Publications by authors named "Claudio Favre"

59 Publications

Childhood cancer in Italy: background, goals, and achievements of the Italian Paediatric Hematology Oncology Association (AIEOP).

Tumori 2021 Apr 20:3008916211007934. Epub 2021 Apr 20.

Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, University of Torino, Piemonte, Italy.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.
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http://dx.doi.org/10.1177/03008916211007934DOI Listing
April 2021

β3-Adrenoreceptors as ROS Balancer in Hematopoietic Stem Cell Transplantation.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

In the last decades, the therapeutic potential of hematopoietic stem cell transplantation (HSCT) has acquired a primary role in the management of a broad spectrum of diseases including cancer, hematologic conditions, immune system dysregulations, and inborn errors of metabolism. The different types of HSCT, autologous and allogeneic, include risks of severe complications including acute and chronic graft-versus-host disease (GvHD) complications, hepatic veno-occlusive disease, lung injury, and infections. Despite being a dangerous procedure, it improved patient survival. Hence, its use was extended to treat autoimmune diseases, metabolic disorders, malignant infantile disorders, and hereditary skeletal dysplasia. HSCT is performed to restore or treat various congenital conditions in which immunologic functions are compromised, for instance, by chemo- and radiotherapy, and involves the administration of hematopoietic stem cells (HSCs) in patients with depleted or dysfunctional bone marrow (BM). Since HSCs biology is tightly regulated by oxidative stress (OS), the control of reactive oxygen species (ROS) levels is important to maintain their self-renewal capacity. In quiescent HSCs, low ROS levels are essential for stemness maintenance; however, physiological ROS levels promote HSC proliferation and differentiation. High ROS levels are mainly involved in short-term repopulation, whereas low ROS levels are associated with long-term repopulating ability. In this review, we aim summarize the current state of knowledge about the role of β3-adrenoreceptors (β3-ARs) in regulating HSCs redox homeostasis. β3-ARs play a major role in regulating stromal cell differentiation, and the antagonist SR59230A promotes differentiation of different progenitor cells in hematopoietic tumors, suggesting that β3-ARs agonism and antagonism could be exploited for clinical benefit.
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http://dx.doi.org/10.3390/ijms22062835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000316PMC
March 2021

Planned hematopoietic stem cell transplantation in a 17-month-old patient with high-risk acute myeloid leukemia and persistent SARS-CoV-2 infection.

Transfusion 2021 05 25;61(5):1657-1659. Epub 2021 Mar 25.

Pediatric Haematology/Oncology and HSCT Department, Meyer Children's University Hospital, Florence, Italy.

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http://dx.doi.org/10.1111/trf.16361DOI Listing
May 2021

Post-transplantation lymphoproliferative disorder after haematopoietic stem cell transplantation.

Ann Hematol 2021 Apr 6;100(4):865-878. Epub 2021 Feb 6.

Paediatric Haematology/Oncology and HSCT Department, Anna Meyer Children's University Hospital, Viale G. Pieraccini, 24, 50139, Florence, Italy.

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication of haematopoietic stem cell transplantation (HSCT), occurring in a setting of immune suppression and dysregulation. The disease is in most cases driven by the reactivation of the Epstein-Barr virus (EBV), which induces B cell proliferation through different pathomechanisms. Beyond EBV, many factors, variably dependent on HSCT-related immunosuppression, contribute to the disease development. PTLDs share several features with primary lymphomas, though clinical manifestations may be different, frequently depending on extranodal involvement. According to the WHO classification, histologic examination is required for diagnosis, allowing also to distinguish among PTLD subtypes. However, in cases of severe and abrupt presentation, a diagnosis based on a combination of imaging studies and EBV-load determination is accepted. Therapies include prophylactic and pre-emptive interventions, aimed at eradicating EBV proliferation before symptoms onset, and targeted treatments. Among them, rituximab has emerged as first-line option, possibly combined with a reduction of immunosuppression, while EBV-specific cytotoxic T lymphocytes are effective and safe alternatives. Though prognosis remains poor, survival has markedly improved following the adoption of the aforementioned treatments. The validation of innovative, combined approaches is the future challenge.
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http://dx.doi.org/10.1007/s00277-021-04433-yDOI Listing
April 2021

Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia.

Front Immunol 2020 15;11:620046. Epub 2021 Jan 15.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.

gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.
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http://dx.doi.org/10.3389/fimmu.2020.620046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843414PMC
January 2021

Preliminary Study on β3-Adrenoreceptor as Predictor Marker of Relapse in Ewing Sarcoma Patients.

Biomedicines 2020 Oct 13;8(10). Epub 2020 Oct 13.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

Ewing sarcoma (EWS) is a paediatric aggressive malignant tumour of bones and soft tissues. Multidisciplinary chemotherapies, surgical resection, and radiation represent the only strategies counteracting the disease, however spreading and relapse of disease still remain a clinical issue. Circulating tumour cells (CTCs) are an important feature of EWS but the prognostic significance has not been, yet, clarified. CTCs have been found both in patients with localized disease and in those who recur or metastasize. The identification of markers that can detect recurrences and metastasis remains an important challenge for research. Unfortunately, even most of patients with localized cancer relapsed and the reason has not yet been fully understood. In this clinical study on EWS patients, we evaluated the expression of CD99 antigen and beta-3 adrenergic receptor (β3-AR) on CTCs and bioptic derived cells by flow cytometry. The preliminary data revealed a higher β3-AR expression on cells derived from metastatic or relapsed patients, suggesting a role for the β3-AR as a possible predictive maker of disease recurrence in both patients with metastatic and localized disease.
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http://dx.doi.org/10.3390/biomedicines8100413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600453PMC
October 2020

β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy.

Front Immunol 2020 2;11:2098. Epub 2020 Sep 2.

Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children's Hospital, Florence, Italy.

Understanding the mechanisms of immune tolerance is currently one of the most important challenges of scientific research. Pregnancy affects the immune system balance, leading the host to tolerate embryo alloantigens. Previous reports demonstrated that β-adrenergic receptor (β-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of β2-ARs, but recently we have demonstrated that also β3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that β3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that β3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of β3-AR, promotes the biological shift toward a tolerant immunophenotype and that this is the same trick that embryo and cancer use to create an aura of immune-tolerance in a competent immune environment. This study confirms the analogies between fetal development and tumor progression and suggests that the expression of β3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.
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http://dx.doi.org/10.3389/fimmu.2020.02098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492666PMC
May 2021

Beta-Blockers and Berberine: A Possible Dual Approach to Contrast Neuroblastoma Growth and Progression.

Oxid Med Cell Longev 2020 12;2020:7534693. Epub 2020 Aug 12.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

The use of nutraceuticals during cancer treatment is a long-lasting debate. Berberine (BBR) is an isoquinoline quaternary alkaloid extracted from a variety of medicinal plants. BBR has been shown to have therapeutic effects in different pathologies, particularly in cancer, where it affects pathways involved in tumor progression. In neuroblastoma, the most common extracranial childhood solid tumor, BBR, reduces tumor growth by regulating both stemness and differentiation features and by inducing apoptosis. At the same time, the inhibition of -adrenergic signaling leads to a reduction in growth and increase of differentiation of neuroblastoma. In this review, we summarize the possible beneficial effects of BBR in counteracting tumor growth and progression in various types of cancer and, in particular, in neuroblastoma. However, BBR administration, besides its numerous beneficial effects, presents a few side effects due to inhibition of MAO A enzyme in neuroblastoma cells. Therefore, herein, we proposed a novel therapeutic strategy to overcome side effects of BBR administration consisting of concomitant administration of BBR together with -blockers in neuroblastoma.
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http://dx.doi.org/10.1155/2020/7534693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443044PMC
May 2021

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance.

Int J Mol Sci 2020 Jun 12;21(12). Epub 2020 Jun 12.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed β3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, β3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias.
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http://dx.doi.org/10.3390/ijms21124210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352890PMC
June 2020

Current Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor.

Cancers (Basel) 2020 May 30;12(6). Epub 2020 May 30.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, 50139 Florence, Italy.

Melanoma is one of the most aggressive types of cancer and the most deadly skin cancer. According to World Health Organization, about 132,000 melanoma skin cancers occur globally each year. Thanks to the efficacy of new therapies, life expectation has been improved over the last years. However, some malignant melanomas still remain unresponsive to these therapies. The β-adrenergic system, among its many physiological roles, has been recognized as the main mediator of stress-related tumorigenic events. In particular, catecholamine activation of β-adrenergic receptors (β-ARs) affects several processes that sustain cancer progression. Among the β-AR subtypes, the β3-AR is emerging as an important regulator of tumorigenesis. In this review, we summarize data of different experimental studies focused on β3-AR involvement in tumor development in various types of cancer and, particularly, in melanoma. Taken together, the preclinical evidences reported in this review demonstrate the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression. Therefore, a need exists to further disseminate this new concept and to investigate more deeply the role of β3-AR as a possible therapeutic target for counteracting melanoma progression at clinical level.
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http://dx.doi.org/10.3390/cancers12061415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352170PMC
May 2020

Nutraceutical Boom in Cancer: Inside the Labyrinth of Reactive Oxygen Species.

Int J Mol Sci 2020 Mar 12;21(6). Epub 2020 Mar 12.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

In recent years, epidemiological studies have shown that food is a very powerful means for maintaining a state of well-being and for health prevention. Many degenerative, autoimmune and neoplastic diseases are related to nutrition and the nutrient-organism interaction could define the balance between health and disease. Nutrients and dietary components influence epigenetic phenomena and modify drugs response; therefore, these food-host interactions can influence the individual predisposition to disease and its potential therapeutic response. Do nutraceuticals have positive or negative effects during chemotherapy? The use of nutraceutical supplements in cancer patients is a controversial debate without a definitive conclusion to date. During cancer treatment, patients take nutraceuticals to alleviate drug toxicity and improve long-term results. Some nutraceuticals may potentiate the effect of cytotoxic chemotherapy by inducing cell growth arrest, cell differentiation, and alteration of the redox state of cells, but in some cases, high levels of them may interfere with the effectiveness of chemotherapy, making cancer cells less reactive to chemotherapy. In this review, we highlighted the emerging opinions and data on the pros and cons on the use of nutraceutical supplements during chemotherapy.
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http://dx.doi.org/10.3390/ijms21061936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139678PMC
March 2020

β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment.

Int J Mol Sci 2020 Feb 20;21(4). Epub 2020 Feb 20.

Hematology-Oncology Department, "Anna Meyer Children's Hospital", 50139 Florence, Italy.

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of β-adrenergic signaling in enhancing tumor growth through β2-adrenoreceptors (β2-ARs) has been confirmed in different cancer models, but the role played by the β3-adrenergic receptor (β3-AR) has recently emerged. Previous studies showed that β3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological β3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that β3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of β3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that β3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression.
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http://dx.doi.org/10.3390/ijms21041420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073111PMC
February 2020

Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study.

Bone Marrow Transplant 2020 10 29;55(10):1918-1927. Epub 2020 Jan 29.

Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Torino, Italy.

Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 × 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
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http://dx.doi.org/10.1038/s41409-020-0806-8DOI Listing
October 2020

Spotlight on ROS and 3-Adrenoreceptors Fighting in Cancer Cells.

Oxid Med Cell Longev 2019 14;2019:6346529. Epub 2019 Dec 14.

Oncohematology Unit, Department of Pediatric Oncology, A. Meyer Children's University Hospital, Florence 50139, Italy.

The role of ROS and RNS is a long-standing debate in cancer. Increasing the concentration of ROS reaching the toxic threshold can be an effective strategy for the reduction of tumor cell viability. On the other hand, cancer cells, by maintaining intracellular ROS concentration at an intermediate level called "mild oxidative stress," promote the activation of signaling that favors tumor progression by increasing cell viability and dangerous tumor phenotype. Many chemotherapeutic treatments induce cell death by rising intracellular ROS concentration. The persistent drug stimulation leads tumor cells to simulate a process called hormesis by which cancer cells exhibit a biphasic response to exposure to drugs used. After a first strong response to a low dose of chemotherapeutic agent, cancer cells start to decrease the response even if high doses of drugs were used. In this framework, 3-adrenoreceptors (3-ARs) fit with an emerging antioxidant role in cancer. 3-ARs are involved in tumor proliferation, angiogenesis, metastasis, and immune tolerance. Its inhibition, by the selective 3-ARs antagonist (SR59230A), leads cancer cells to increase ROS concentration thus inducing cell death and to decrease NO levels thus inhibiting angiogenesis. In this review, we report an overview on reactive oxygen biology in cancer cells focusing on 3-ARs as new players in the antioxidant pathway.
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http://dx.doi.org/10.1155/2019/6346529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942895PMC
June 2020

β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P modulation.

Oncogene 2020 01 2;39(2):368-384. Epub 2019 Sep 2.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P signaling.
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http://dx.doi.org/10.1038/s41388-019-0993-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949192PMC
January 2020

β3-Adrenoreceptor Activity Limits Apigenin Efficacy in Ewing Sarcoma Cells: A Dual Approach to Prevent Cell Survival.

Int J Mol Sci 2019 Apr 30;20(9). Epub 2019 Apr 30.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

Ewing Sarcoma (ES) is an aggressive paediatric tumour where oxidative stress and antioxidants play a central role in cancer therapy response. Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression. Flavonoid intake can affect free radical and nutritional status in children receiving cancer treatment, but it is not clear if it can arrest cancer progression. In particular, apigenin may enhance the effect of cytotoxic chemotherapy by inducing cell growth arrest, apoptosis, and by altering the redox state of the cells. Little is known about the use of apigenin in paediatric cancer. Recently, β3-adrenergic receptor (β3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS. In this study we show that apigenin induces cell death in ES cells by modulating apoptosis, but not increasing ROS content. Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of β3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying β3-AR as a potential discriminating factor that could address the use of apigenin in ES.
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http://dx.doi.org/10.3390/ijms20092149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540192PMC
April 2019

β -Adrenoceptor as a potential immuno-suppressor agent in melanoma.

Br J Pharmacol 2019 07 9;176(14):2509-2524. Epub 2019 May 9.

Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, Meyer University Children's Hospital, Florence, Italy.

Background And Purpose: Stress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β -adrenoceptors have been identified as new targets in treating melanoma. Recently, β -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β -adrenoceptors in immune-tolerance regulation.

Experimental Approach: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β - or β -adrenoceptors were used.

Key Results: Only β -, but not β -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes.

Conclusions And Implications: Our data suggest that β -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth.

Linked Articles: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592854PMC
July 2019

Late mortality and causes of death among 5-year survivors of childhood cancer diagnosed in the period 1960-1999 and registered in the Italian Off-Therapy Registry.

Eur J Cancer 2019 03 14;110:86-97. Epub 2019 Feb 14.

Department of Hematology and Oncology, University Hospital AOU Meyer, Florence, Italy.

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.
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http://dx.doi.org/10.1016/j.ejca.2018.12.021DOI Listing
March 2019

CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface.

Clin Immunol 2019 04 8;201:15-19. Epub 2019 Feb 8.

Department of "NEUROFARBA", Section of Child's Health, University of Florence, Italy; Department of Haematology-Oncology "Anna Meyer" Children's Hospital, Florence, Italy. Electronic address:

CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease.
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http://dx.doi.org/10.1016/j.clim.2019.02.003DOI Listing
April 2019

3-Adrenoreceptors Control Mitochondrial Dormancy in Melanoma and Embryonic Stem Cells.

Oxid Med Cell Longev 2018 13;2018:6816508. Epub 2018 Nov 13.

Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, A. Meyer Children's University Hospital, Florence, Italy.

The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that 3-adrenergic receptor (3-AR) is involved in tumor progression, playing an important role in metastasis. Among -adrenergic receptors, 3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. 3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, 3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that 3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The 3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific 3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of 3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.
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http://dx.doi.org/10.1155/2018/6816508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258109PMC
January 2019

β-Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β -adrenoceptors.

Br J Pharmacol 2019 07 18;176(14):2496-2508. Epub 2018 Dec 18.

Department of Biology, University of Pisa, Pisa, Italy.

Stress plays a role in tumourigenesis through catecholamines acting at β-adrenoceptors including β -, β - and β -adrenoceptors, and the use of β-adrenoceptor antagonists seems to counteract tumour growth and progression. Preclinical evidence and meta-analysis data demonstrate that melanoma shows a positive response to β-adrenoceptor blockers and in particular to propranolol acting mainly at β - and β -adrenoceptors. Although evidence suggesting that β -adrenoceptors may play a role as a therapeutic target in infantile haemangiomas has been recently reviewed, a comprehensive analysis of the data available from preclinical studies supporting a possible role of β -adrenoceptors in melanoma was not available. Here, we review data from the literature demonstrating that propranolol may be effective at counteracting melanoma growth, and we provide preclinical evidence that β -adrenoceptors may also play a role in the pathophysiology of melanoma, thus opening the door for further clinical assays trying to explore β -adrenoceptor blockers as novel alternatives for its treatment. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592869PMC
July 2019

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.

Front Immunol 2018 1;9:2411. Epub 2018 Nov 1.

Seattle Children's Research Institute, University of Washington, Seattle, WA, United States.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the gene. In addition, there has been an increasing number of patients with wild-type gene and, in some cases, mutations in other immune regulatory genes. To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of mutation-positive (IPEX patients) with those from mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Forty-four distinct variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.
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http://dx.doi.org/10.3389/fimmu.2018.02411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223101PMC
October 2019

Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia.

Blood 2018 12 22;132(24):2594-2607. Epub 2018 Oct 22.

Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Bambino Gesù, Rome, Italy.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients ( < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD ( < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively ( < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS ( < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.
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http://dx.doi.org/10.1182/blood-2018-07-861575DOI Listing
December 2018

Classical pediatric Hodgkin lymphoma in very young patients: the Italian experience.

Leuk Lymphoma 2019 03 10;60(3):696-702. Epub 2018 Oct 10.

u Oncoematologia Pediatrica , Azienda Ospedaliera Universitaria Ospedale Sant'Anna , Ferrara , Italy.

Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.
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http://dx.doi.org/10.1080/10428194.2018.1493732DOI Listing
March 2019

Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

Bone Marrow Transplant 2019 02 13;54(2):275-283. Epub 2018 Jun 13.

Oncoematologia Pediatrica, I.R.C.C.S. Ospedale Pediatrico Bambino Gesù, Roma, Italy.

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.
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http://dx.doi.org/10.1038/s41409-018-0259-5DOI Listing
February 2019

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy.

Biol Blood Marrow Transplant 2018 06 2;24(6):1223-1231. Epub 2018 Feb 2.

Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy; Department of Pediatric Sciences, University of Pavia, Italy. Electronic address:

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34 cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.022DOI Listing
June 2018

The dawn of "immune-revolution" in children: early experiences with checkpoint inhibitors in childhood malignancies.

Cancer Chemother Pharmacol 2017 Dec 24;80(6):1047-1053. Epub 2017 Oct 24.

Department of Pediatric Oncology, Hematology, and Transplants, Anna Meyer Children's Hospital, Florence, Italy.

Modern immunotherapy with checkpoint inhibitors has changed clinical practice of adult patients with advanced cancer. Blockade of CTLA-4 and PD-1 pathways have shown survival benefits in different diseases. In children, combination of surgery, radiotherapy and chemotherapy have improved survival rates of solid tumors. However, the outcomes for subsets of patients such as those with high-grade, refractory, or metastatic disease remain extremely poor. Currently, the treatment of these patients is almost exclusively based on standard chemotherapy. The significant proportion of pediatric cancers with high number of mutations and subsequent high expression of neoantigens, together with the potential prognostic role of the immunosuppressive checkpoint molecules (CTLA-4, PD-L1) can represent a promising rationale that support the use of checkpoint inhibitors. We made a revision about emerging data regarding safety and activity of checkpoint inhibitors in children with solid tumors.
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http://dx.doi.org/10.1007/s00280-017-3450-2DOI Listing
December 2017

Spinal cord involvement in two children with posterior reversible encephalopathy syndrome.

CNS Oncol 2017 10 6;6(4):287-290. Epub 2017 Oct 6.

Neuro-Oncology Unit, Department of Pediatric Oncology, Anna Meyer Children's University Hospital, Florence 50139, Italy.

Spinal cord involvement (SCI) is a rare feature of posterior reversible encephalopathy syndrome (PRES), especially in children. SCI is generally symptomatic, and may have a different outcome compared with encephalic localization of PRES. We reported about two cases of SCI in pediatric patients with PRES, after multimodal anticancer therapies, including radiotherapy, chemotherapy and targeted agents.
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http://dx.doi.org/10.2217/cns-2017-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004885PMC
October 2017