Unveiling the genetic landscape of suspected congenital dyserythropoietic anemia type I: A retrospective cohort study of 36 patients.

Congenital Dyserythropoietic Anemia type I (CDA I) is a rare hereditary condition characterized by macrocytic/normocytic anemia, splenomegaly, iron overload, and distinct abnormalities during late erythropoiesis, particularly internuclear bridges between erythroblasts. Diagnosis of CDA I remains challenging due to its rarity, clinical heterogeneity, and overlapping phenotype with other rare hereditary anemias. In this case series, we present 36 patients with suspected CDA I. A molecular diagnosis was successfully established in 89% of cases, identifying 16 patients with CDA I through the presence of 18 causative variants in the CDAN1 or CDIN1 genes. Transcriptomic analysis of CDIN1 variants revealed impaired erythroid differentiation and disruptions in transcription, cell proliferation, and histone regulation. Conversely, 16 individuals received a different diagnosis, primarily pyruvate kinase deficiency. Comparisons between CDA I and non-CDA I patients revealed no significant differences in erythroblast morphological features. However, hemoglobin levels and red blood cell count differed between the two groups, with non-CDA I subjects being more severely affected. Notably, most patients with severe anemia belonged to the non-CDA I group (82% non-CDA I vs. 18% CDA I), with a subsequent absolute prevalence of transfusion dependency among non-CDA I patients (100% vs. 41.7%). All patients exhibited reduced bone marrow responsiveness to anemia, with a more pronounced effect observed in non-CDA I patients. Erythropoietin levels were significantly higher in non-CDA I patients compared to CDA I patients. However, evaluations of erythroferrone, soluble transferrin receptor, and hepcidin revealed no significant differences in plasma concentration between the two groups.

From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models.

BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. METHODS: Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. RESULTS: Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. CONCLUSIONS: PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

Current practices for nutritional evaluation and care during the treatment of pediatric oncology patients: a survey among AIEOP centers.

Nutritional status plays a crucial role in the mortality rates of the pediatric oncology patients. However, there is a lack of systematic approaches for nutritional assessment in this population. This study aims to assess the current practice for nutritional assessment and care of pediatric cancer patients in Italy. A 25-items web-based, nation-wide questionnaire was circulated as of January 9, 2023 among physicians within the AIEOP network, composed of 49 national centers, out of which 21 routinely perform HCT. This survey examined the practices of 21 Italian pediatric oncology centers, revealing significant heterogeneity in nutritional practices. Only half of the centers routinely assessed all patients, utilizing different clinical and biochemical parameters. The use of neutropenic diets remained prevalent after chemotherapy or stem cell transplantation. CONCLUSION: This study underscores the pressing need for unified recommendations to improve nutritional care and potentially enhance outcomes for pediatric cancer patients. WHAT IS KNOWN: • The assessment and support of nutrition are gaining interest in the overall care of children with cancer. • The assessment and management of nutritional needs in pediatric cancer patients, including those undergoing hematopoietic cell transplantation, currently lack a systematic approach. WHAT IS NEW: • There is considerable variability in the nutritional assessment and support among Italian centers treating pediatric patients with cancer. • To enhance nutritional assessment and support for pediatric cancer patients, it is essential to establish shared national and international guidelines.

Use of music therapy in pediatric oncology: an Italian AIEOP multicentric survey study in the era of COVID-19.

Music therapy (MT) is a complementary therapy offered to children, young adults, and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in this survey. 27/32 (84.4%) centers belonging to the Infections and Supportive Therapy Working Group of Association of Pediatric Hematology and Oncology (AEIOP) completed in 2 different time points (T1 and T2) an online survey on MT, before and after COVID-19 pandemia. Different kinds of music approach were used taking care of patients in 21/27 centers, while in 14/21 (66%), a specific project of MT conducted by a music therapist was present. In 6/14 centers, MT activities were delivered for < 3 h/week, in 3 centers for > 3 and < 10 h/week, and in the remaining 5 for > 3 h/week. MT sessions were in different areas, day hospital, or ward (patient rooms, operating rooms, waiting rooms), on an individual basis or by groups. Patients were invited to MT by psychologists, caring physician, or nurse, or on equipé decision. MT was evaluated with tools self-made by music therapist in 11/14 centers. After COVID-19, MT has been withdrawn in 3 centers, sessions in the waiting rooms were reduced, individual sessions were preferred, and enrollment by multidisciplinary teams increased. CONCLUSION: This survey represents the starting platform to compare and discuss different experience of MT in AIEOP centers, to implement MT in pediatric oncology for a more qualified assistance to patients, and to improve quality of care. WHAT IS KNOWN: • Music therapy in pediatric oncology and palliative care can be used for the management and prevention of various somatic and psychological symptoms of patients and often is provided to children together with their families. • In Italy the application of Music therapy in the AIEOP pediatric oncology centers is constantly increasing, but due to the outbreak of Covid-19 Pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures. WHAT IS NEW: • Although the majority of Centres did not abrogate MT interventions, judgment about limitation should be carefully taken since MT helps children and even more adolescents in their fight against cancer. • The best practice of Music therapy in pediatric oncology requires communication and collaboration among qualified music therapists and multidisciplinary care team, using a model of family-centered care that actively involves parents/ caregivers in assessment, treatment planning, and care delivery.

Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network.

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

Acute chemotherapy-induced nausea and vomiting in children with cancer: Still waiting for a common consensus on treatment.

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common treatment side-effects, and remains a significant concern, in children undergoing chemotherapy. Although adult patients receive chemotherapy regimens combined with appropriate standardized antiemetic treatment, children can receive markedly varying antiemetic treatments. A narrative review of CINV was performed regarding CINV definition, scoring system, prevention and treatment, specifically focussing on studies conducted with paediatric oncology patients. The review highlighted a lack of rigorously developed CINV scoring systems and standardized CINV pharmacological treatment for paediatric oncology patients. Different scoring systems were found to identify potential risk factors for CINV associated with the use of several different antiemetic drugs, however, few studies have been performed in children undergoing chemotherapy. Thus, CINV remains a distressing and partially controlled side-effect in the paediatric patient population. To reduce emesis and improve quality of life in paediatric oncology patients, standardized antiemetic treatment may be preferred, using a unique CINV scoring system that accounts for the emetogenic level of the chemotherapy regimen adopted and the children's clinical characteristics.

Safe lumbar puncture under analgo-sedation in children with acute lymphoblastic leukemia.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) undergo multiple lumbar punctures (LPs) during their course of treatment for diagnostic and therapeutic purposes. LP is a stressful and painful procedure, affecting the quality of life of these children. Procedural analgo-sedation might improve the child's comfort and prevent the child's movements, reducing the risk of traumatic lumbar puncture with blasts (TLP+), mainly at diagnosis, when higher numbers of blast cells are circulating in the peripheral blood. The aim of this study was to evaluate the safety and efficacy of procedural analgo-sedation in children with ALL. METHODS: From September 2006 to November 2008, we performed a total of 252 lumbar punctures under deep sedation with propofol and ketamine in 25 children with ALL treated at our division. During the procedures, vital parameters were monitored and side effects were recorded. The efficacy of deep sedation was evaluated using Ramsay and Children's Hospital Eastern Ontario Pain scales. Cerebrospinal fluid was collected for chemical and cytological examinations. RESULTS: In all patients a satisfactory sedation and analgesia were achieved. The evaluation of vital parameters did not show any significant variation compared to baseline values. No side effects were recorded. Only 3 (1.2 %) of 252 lumbar punctures resulted in traumatic effects. CONCLUSION: To strongly improve comfort and quality of life of children with ALL and reduce the risk of TLP+ mainly at diagnosis, we recommend performing the lumbar punctures under analgo-sedation because it is a safe and effective procedure.

Efficacy and safety of transdermal buprenorphine in the management of children with cancer-related pain.

BACKGROUND: The current study investigated the efficacy, safety, tolerability, and compliance of a transdermal buprenorphine delivery system for the management of chronic cancer pain in the pediatric population. PROCEDURE: Sixteen pediatric patients with moderate to severe cancer-related pain not satisfactorily controlled with previous non-opioid therapies were enrolled. Transdermal buprenorphine was administered following a 72 hour schedule and rescue medication (tramadol) was allowed for breakthrough pain. Pain intensity was assessed using the Wong-Baker faces pain rating scale (WBS) and other parameters related to the global quality of life were evaluated. Children's evaluations of efficacy, compliance, and tolerability were recorded using numerical scales. Adverse events were monitored during the study and the medications needed to control opioid-related nausea and constipation were recorded. RESULTS: Eleven patients (68.75%) responded to transdermal buprenorphine after 2 weeks of treatment. Pain intensity measured with WBS decreased from 6.25 at baseline to 1.38 at Day +60 (P < 0.001). All outcome measures of global quality of life (quality of sleep, alimentation, play and activity, speech, and crying) significantly improved over the 60-day study period. Children's evaluations of compliance and tolerability of the drug were always positive over the entire period of treatment. No severe adverse events were recorded. Opioid-related nausea was well controlled with medication on request, and the need for laxative therapy was greater at the end of the second month of treatment. CONCLUSIONS: Transdermal buprenorphine was found to represent an efficient, safe and well tolerated approach to the management of children's chronic cancer pain.

Cardiac metastases of Ewing sarcoma detected by 18F-FDG PET/CT.

Positron emission tomography (PET) is widely used in the diagnostic evaluation and staging of different malignant tumors. The role of PET/computed tomographic scan in detecting distant metastases in the workup of Ewing sarcoma in children or young adults is less well defined. We report a case of a boy affected by a metastatic Ewing sarcoma with cardiac asymptomatic metastasis detected by F-FDG PET/computed tomography.

Treatment of pharyngeal non-Hodgkin lymphoma in a patient with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is characterized by primary immunodeficiency, thrombocytopenia and eczema. Patients with WAS have an increased risk to develop tumors. Non-Hodgkin lymphoma (NHL) represents the most common malignancy occurring in WAS-affected patients, diffuse-large-B-cell lymphoma is the most frequently encountered variant. We describe a case of a patient with WAS and NHL in the pharynx, an atypical tumor site presentation. The patient was successfully treated with a reduced dose chemotherapy regimen plus anti-CD20 monoclonal antibody. He is in complete remission 3 years from the start of treatment.

The role of diet on the clinical pharmacology of oral antineoplastic agents.

PURPOSE: The number of oral anticancer agents has greatly increased in recent years. It is a well-known fact that food intake can induce significant variations in the bioavailability of these drugs. The aim of this review is to describe the interactions between diet and oral anticancer drugs in terms of the possible effects of such interactions on reducing the antineoplastic activity of the drug or increasing its side effects. METHODS: This was an analytical study of the numerous mechanisms leading to changes in the bioavailability of oral antineoplastic agents due to diet. RESULTS: Food-drug interactions can induce a delay, decrease or increase in the absorption of the oral chemotherapeutic agent. The concomitant intake of food and antineoplastic drugs influence the pharmacokinetic and pharmacodynamic drug processes depending on the composition of the food consumed and the specific interactions of the food with transport mechanisms (p-glycoprotein, multidrug resistance proteins) and intestinal enzymatic systems (cytochrome P450). CONCLUSIONS: In prescribing an oral anticancer agent, clinicians must consider the possibility that the consumption of specific food items has the potential to interfere with the pharmacokinetics and pharmacodynamics of the prescribed drug.

Management of children with thrombocytopenia-absent radius syndrome: an institutional experience.

AIM: Thrombocytopenia-absent radius (TAR) syndrome is characterised by bilateral absence of the radii in the presence of both thumbs and hypomegakaryocytic thrombocytopenia. We report our experience of three patients affected by TAR syndrome presenting with different clinical manifestations focusing on the management of these patients. METHODS AND RESULTS: We propose the use of long-term central venous catheters to reduce discomfort because of repeated vein punctures in search for a venous access, rendered difficult by upper limbs abnormalities. CONCLUSIONS: It is important to improve the quality of life of affected patients.

How to manage vaccinations in children with cancer.

The optimal use of routine childhood immunizations in children with malignancy is still a matter of debate. Despite their higher risk of contracting vaccine preventable diseases and of suffering important complications, there is little understanding of the magnitude of the possible benefit of administering active immunization in this population due to a paucity of clinical trial data. Our review focuses on the management of children with cancer and offers some suggestions regarding their vaccination schedules.

Expression of liquoral neuroprotection markers in children with acute lymphoblastic leukemia.

Brain damage related to intrathecal methotrexate in children with acute lymphoblastic leukemia (ALL) is still unclear. Neuroinflammatory mechanisms and intracerebral production of specific biomarkers, play a key role in determining neuroprotective mechanisms after brain injury. To determine whether the CSF concentrations of neuron-specific enolase (NSE), neurotrophic factors and doublecortin (DCX) are influenced by repeated intrathecal methotrexate administrations, we prospectively collected CSF samples from 10 children with ALL and 10 controls. Our results showed an increased expression of the liquoral markers. This up-regulation could be interpreted as a neuroprotective response of the brain against the neuronal damages induced by MTX.

Two cases of pediatric high-grade astroblastoma with different clinical behavior.

Astroblastoma is a rare glial tumor occurring in older children and defined by histological criteria as low or high-grade. We describe two children with high-grade astroblastoma. The first patient, with multiple recurrences of a frontoparietal tumor, died 10 years from diagnosis after progression of the disease despite surgery, radiotherapy and chemotherapy. The second patient underwent subtotal resection of a temporal mass; the residual tumor progressed five months after radiotherapy, but after a subsequent gross total resection the patient is now in complete remission 54 months from diagnosis. Although both patients had high-grade astroblastomas, there were histological differences between the two tumors, in particular regarding the proliferative index, which was 30% and 5-10%, respectively. High-grade astroblastoma is usually treated with surgery and radiotherapy, but may have an unpredictable behavior even when tumor excision is deemed complete. The two cases reported here illustrate the variable clinical course of this rare tumor. The proliferative index may be a useful tool to better define prognosis.

Neurofibromatosis type 1 clinical features and management.

Neurofibromatosis type 1 (NF1) or von Recklinghausen's disease is one of the most common genetic disorder. It is characterized by a wide variability and unpredictability of clinical manifestations involving multiple organ systems. Several complications affecting life expectancy can occur in affected patients. We reviewed genetic mechanisms, clinical aspects of the syndrome and multidisciplinary management required for NF1 patients.

Extragonadal yolk sac tumor outside of the midline of the body: a case report of a child with a yolk sac tumor of the pontocerebellar angle.

Yolk sac tumor is a rare germ cell neoplasm occurring mainly in the gonads. Extragonadal yolk sac tumor is a very rare malignancy; its main distribution is along the midline of the body at three principal sites: mediastinum, central nervous system and retroperitoneum. Most yolk sac tumors are diagnosed between seven months and three years of age. We report a case of primary yolk sac tumor in a 13-month-old child. The tumor was located in the pontocerebellar angle, an atypical location that may not have suggested a yolk sac tumor as first diagnosis. We want to highlight the importance of performing tumor marker measurements during the first year of life, also for tumors located away from the midline.

MRI findings in Shwachman diamond syndrome.

Shwachman Diamond Syndrome (SDS) is a rare congenital disorder characterized by pancreatic insufficiency, bone marrow dysfunction, and skeletal changes. Because of the heterogeneous clinical presentation and the limits of laboratory tests that assess pancreatic insufficiency, the diagnosis of SDS can be challenging. Pancreatic lipomatosis, a typical feature of this syndrome, is also difficult to assess by direct tissue sampling. In these circumstances, magnetic resonance imaging (MRI) provides a readily available, noninvasive tool to evaluate the pancreatic fat content. We report a case of a 12-month-old male in which abdominal MRI was used to confirm the clinical diagnosis of SDS.