A child with hyperferritinemia: Case report

Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare condition caused by mutations in the gene coding for the light chain of ferritin; it does not lead to iron overload, but it is associated with the risk of developing a bilateral nuclear cataract also in childhood. On the contrary, a raise of serum ferritin levels is a common finding in pediatrics. We describe here a case of HHCS that offers some interesting clues for the daily practice. Our patient is a 6 year old Italian boy who came to our attention after some time of diagnostic uncertainties because of persistently high levels of ferritin with no apparent cause. We were guided to the suspect of this syndrome by the family history (5 members with various degrees of cataract developed in first infancy). High levels of serum ferritin and specific genetic testing (mutation A37C) confirmed the diagnosis. This case underlines the need of considering rare genetic syndromes, including hereditary hyperferritinemia cataract syndrome, in the differential diagnosis of raised serum ferritin in children and the importance of paying attention to family history in considering a patient with isolated raised levels of serum ferritin

Worsening of myocardial performance index in beta-thalassemia patients despite permanently normal iron load at MRI: A simple and cheap index reflecting cardiovascular involvement?

Abstract Background Iron Overload Cardiomyopathy (IOC) due to repeated transfusions still represents the main cause of death in Thalassemia major (TM) patients. Because iron overload remains asymptomatic for long time, it is important to stratify the patients based on the risk of developing IOC before the appearance of clinical signs of heart failure. The magnetic resonance imaging (MRI) T2* may be useful but it is expensive and its MRI software has limited availability; conventional echocardiographic parameters, although easy availability, remain normal until advanced stages of IOC. Tissue Doppler Imaging (TDI) opened a new way to explore systolic and diastolic function directly or through derived index such as myocardial performance index (MPI) which has a prognostic value in different cardiomyopathies. Methods We enrolled 46 consecutive β-TM patients without clinical signs of heart failure and we tested them with echocardiography in 2011 and again in 2015. MPI of left and right ventricular lateral wall was calculated by TDI. All TM patients had a T2* MRI evaluation of the heart in the year before. Results Despite the absence of significant changes in morphological data at echo and at T2* evaluation, S′ waves of the lateral ventricular wall decrease while time passed, MPI worsened during the follow-up period and the derived systolic pulmonary artery systolic pressure (PAPs) increased in 2015 with respect to 2011. Conclusion TDI and MPI may reveal very early myocardial dysfunction in TM patients despite a normal T2* value. Together with PAPs they should be periodically checked in these patients

Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients

Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients.BackgroundGuidelines for treating anemia in dialysis patients accept, as high-end range of serum ferritin useful to optimize erythropoietin therapy, values high as 500 to 900 μg/L, on the hypothesis that ferritin might be not representative of iron overload.MethodsA superconducting quantum interference device (SQUID) was used to make direct noninvasive magnetic measurements of nonheme hepatic iron content in 40 dialysis patients treated with intravenous iron, and liver iron content was compared with biochemical markers of iron status.ResultsOnly 12/40 (30%) patients showed normal hepatic iron content (SQUID <400 μg/g), while 32.5% had mild (400 to 1000 μg/g) and 37.5% severe (>1000 μg/g) iron overload, although 28/40 patients (70%) had serum ferritin below 500 μg/L. Among many parameters, hepatic iron content was only correlated with ferritin (r = 0.324, P = 0.04). The receiver operating characteristic (ROC) analysis showed the best specificity/sensitivity ratio to identify iron overload for ferritin >340 μg/L (W = 0.716). Multivariate logistic regression analysis demonstrated that an increase in serum ferritin of 100 μg/L and female gender were independent variables associated with moderate to severe hepatic iron overload: OR 1.71 (95% CI 1.10 to 2.67) and OR 10.68 (95% CI 1.81 to 63.15), respectively.ConclusionHepatic iron overload is frequent in dialysis patients with ferritin below currently proposed high-end ranges, and the diagnostic power of ferritin in indicating true iron stores is better than presumed. Safety concerns should prompt a reevaluation of acceptable iron parameters, focusing on potential gender-specific differences, to avoid potentially harmful iron overload in a majority of dialysis patients, mainly females

Differential effect of zoledronic acid on normal trabecular and cortical bone density in oncologic patients with bone metastases

AbstractPurposeTo evaluate bone density changes at the level of normal bone and bone metastases after zoledronic acid (ZA) treatment in oncologic patients.Materials and methodsWe retrospectively evaluated 72 consecutive adult patients with histologically confirmed solid tumors with at least 1 newly diagnosed bone metastatic lesion. Bone metastases were diagnosed by bone scans and confirmed with computed tomography (CT). Patients received intravenous ZA, 4mg, by 15-min infusion every 28 day through a peripheral or a central venous access and were monitored for at least 3 months and a maximum of 24 months. Bone density was determined at the level of bone metastases and at the level of normal trabecular and cortical bone using a ROI-based approach.ResultsA significant increase was demonstrated at the level of normal trabecular bone of the calvarium and the femoral neck. No significant increase of density was observed at the level of the normal cortical bone. Bone metastases showed a significant increase in CT density as compared to baseline up to 24 months after zoledronic acid.ConclusionWe have found that long term treatment with ZA increases trabecular bone density in oncologic patients whereas normal cortical bone changes are not detectable

Iron Overload in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation: Quantification of Iron Burden by a Superconducting Quantum Interference Device (SQUID) and Therapeutic Effectiveness of Phlebotomy

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Left atrial strain in patients with β-thalassemia major: a cross-sectional CMR study

Objectives The aim of this cross-sectional study was to investigate the association of left atrial (LA) strain parameters with demographics, clinical data, cardiovascular magnetic resonance (CMR) fndings, and cardiac complications (heart failure and arrhythmias) in a cohort of patients with β-thalassemia major (β-TM). Materials and methods We considered 264 β-TM patients (133 females, 36.79 ± 11.95 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. Moreover, we included 35 sex- and agematched healthy controls (14 females, mean age 37.36 ± 17.52 years). Reservoir, conduit, and booster LA functions were analysed by CMR feature tracking using dedicated software. Results Compared to the healthy control group, β-TM patients demonstrated lower LA reservoir strain and booster strains, as well as LA reservoir and booster strain rates. However, no diferences were found in LA conduit deformation parameters. In β-TM patients, ageing, sex, and left ventricle (LV) volume indexes were independent determinants of LA strain parameters. The number of segments with late gadolinium enhancement (LGE) signifcantly correlated with all LA strain parameters, with the exception of the LA conduit rate. Patients with cardiac complications exhibited signifcantly impaired strain parameters compared to patients without cardiac complications. Conclusion In patients with β-TM, LA strain parameters were impaired compared to control subjects, and they exhibited a signifcant correlation with the number of LV segments with LGE. Furthermore, patients with cardiac complications had impaired left atrial strain parameters. Clinical relevance statement In patients with β-thalassemia major, left atrial strain parameters were impaired compared to control subjects and emerged as a sensitive marker of cardiac complications, stronger than cardiac iron levels

SARS-CoV-2 infection in beta thalassemia: Preliminary data from the Italian experience

Patients with pre\u2010existent chronic morbidities are likely to be more severely affected by SARS\u2010Cov2 infection, but no data are available regarding Thalassemic Syndromes (TS). Note, TS and hemoglobin variants represent, according to WHO, one of the most frequent causes of anemia, affecting more than 7% of the world population.1 Thalassemic Syndromes are classified in either transfusion\u2010dependent thalassemia (TDT) or non\u2010transfusion\u2010dependent thalassemia (NTDT). Infectious complications, mainly from bacteria, constitute a common cause of mortality and morbidity in TS. Stress erythropoiesis, iron overload, splenectomy and adrenal insufficiency among others may contribute to increase susceptibility to infection.2 To verify the impact of SARS\u2010CoV\u20102 infection on TS, we set\u2010up a specific survey by electronic Case Report Form (eCRF).3 Inclusion criteria require at least 15\u2009days of follow\u2010up from either the onset of symptoms or SARS\u2010CoV2 positivity. The survey was approved by Ethics Committee and eCRF was shared with the Centers of Italian Hemoglobinopathies Network. The \u201cSociet\ue0 Italiana Talassemie ed Emoglobinopatie\u201d (SITE), has estimated the presence in Italy of approximately 5000 TDT and 1900 NTDT patients.3 As of 10 April 2020, 11 cases of TS and COVID\u201019 have been collected (see supplementary information). All the reported patients are in Northern Italy, where the rate of infection is higher, reflecting the national epidemiology. The mean age is 44\u2009\ub1\u200911\u2009years (range 31\u201061\u2009years) and 55% (6/11) are females. Ten patients are TDT, and one is NTDT. All the patients have thalassemia associated comorbidities, eight are splenectomized, and one patient (#9 in the supplementary table) has pulmonary hypertension treated with sildenafil. The likely source of infection has been detected in 55% (6/11) of cases: two had contacts with COVID\u201019 positive subjects, and four had occupational exposure (three are nurses working in hospital or assisted living facilities). Three patients were asymptomatic. One patient (#3 in supplementary information) was admitted for high fever and bone marrow hypoplasia, lymphopenia, and agranulocytosis (on treatment with deferiprone) and tested positive at the third swab. Six out of 11 were hospitalized, but no one required mechanical ventilation. The patient with more severe symptoms who required more intensive ventilation support with continuous positive airway pressure (CPAP) has a history of diffuse large B\u2010cell lymphoma, treated with chemotherapy in the previous year, currently in complete remission. Of the six people admitted to the hospital, only three received supposedly specific treatment for COVID\u201019: one hydroxychloroquine (HCQ), one HCQ plus ritonavir/darunavir, and one HCQ plus anakinra. Patient #3 did not receive HCQ due to concomitant therapy with amiodarone and an increased risk of life\u2010threatening arrhythmia. The clinical course ranged from 10 to 29\u2009days. Ten patients have clinically recovered and are on a daily remote phone call follow\u2010up. Splenectomy which was present in 8/11 patients did not seem to affect the clinical course. Of note, except for the patient with myelosuppression, no increase in blood requirement was observed. When luspatercept treatment was halted in the NTDT patient, hemoglobin fell from 110 to 82 g/L, a value similar to the pre\u2010luspatercept period. Neither death nor severe SARS or signs of cytokines storm were observed in these 11 subjects, which may be surprising, taking into account the mean age and the presence of severe comorbidities. Our data, although preliminary, do not indicate increased severity of COVID\u201019 in TS. A larger number of cases needs to be collected to define the impact of this new infection and its outcome in these fragile patients

Array comparative genomic hybridization in retinoma and retinoblastoma tissues

In retinoblastoma, two RB1 mutations are necessary for tumor development. Recurrent genomic rearrangements may represent subsequent events required for retinoblastoma progression. Array-comparative genomic hybridization was carried out in 18 eye samples, 10 from bilateral and eight from unilateral retinoblastoma patients. Two unilateral cases also showed areas of retinoma. The most frequent imbalance in retinoblastomas was 6p gain (40%), followed by gains at 1q12-q25.3, 2p24.3-p24.2, 9q22.2, and 9q33.1 and losses at 11q24.3, 13q13.2-q22.3, and 16q12.1-q21. Bilateral cases showed a lower number of imbalances than unilateral cases (P = 0.002). Unilateral cases were divided into low-level (≤4) and high-level (÷7) chromosomal instability groups. The first group presented with younger age at diagnosis (mean 511 days) compared with the second group (mean 1606 days). In one retinoma case ophthalmoscopically diagnosed as a benign lesion no rearrangements were detected, whereas the adjacent retinoblastoma displayed seven aberrations. The other retinoma case identified by retrospective histopathological examination shared three rearrangements with the adjacent retinoblastoma. Two other gene-free rearrangements were retinoma specific. One rearrangement, dup5p, was retinoblastoma specific and included the SKP2 gene. Genomic profiling indicated that the first retinoma was a pretumoral lesion, whereas the other represents a subclone of cells bearing 'benign' rearrangements overwhelmed by another subclone presenting aberrations with higher 'oncogenic' potential. In summary, the present study shows that bilateral and unilateral retinoblastoma have different chromosomal instability that correlates with the age of tumor onset in unilateral cases. This is the first report of genomic profiling in retinoma tissue, shedding light on the different nature of lesions named 'retinoma'. (Cancer Sci 2009; 100: 465–471

Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors

Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKIs), but is successful for only a limited amount of time; most cases relapse due to the development of drug resistance. Here we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC