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Iron is an essential nutrient and a constituent of ferroproteins and enzymes crucial for human life. Generally, nonmenstruating individuals preserve iron very efficiently, losing less than 0.1% of their body iron content each day, an amount that is replaced through dietary iron absorption. Most of the iron is in the hemoglobin (Hb) of red blood cells (RBCs); thus, blood loss is the most common cause of acute iron depletion and anemia worldwide, and reduced hemoglobin synthesis and anemia are the most common consequences of low plasma iron concentrations. The term iron deficiency (ID) refers to the reduction of total body iron stores due to impaired nutrition, reduced absorption secondary to gastrointestinal conditions, increased blood loss, and increased needs as in pregnancy. Iron deficiency anemia (IDA) is defined as low Hb or hematocrit associated with microcytic and hypochromic erythrocytes and low RBC count due to iron deficiency. IDA most commonly affects women of reproductive age, the developing fetus, children, patients with chronic and inflammatory diseases, and the elderly. IDA is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39% and 48.1% in developing countries). The diagnosis, management, and treatment of patients with ID and IDA change depending on age and gender and during pregnancy. We herein summarize what is known about the diagnosis, treatment, and prevention of ID and IDA and formulate a specific set of recommendations on this topic.

Background: The recently published WHO classification of central nervous system (CNS) tumours recognizes DNA methylation profiling as a desirable and, for some diagnoses, essential diagnostic tool adjunctive to conventional histopathology. DNA methylation profiling is not routinely available in many countries, including Greece. Methods: In this collaborative study, we report the DNA methylation results in a series of children and adolescents with CNS tumours in Greece (2018–2023). In total, 130 tumour samples were analyzed using the latest applicable version of the Heidelberg brain tumour classifier. Results: Upon initial analysis, 80 % (104/130) achieved calibrated scores (Cs) ≥ 0.9 and matched an established methylation class family/subclass. Among them, methylation results confirmed (90/104, 86.5 %), refined (50/104, 48 %) or changed (10/104, 9.6 %) the histological diagnosis. Only four results were regarded as non-contributing (4/104, 3.9 %). Twenty-six tumour samples received Cs < 0.9. Despite low scores, methylation results supported the initial diagnosis with lower confidence in 38.5 % (10/26) and established the diagnosis in two tumours with non-conclusive histopathology. Additional t-distributed stochastic neighbour embedding (t-SNE) analysis allowed the possible classification of twelve tumours. Nine more samples reached high Cs using the newer brain tumour classifiers, since available. Samples co-tested in Greece demonstrated excellent test reproducibility, supporting the analysis' local implementation. Methylome profiling impacted the clinical management of 40 % of patients, modifying stratification, prognosis, or treatment approach. Conclusions: This study supports the need to integrate methylome analysis into routine diagnostics in our country and highlights the importance of collaboration between European pediatric oncology centres.

Objectives To estimate thresholds for defining meaningful within-patient improvement from baseline to weeks 13–24 and interpreting meaningfulness of between-group difference for the non-transfusion-dependent beta-thalassaemia patient-reported outcome (NTDT-PRO) tiredness/weakness (T/W) and shortness of breath (SoB) scores. A secondary objective was to determine the symptom severity threshold for the NTDT-PRO T/W domain to identify patients with symptomatic T/W.Design Pooled blinded data from the phase 2, double-blind, placebo-controlled, randomised BEYOND trial in NTDT (NCT03342404) were used. Anchor-based analyses supplemented with distribution-based analyses and empirical cumulative distribution function (eCDF) curves were applied. Distribution-based analyses and receiver operating characteristic curves were used to estimate between-group difference and symptomatic thresholds, respectively.Setting Greece, Italy, Lebanon, Thailand, the UK and the USA.Participants Adults (N=145; mean age 39.9 years) with NTDT who were transfusion-free ≥8 weeks before randomisation.Measures Score changes from baseline to weeks 13–24 in PROs used as anchors (correlation coefficient ≥0.3): NTDT-PRO T/W and SoB scores, Patient Global Impression of Severity, Functional Assessment of Chronic Illness Therapy–Fatigue (Fatigue Subscale, item HI12 and item An2) and Short Form Health Survey version 2.Results The eCDF curves support the use of estimates from the improvement by one level group for all anchors to determine the threshold(s) for meaningful within-patient improvement. Mean (median) changes from these groups and estimates from distribution-based analyses suggest that a ≥1-point reduction in the NTDT-PRO T/W or SoB domains represents a clinically meaningful improvement. Meaningful between-group difference threshold ranges were 0.53–1.10 for the T/W domain and 0.65–1.15 for the SoB domain. The optimal symptomatic threshold for the T/W domain (by maximum Youden’s index) was ≥3 points.Conclusions The thresholds proposed may support the use of NTDT-PRO in assessing and interpreting treatment effects in clinical studies and identifying patients with NTDT in need of symptom relief.

Background: Thalassemia, a group of inherited disorders characterized by ineffective erythropoiesis and chronic hemolytic anemia, is associated with wide-ranging impacts on health-related quality of life (HRQoL), such as impaired physical functioning and fatigue. Anemia has been associated with increased symptom burden and poor HRQoL in patients (pts) with non–transfusion-dependent thalassemia (NTDT). There are no available oral disease-modifying therapies that have been shown to improve HRQoL in β-thalassemia and no agents are approved for α-thalassemia. In a phase 2 study of pts with NTDT, improvements in hemoglobin were observed with mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, and it has the potential to improve HRQoL. Aims: To evaluate the impact of mitapivat vs placebo on fatigue, physical function, and other thalassemia symptoms in adults with α- or β-NTDT in ENERGIZE, a phase 3, double-blind, randomized, placebo-controlled, global trial. Methods: Adults (≥18 years) were randomized 2:1 to mitapivat 100 mg twice daily or placebo for 24 weeks (wks). NTDT was defined as ≤5 red blood cell (RBC) units transfused in the 24 wks before randomization and no RBC transfusions ≤8 wks before informed consent or during screening. The Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue), 6-Minute Walk Test (6MWT), and Patient Global Impression of Change (PGIC) of Fatigue, Thalassemia Symptoms, and Walking Capacity were among the outcomes assessed. Changes from baseline (BL) for FACIT-Fatigue (Wks 12–24) and 6MWT (Wk 24), and the results of PGIC-Fatigue, (Wks 12–24), PGIC-Thalassemia Symptoms, and PGIC-Walking Capacity (both Wk 24) were summarized. The clinically meaningful within-person change (MWPC) threshold for FACIT-Fatigue was estimated to be a ≥4.5-point change from BL in average score from Wks 12–24, using an anchor-based method. Results: 194 pts were randomized (mitapivat n = 130; placebo n = 64); BL characteristics were similar between treatment arms. Mitapivat demonstrated a statistically significant improvement compared with placebo in change from BL to Wk 12–24 average FACIT-Fatigue score; least-squares mean (LSM) change from BL was 4.85 for mitapivat vs 1.46 for placebo (LSM difference (95% CI): 3.40 (1.21, 5.59); 2-sided p < 0.0026), and 36.2% of pts in the mitapivat arm achieved the MWPC threshold of ≥4.5 vs 21.9% in the placebo arm. For the 6MWT, LSM change from BL to Wk 24 was 30.48 m for mitapivat and 7.11 m for placebo (LSM difference (95% CI): 23.36 m (6.90, 39.83)). The observed frequency of pts with improvements (reporting feeling much/a little better) in PGIC-Fatigue was higher for pts in the mitapivat arm than the placebo arm at Wk 12 (63.1% vs 23.4%), Wk 16 (69.2% vs 23.4%), Wk 20 (62.3% vs 28.1%), and Wk 24 (60.8% vs 31.3%). Improvements in PGIC-Thalassemia Symptoms and PGIC-Walking Capacity were also reported in a higher frequency of pts in the mitapivat arm than in the placebo arm at Wk 24 (67.7% vs 32.8%; 55.4% vs 28.1%, respectively). Summary/Conclusion: Mitapivat is the first oral, disease-modifying, investigational therapy with which meaningful improvements in aspects of HRQoL, including fatigue and walking capacity, were observed in a clinical trial that enrolled both pts with α-NTDT and pts with β-NTDT.

Background: In thalassemia, ATP production in erythroid cells is too low to meet the demand of oxidative stress and ensuing cellular damage; this leads to ineffective erythropoiesis (IE) and chronic hemolytic anemia. Guidelines for non–transfusion-dependent thalassemia (NTDT) recommend raising hemoglobin (Hb) by ≥1 g/dL to reduce morbidities from IE and anemia. No oral disease-modifying therapies are approved for the treatment of β-thalassemia, and no agents are approved for α-thalassemia. Mitapivat is a first-in-class, oral, activator of pyruvate kinase that increases ATP production. Mitapivat may reduce metabolic stress, addressing the underlying pathophysiology across the full range of thalassemias, with the potential to reduce complications and improve health-related quality of life (HRQoL). Aims: To assess the efficacy and safety of mitapivat vs placebo (pbo) in adults with α- or β-NTDT in ENERGIZE (NCT04770753), a phase 3, double-blind, randomized, pbo-controlled, global trial. Methods: Adults (≥18 years) with α- or β-NTDT and baseline (BL) Hb ≤10 g/dL were randomized 2:1 to mitapivat 100 mg twice daily or pbo for 24 weeks (wks). NTDT was defined as ≤5 red blood cell (RBC) units transfused 24 wks before randomization and no RBC transfusions ≤8 wks before informed consent or during screening. The primary endpoint was Hb response: ≥1.0 g/dL increase in average Hb concentration over Wks 12–24 compared with BL. Key secondary endpoints were changes from BL in average Hb concentration and Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue) score over Wks 12–24. Safety and markers of hemolysis and erythropoiesis were among the secondary endpoints. Results: 194 patients (pts) were randomized (mitapivat n = 130; pbo n = 64); 94.8% completed the 24-wk trial. Mean age was 41.2 years, mean BL Hb was 8.3 g/dL, 86.6% received no transfusions in the 24 wks before randomization, and 32.0% had α-NTDT. BL characteristics were similar between treatment arms. Mitapivat demonstrated statistically significant improvements vs pbo for Hb response (42.3% vs 1.6%, respectively; 2-sided p < 0.0001), and for changes from BL in Wks 12–24 average Hb (least-squares mean [LSM] difference (95% CI): 0.96 g/dL (0.78, 1.15); 2-sided p < 0.0001) and Wks 12–24 average FACIT-Fatigue score (LSM difference (95% CI): 3.40 (1.21, 5.59); 2-sided p < 0.0026). Results favored mitapivat across all prespecified subgroups. Improvements in several markers of hemolysis and erythropoiesis were also observed, consistent with the proposed mechanism of mitapivat. The proportion of pts with treatment-emergent adverse events (TEAEs) of any grade was similar across treatment arms (mitapivat 82.9%; pbo 79.4%). The most common TEAEs (≥10% of pts) with mitapivat were headache, initial insomnia, nausea, and upper respiratory tract infection. Among mitapivat-treated pts, 6.2% had serious TEAEs (none considered treatment related) and 3.1% had TEAEs leading to treatment discontinuation; none occurred with pbo. Summary/Conclusion: Mitapivat significantly increased Hb and improved fatigue vs pbo; improvements were observed across all prespecified subgroups. Mitapivat was generally well tolerated with a low treatment discontinuation rate. These data are the first proof of efficacy of a disease-modifying therapy across the full range of NTDT (α- and β-thalassemia). Mitapivat may represent a new oral treatment option addressing both pathophysiology and HRQoL in thalassemia.

Abstract Iron is an essential nutrient and a constituent of ferroproteins and enzymes crucial for human life. Generally, nonmenstruating individuals preserve iron very efficiently, losing less than 0.1% of their body iron content each day, an amount that is replaced through dietary iron absorption. Most of the iron is in the hemoglobin (Hb) of red blood cells (RBCs); thus, blood loss is the most common cause of acute iron depletion and anemia worldwide, and reduced hemoglobin synthesis and anemia are the most common consequences of low plasma iron concentrations. The term iron deficiency (ID) refers to the reduction of total body iron stores due to impaired nutrition, reduced absorption secondary to gastrointestinal conditions, increased blood loss, and increased needs as in pregnancy. Iron deficiency anemia (IDA) is defined as low Hb or hematocrit associated with microcytic and hypochromic erythrocytes and low RBC count due to iron deficiency. IDA most commonly affects women of reproductive age, the developing fetus, children, patients with chronic and inflammatory diseases, and the elderly. IDA is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39% and 48.1% in developing countries). The diagnosis, management, and treatment of patients with ID and IDA change depending on age and gender and during pregnancy. We herein summarize what is known about the diagnosis, treatment, and prevention of ID and IDA and formulate a specific set of recommendations on this topic.

Background: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma (NHL), subdivided into endemic, sporadic, and immunodeficiency-associated forms. While jaw lesions are common in endemic BL, they are infrequent in sporadic cases, only rarely constituting the first manifestation of the disease. The aim of this study is to present a rare pediatric case of sporadic BL first manifesting as gingival swellings and tooth hypermobility and provide a review of all the published sporadic BL case reports as the first sign of disease. Case report: An 11-year-old Caucasian female was referred for the evaluation of hypermobility of posterior lower teeth, associated with painful gingival swellings of 20 days duration. Clinical examination revealed right facial asymmetry and bilateral prominent swellings of the posterior lower gingiva. A panoramic radiograph revealed ill-defined radiolucent lesions in the posterior mandible bilaterally. On computed tomography, soft-tissue masses were identified along the mandibular ramus extending into the maxillary sinus bilaterally. The histopathologic and immunohistochemical analyses of the lesions led to a diagnosis of Burkitt lymphoma (BL). The patient underwent a full staging work-up, revealing bone marrow involvement and widespread disease. A multi-chemotherapy regimen was initiated with the regression of oral lesions and symptoms within a few weeks and complete disease remission after nine chemotherapy cycles. The patient remains free of disease 11 years later. Conclusions: This case underscores the critical importance of the timely diagnosis and life-saving referral of rapidly growing jaw lesions, which may represent the first sign of an underlying lymphoreticular malignancy with aggressive course, such as BL.

Abstract Patients with transfusion‐dependent beta (β)‐thalassaemia experience a broad range of complications. ULYSSES, an epidemiological, multicentre, retrospective cross‐sectional study, aimed to assess the prevalence and severity of treatment and disease complications, capture disease management and identify predictors of complications in patients with transfusion‐dependent β‐thalassaemia, treated in routine settings in Greece. Eligible patients were adults diagnosed with β‐thalassaemia ≥12 months before enrolment and having received ≥6 red blood cell (RBC) units (excluding elective surgery) with no transfusion‐free period ≥35 days in the 24 weeks before enrolment. Primary data were collected at a single visit and through chart review. Between Oct 21, 2019, and Jun 15, 2020, 201 eligible patients [median (interquartile range, IQR) age 45.7 (40.2–50.5) years; 75.6% > 40 years old; 64.2% female] were enrolled, a mean (standard deviation) of 42.9 (7.8) years after diagnosis. Median (IQR) age at diagnosis and RBC transfusion initiation were 0.8 (0.4–2.8) and 1.3 (1.0–5.0) years, respectively. From diagnosis to enrolment, patients had developed a median of six (range: 1–55) complications; 19.6% were grade ≥3. The most represented complications were endocrine/metabolic/nutrition disorders (91.5%), surgical/medical procedures (67.7%) and blood/lymphatic system disorders (64.7%). Real‐world data generated by ULYSSES underscore the substantial complication burden of transfusion‐dependent β‐thalassaemia patients, routinely managed in Greece.

We analyzed data on pediatric invasive fungal diseases of the central nervous system (CNS-IFDs) reported by five of a total of eight Pediatric Hematology-Oncology Departments in Greece for 16 years (2007–2022). A total of twelve patients (11 boys, median age: 9.5 years, range: 2–16) were reported suffering from CNS-IFDs. The underlying malignancy was acute lymphoblastic leukemia in 9/12 and acute myeloid leukemia, Ewing sarcoma, and rhabdomyosarcoma in one each. Eleven patients presented with CNS-related symptoms (i.e., seizures, headache, cerebral palsy, ataxia, hallucination, seizures, blurred vision, amaurosis). All patients had pathological MRI findings. Multifocal fungal disease was observed in 6/12 patients. Nine proven and three probable CNS-IFD cases were diagnosed. Causative pathogens in proven cases were Aspergillus spp. and Candida albicans (n = 2 each), Mucor spp., Rhizopus arrhizus, Absidia spp., Fusarium oxysporum and Cryptococcus neoformans (n = 1 each). Causative pathogens in probable cases were Aspergillus spp. (n = 2) and Candida spp. (n = 1). All patients received appropriate antifungal therapy (median duration: 69.5 days, range 19–364). Two patients underwent additional surgical treatment. Six patients were admitted to the Intensive Care Unit due to complications. Three patients (25%) died, two due to IFD and one due to an underlying disease. Early recognition and prompt intervention of CNS-IFDs may rescue the patients and improve overall survival.

Background: Prediabetes and diabetes mellitus (DM) are complications in adult patients with transfusion dependent β-thalassemia (β-TDT), with their incidence increasing with age. Objective: This retrospective observational study describes the glycemic trajectories and evaluates predictive indices of β-cell function and insulin sensitivity/resistance in β-TDT patients with prediabetes, both in a steady state and during 3-h oral glucose tolerance test (OGTT), in order to identify patients at high risk for incipient diabetes. Setting: The study was mainly conducted at the Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara (Italy) in collaboration with thalassemia referring centers across Italy. Patients: The study included 11 β-TDT (aged 15.11- 31.10 years) with history of prediabetes. Methods: The ADA criteria for the diagnosis of glucose dysregulation were adopted. Investigations included evaluation of plasma glucose levels and insulin secretion, analysis of glycemic trajectories and indices of β-cell function and insulin sensitivity/resistance assessed in steady state and during OGTT. Results: The duration of progression from prediabetes to DM, expressed in years, showed a positive direct correlation with corrected insulin response (CIR-30 = r: 0.7606, P: 0.0065), insulinogenic index (IGI 0-120 = r: 0.6121, P:0.045), oral disposition index (oDI = r: 0.7119, P:0.013), insulin growth factor-1 (IGF-1= r: 0.6246, P: 0.039) and an inverse linear correlation with serum ferritin (SF = r: -0.7197, P: 0.012). Conclusions: Progressive β-cell failure, peripheral resistance to the action of insulin and reduction of oDI were the principal factors responsible for the progression from prediabetes to incipient DM.

Khaled M Musallam,1 Ali T Taher,2 Antonis Kattamis,3 Kevin HM Kuo,4 Sujit Sheth,5 Maria Domenica Cappellini6 1Thalassemia Center, Burjeel Medical City, Abu Dhabi, United Arab Emirates; 2Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 3First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece; 4Division of Hematology, University of Toronto, Toronto, ON, Canada; 5Division of Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; 6Department of Clinical Sciences and Community, University of Milan, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, ItalyCorrespondence: Maria Domenica Cappellini, Department of Clinical Sciences and Community, University of Milan, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, 20122, Italy, Tel + 39 02 5503 3752, Email maria.cappellini@unimit.itAbstract: Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤ 10 g/dL. These data led to luspatercept’s approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population.Keywords: anemia, ineffective erythropoiesis, iron, management, thalassemia, transfusion

Abstract. Objective: To evaluate the age at menarche and menstrual characteristics in patients with transfusion-dependent thalassemia (TDT) who started early chelation therapy (≤ 3 years) with a variety of chelating agents. Design: A retrospective multicenter study promoted by International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A). Setting: Eight of 13 International Thalassemia Centers (61.5%) in the ICET-A Network participated. Patients: Fifty-seven female TDT patients, aged 11 to 26 years, were enrolled in the study. Seven patients were excluded, 4 who were still prepubertal (age 12-14 years) and 3 with primary amenorrhea. The remaining 50 patients were from Iran (33 patients), 9 from Bulgaria, 8 from Greece, 4 from Oman, 2 from Cyprus, and 1 from Italy. Results: At start of chelation therapy, 22 patients received desferrioxamine mesylate (DFO), 26 deferasirox (DFX) and 2 deferiprone (DFP). All fifty TDT patients developed spontaneous menarche at a mean age of 14.2 ± 2.24 years (range 9 – 20). A significant positive correlation was observed between age at menarche and serum ferritin (SF) levels (r: 0. 41, P: 0.005). Thirty-two patients (64%) reported regular menstrual cycles, 7 (14 %) oligomenorrhea, 3 (6%) short/light menses (hypomenorrhea), and 8 (16%) secondary amenorrhea (SA) (16%). Conclusions: Early chelation does not necessary correlate with efficient chelation during pubertal age. Delayed menarche, related to high SF levels, was still frequent in most Centers and was a forerunner of irregular menstrual cycles, SA and associated complications. Neglecting the importance of adherence to iron chelation therapy (ICT), despite innovative and expensive therapies, may lead to complications and decreased quality of life. Key words: Transfusion-dependent thalassemia, menarche, menstrual cycles, iron chelation therapy (ICT), iron overload, adherence to treatment.

Abstract The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.

Background: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma (NHL), subdivided into endemic, sporadic, and immunodeficiency-associated forms. While jaw lesions are common in endemic BL, they are infrequent in sporadic cases, only rarely constituting the first manifestation of the disease. The aim of this study is to present a rare pediatric case of sporadic BL first manifesting as gingival swellings and tooth hypermobility and provide a review of all the published sporadic BL case reports as the first sign of disease. Case report: An 11-year-old Caucasian female was referred for the evaluation of hypermobility of posterior lower teeth, associated with painful gingival swellings of 20 days duration. Clinical examination revealed right facial asymmetry and bilateral prominent swellings of the posterior lower gingiva. A panoramic radiograph revealed ill-defined radiolucent lesions in the posterior mandible bilaterally. On computed tomography, soft-tissue masses were identified along the mandibular ramus extending into the maxillary sinus bilaterally. The histopathologic and immunohistochemical analyses of the lesions led to a diagnosis of Burkitt lymphoma (BL). The patient underwent a full staging work-up, revealing bone marrow involvement and widespread disease. A multi-chemotherapy regimen was initiated with the regression of oral lesions and symptoms within a few weeks and complete disease remission after nine chemotherapy cycles. The patient remains free of disease 11 years later. Conclusions: This case underscores the critical importance of the timely diagnosis and life-saving referral of rapidly growing jaw lesions, which may represent the first sign of an underlying lymphoreticular malignancy with aggressive course, such as BL. [ABSTRACT FROM AUTHOR]

Cafe-au-lait macules are the most distinctive clinical finding in neurofibromatosis type I. The aim of this prospective study of Greek children diagnosed with neurofibromatosis type I was to describe the dermatological phenotype and to analyse the characteristics of cafe-au-lait macules and their association with genotype. Pigment intensity and melatonin content of cafe-au-lait macules were measured with a narrowband spectrophotometer. A total of 63 children aged 6 months to 16 years old were studied. Mean melanin content varied, both among patients, and within each patient (p

Variations in the length of telomeres and pathogenic variants involved in telomere length maintenance have been correlated with several human diseases. Recent breakthroughs in telomere biology knowledge have contributed to the identification of illnesses named “telomeropathies” and revealed an association between telomere length and disease outcome. This review emphasizes the biology and physiology aspects of telomeres and describes prototype diseases in which telomeres are implicated in their pathophysiology. We also provide information on the role of telomeres in hematological diseases ranging from bone marrow failure syndromes to acute and chronic leukemias.

Objectives The non-transfusion-dependent beta-thalassaemia-patient-reported outcome (NTDT-PRO) questionnaire was developed for assessing anaemia-related tiredness/weakness (T/W) and shortness of breath (SoB) among patients with NTDT. Psychometric properties were evaluated using blinded data from the BEYOND trial (NCT03342404).Design Analysis of a phase 2, double-blind, randomised, placebo-controlled trial.Setting USA, Greece, Italy, Lebanon, Thailand and the UK.Participants Adults (≥18 years) (N=145) with NTDT who had not received a red blood cell transfusion within 8 weeks prior to randomisation, with mean baseline haemoglobin level ≤100 g/L.Measures NTDT-PRO daily scores from baseline until week 24, and scores at select time points for the 36-Item Short Form Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Patient Global Impression of Severity (PGI-S).Results Cronbach’s alpha at weeks 13–24 was 0.95 and 0.84 for the T/W and SoB domains, respectively, indicating acceptable internal consistency reliability. Among participants self-reporting no change in thalassaemia symptoms via the PGI-S between baseline and week 1, intraclass correlation coefficients were 0.94 and 0.92 for the T/W and SoB domains, respectively, indicating excellent test–retest reliability. In a known-groups validity analysis, least-squares mean T/W and SoB scores at weeks 13–24 were worse in participants with worse scores for the FACIT-F Fatigue Subscale (FS), SF-36v2 vitality or PGI-S. Indicating responsiveness, changes in T/W and SoB domain scores were moderately correlated with changes in haemoglobin levels, and strongly correlated with changes in SF-36v2 vitality, FACIT-F FS, select FACIT-F items and the PGI-S. Improvements in least-squares mean T/W and SoB scores were higher in participants with greater improvements in scores on other PROs measuring similar constructs.Conclusions The NTDT-PRO demonstrated adequate psychometric properties to assess anaemia-related symptoms in adults with NTDT and can be used to evaluate treatment efficacy in clinical trials.

Aims: The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indexes of insulin sensitivity and resistance, during a 3-hour oral glucose tolerance test (OGTT), in β- thalassemia major patients (β-TM) with serum ferritin (SF) below 1,000 ng/mL. Patients and methods: The retrospective cohort study evaluated the medical records of 24 β-ΤΜ patients from 2010 to 2022. Αt the year of study the mean age of patients was 31.0 ± 4.1 (20-37.11) years; 13 (54.1%) were females. The most commonly used iron chelator was deferoxamine (DFO: 75%), followed by deferiprone (DFP:12.5%) and deferasirox (DFX: 12.5%). Insulin sensitivity and resistance indexes were derived from OGTT. A liver iron concentration (LIC) < 3 mg/g d.w. and a global heart T2* value < 20 ms were considered as conservative cut-off values for insignificant iron overload (IOL). Results: The mean SF levels in the whole study cohort population at the age of evaluation was 549.6 ± 232.3 ng/mL. Based on the SF levels, two groups were identified: Group A (N = 14) < 500 ng/mL and Group B (N=10) 500-1,000 ng/mL. Normal glucose tolerance (NGT) during OGTT was observed in 4 patients of Group A (28.5 %) and in 5 patients of Group B (50%) (P: 0.29). The remaining 15/24 patients (62.5%) had glucose dysregulation (GD). The mean age at starting iron chelation therapy (ICT) and the mean SF peak in Group A versus Group B were significantly higher in group Α. The GD was associated with significantly attenuated IGI (first phase of insulin response) and impaired oral disposition index (oDI). Hypogonadotropic hypogonadism (HH) was the most common associated endocrine complication in both groups of patients. Conclusions: This study showed that efficient iron chelation monotherapy in patients with β-TM and SF < 1,000 ng/ml did not entirely prevent glucose metabolism disorders, insulin secretion and sensitivity, and development of acquired hypogonadism.

Diamond–Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated.

Background: The purpose of this study was to compare the immediate and long-term complications that are associated with the utilized techniques for the insertion of indwelling central venous catheters, that is the open surgical technique, the ultrasound-guided technique, and the transcutaneous technique based on external anatomical landmarks in the right internal jugular vein, to a pediatric population. Methods: This was a prospective randomized trial based on a pediatric patient population under 16 years of age of a tertiary pediatric-oncological hospital. The procedure was performed by a medical team with varying experience regarding the percutaneous and open insertion methods. We studied the outcome of our procedure, based on the immediate and delayed complication rate, as well as the needed time in order to complete the procedure and mean duration of line use. Results: The patients that were inserted in our protocol were divided into three subgroups based on the selected technique for the insertion of the central venous catheter. A total number of 88 insertions (25.4%) (out of 346) were based on the technique that was using external anatomical landmarks, 121 insertions were based on the ultrasound-guided transcutaneous technique (34.9%), whereas in 137 cases (39.5%) the open surgical technique was preferred. All cases that were related to catheter re-insertion were excluded from our study. We performed a statistical analysis regarding the catheter dwell time between the three subgroups of patients and no significant difference was recorded. Moreover, the development of thrombosis was investigated, and we noted that a higher percentage of this complication was related to the transcutaneous external landmark and open surgical technique. Also, the incidence of infection was taken into consideration, which manifested an increased incidence when the transcutaneous technique based on external landmarks was used. Conclusions: Ultrasound-guided percutaneous insertion was considered to be a safe and effective technique for the insertion of central venous catheters. Our study also demonstrated a decrease in operating times when performed by operators with increasing expertise, increased preservation of the diameter of the venous lumen, and no increase in complication rates when the ultrasound-guided technique was selected.