favorable in some subtypes of SMNs after childhood NHL (carcinomas, lymphoid neoplasms), other SMNs such as myeloid neoplasms and CNS tumors had a dismal prognosis.
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http://dx.doi.org/10.1038/s41375-020-0841-xDOI Listing
February 2021

Health Locus of Control in Parents of Children with Leukemia and Associations with Their Life Perceptions and Depression Symptomatology.

Children (Basel) 2020 May 1;7(5). Epub 2020 May 1.

Pediatric Hematology, Oncology and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padua, 35128 Padua, Italy.

In childhood cancer, parents have an important role in the promotion of their children's wellbeing and in their adoption of a locus of control style towards their children's health. The current study aimed at identifying types of locus of control in parents of children with leukemia and the possible association with depressive symptomatology and current life perception. One hundred and four parents were recruited at the Hematology-Oncology Clinic of the Department of Woman's and Child's Health, University of Padua, one month after a leukemia diagnosis. Participants were Caucasian with a mean age of 37.28 years (SD = 5.89), mostly mothers (87.5%) and with a mean of 12.16 years of education (SD = 3.82). After signing the informed consent, they filled in the Ladder of Life, the Brief Symptom Inventory-18 and the Parental Health Locus of Control (PHLOC) questionnaires. Paired-samples -test ( = -14.42; df = 103; = 0.0001) showed that parents of children with leukemia were more inclined to have an external locus of control than an internal one. The hierarchical regression analysis model (R = 0.34; F = 4.32; = 0.0001) identified health professional influence (ß = -0.28; = 0.004), current life perception (ß = -0.3; = 0.013) and future life perception (ß = -0.26; = 0.012) as significant predictors of parental depression. Current life perception was best predicted (R = 0.25; F = 3.96; = 0.01) by the parental influence locus of control style (ß = 0.25; = 0.03). Improving trust in the medical staff care and strengthening the internal locus of control in parents could be a preventive program to cope with parental depression symptomatology.
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http://dx.doi.org/10.3390/children7050040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278609PMC
May 2020

Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

Bone Marrow Transplant 2020 09 19;55(9):1796-1809. Epub 2020 Mar 19.

Paediatric Haematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman-Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I-IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8-10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8-73.4) and 19.8% (95% CI 10.8-30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.
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http://dx.doi.org/10.1038/s41409-020-0863-zDOI Listing
September 2020

in Circulating Exosomes of Patients With Pediatric Anaplastic Large Cell Lymphoma: An Active Player?

Front Oncol 2020 27;10:238. Epub 2020 Feb 27.

Clinic of Pediatric Onco-Hematology, Department of Women's and Children's Health, University of Padova, Padova, Italy.

Emerging evidence indicates that extracellular vesicles, particularly exosomes, play a role in several biological processes and actively contribute to cancer development and progression, by carrying and delivering proteins, transcripts and small RNAs (sRNAs). There is high interest in studying exosomes of cancer patients both to develop non-invasive liquid biopsy tests for risk stratification and to elucidate their possible involvement in disease mechanisms. We profiled by RNA-seq the sRNA content of circulating exosomes of 20 pediatric patients with Anaplastic Large Cell Lymphoma (ALCL) and five healthy controls. Our analysis disclosed that non-miRNA derived sRNAs constitute the prominent fraction of sRNA loaded in exosomes and identified 180 sRNAs significantly more abundant in exosomes of ALCL patients compared to controls. YRNA fragments, accounting for most of exosomal content and being significantly increased in ALCL patients, were prioritized for further investigation by qRT-PCR. Quantification of fragments and full-length sequences disclosed that the latter are massively loaded into exosomes of ALCL patients with more advanced and aggressive disease. These results are discussed in light of recent findings on the role of in the modulation of tumor microenvironment.
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http://dx.doi.org/10.3389/fonc.2020.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056873PMC
February 2020

Histology of pediatric classic Hodgkin lymphoma: From diagnosis to prognostic stratification.

Pediatr Blood Cancer 2020 05 5;67(5):e28230. Epub 2020 Mar 5.

Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.

Aims: Classic Hodgkin lymphoma (cHL) is a common malignancy of the pediatric age. Although clinical-radiological features are routinely used for disease risk stratification, the role of tumor histology has yet to be defined. This study aimed to characterize the clinical-pathological features of a large cohort of pediatric cHL specifically investigating the relevance of tumor histology for the prognostic stratification of patients.

Methods And Results: The study considered 96 clinically annotated cases of pediatric cHL treated according to the AIEOP-LH2004 protocol. The following histological parameters were considered: (i) cHL variant; (ii) grade of nodular sclerosis (NS); (iii) staining for Bcl2 and p53, and expression of B-cell (BCA) and T-cell antigens (TCA) by Hodgkin/Reed-Sternberg cells. The study population consisted of 51 males and 45 females (median age: 13.6 years) with five-year overall and progression-free survival of 94% and 81%, respectively. Most cases featured NS morphology (96%) with a prevalence of NS1 over NS2 grades. Two NS2 variants were recognized (sarcomatous/syncytial and fibrohistiocytic). A consistent subset of cases disclosed positivity for BCA (34%), TCA (26%), p53 (13%), and Bcl2 (19%). Clinical-pathological correlations showed a more aggressive clinical course for NS2 over NS1 cases. The NS2 fibrohistiocytic variant was associated with the worst outcome. No other histological features correlated with prognosis.

Conclusions: Pediatric cHL is a clinically and histologically heterogeneous neoplasm. The majority of cases disclose NS morphology and aberrant phenotypes are frequently encountered. In the pediatric population, NS grading and NS2 subtyping bear significant prognostic impact.
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http://dx.doi.org/10.1002/pbc.28230DOI Listing
May 2020

Mucormycosis with peculiar aortic involvement in a child with acute lymphoblastic leukemia.

Pediatr Hematol Oncol 2020 Mar 17;37(2):164-169. Epub 2019 Dec 17.

Pediatric Onco-Hematology Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.

Among fungal infection, mucormycosis is a rare but severe etiology in immunocompromised patients. Lung and sinus are the usual sites; the involvement of blood vessels is also described. The diagnosis is a real challenge, because blood tests (galactomannan, beta-D-glucan) are negative and the only diagnostic tool is usually the biopsy of the affected zone. Aortitis is rare and usually caused by bacterial infection, fungal etiology is unusual and only episodic cases are reported in literature. Medical therapy alone is usually not sufficient and debilitating surgical intervention is required. We report the case of a child affected by B precursor acute lymphoblastic leukemia, presenting a systemic fungal infection complicated by aortitis, probably due to Mucor. The patient developed fever and pneumonia during the Induction phase of chemotherapy. At the beginning, the infection was treated as bacterial and the diagnosis of Mucor infection was possible only after surgical intervention with histological analysis. Medical therapy (antifungal) was not sufficient alone to cure the infection and an urgent surgical intervention was required. This case underlines the challenge in the diagnosis of mucomycosis, that should be suspected in case of prolonged fever during aplasia, not responding to standard antibiotic and antifungal therapies. Mucor infection often require a combined intervention, both medical and surgical to cure the infection.
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http://dx.doi.org/10.1080/08880018.2019.1691294DOI Listing
March 2020

The Developmental Pathways of Preschool Children with Acute Lymphoblastic Leukemia: Communicative and Social Sequelae One Year after Treatment.

Children (Basel) 2019 Aug 13;6(8). Epub 2019 Aug 13.

Department of Women and Child's Health, Pediatric Hematology, Oncology and Stem Cell Transplant Center, University of Padua, 35127 Padova, Italy.

Early childhood is considered to be a period of rapid development, with the acquisition of abilities predicting future positive school competences. Motor, cognitive, and social difficulties related to cancer therapies heavily impact the development of children with cancer. This study focused on two main aims: To assess the developmental pathways of preschool children with acute lymphoblastic leukemia one year post-treatment and to compare these abilities both with those of a control group of healthy peers and with Italian norms. Forty-four children and their families, recruited through the Hematology-Oncologic Clinic of the Department of Child and Woman Health (University of Padua), agreed to participate in this study. The children's mean age was 4.52 years (SD = 0.94, range = 2.5-6 years), equally distributed by gender, all diagnosed with acute lymphoblastic leukemia. Matched healthy peers were recruited through pediatricians' ambulatories. Each family was interviewed adopting the Vineland adaptive behavior scales. Paired sample Wilcoxon tests revealed that children were reported to have significantly more developmental difficulties than their healthy peers. When compared with Italian norms, they scored particularly low in verbal competence, social, and coping skills. No significant association was found between treatment variables and developmental abilities. These findings suggest that the creation of specialized interventions, both for parents and children, may fill the possible delays in children's development probably due to stress, lack of adequate stimulation, or difficult adaptation.
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http://dx.doi.org/10.3390/children6080092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721313PMC
August 2019

Predictors of mortality after admission to pediatric intensive care unit in oncohematologic patients without history of hematopoietic stem cell transplantation: A single-center experience.

Pediatr Blood Cancer 2019 10 28;66(10):e27892. Epub 2019 Jun 28.

Pediatric Intensive Care Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.

Background: Pediatric oncohematologic patients are a high-risk population for clinical deterioration that might require pediatric intensive care unit (PICU) admission. Several studies have described outcomes and mortality predictors for patients post hematopoietic stem cell transplantation (HSCT), but fewer data exist regarding the category of non-HSCT patients.

Procedure: All oncohematologic non-HSCT patients ≤18 years requiring PICU admission from 1998 to 2015 in our tertiary-care academic hospital were retrospectively evaluated by means of the pediatric hematology-oncology unit database and the Italian PICUs data network database. We assessed the relation between demographic and clinical characteristics and 90-day mortality after PICU admission.

Results: Of 3750 hospitalized oncohematologic patients, 3238 were non-HSCT and 63 (2%) of them were admitted to the PICU. Patients were mainly affected by hematological malignancies (70%) and mostly were in the induction-therapy phase. The main reasons for admission were respiratory failure (40%), sepsis (25%), and seizures (16%). The median PICU stay was 5 days (range 1-107). The mortality rate at PICU discharge was 30%, and at 90 days it was 35%. Fifty-five percent of deaths happened in the first 2 days of the PICU stay. Cardiac arrest (P = .007), presence of disseminated intravascular coagulation (DIC, P = .007), and acute kidney injury (AKI) at PICU admission (P < .001) and during PICU stay (P = .021) were significant predictors of mortality in the multivariate analysis. Respiratory failure and mechanical ventilation were not associated with mortality.

Conclusions: A relatively small percentage of non-HSCT patients required PICU admission, but the mortality rate was still high. Hemodynamic instability, DIC, and AKI, but not respiratory failure, were significant predictors of mortality.
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http://dx.doi.org/10.1002/pbc.27892DOI Listing
October 2019

The revised International Paediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS): a test of applicability.

Br J Haematol 2019 09 27;186(6):e201-e203. Epub 2019 Jun 27.

Paediatric Haemato-Oncology Clinic, Hospital-University of Padova, Padova, Italy.

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http://dx.doi.org/10.1111/bjh.16079DOI Listing
September 2019

Successful Treatment of an EBV-positive Diffuse Large B-Cell Lymphoma in a Patient With Trisomy 21.

J Pediatr Hematol Oncol 2020 08;42(6):e472-e474

Department of Women's and Children's Health, Pediatric Hematology-Oncology Unit, University of Padova.

Diffuse large B-cell Lymphoma (DLBCL) secondary to a chronic severe Epstein-Barr virus (EBV) infection has not been previously described in a patient with trisomy 21. Here we report the case of a 14-year-old girl with trisomy 21 with impaired control of EBV and DLBCL. She was cured with dose-adapted chemotherapy and hematopoietic stem cell transplantation without severe treatment-related toxicity. We describe the first case of EBV-positive DLBCL in a patient with trisomy 21 and we propose a treatment modality for this rare entity.
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http://dx.doi.org/10.1097/MPH.0000000000001502DOI Listing
August 2020