Matteo Luciani

Acute thiamine deficiency and refeeding syndrome: Similar findings but different pathogenesis

OBJECTIVEnRefeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life threatening with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to anabolism. This creates a sudden cellular demand for electrolytes (phosphate, potassium, and magnesium) necessary for synthesis of adenosine triphosphate, glucose transport, and other synthesis reactions, resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to refeeding syndrome also are observed in acute thiamine deficiency. The aim of this study was to determine whether thiamine deficiency was responsible for the electrolyte imbalance caused by tubular electrolyte losses.nnnMETHODSnWe describe two patients with leukemia who developed acute thiamine deficiency with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis, and evidence of proximal renal tubular dysfunction.nnnRESULTSnA single thiamine administration led to rapid resolution of the tubular dysfunction and normalization of acidosis and electrolyte imbalance. This demonstrated that thiamine deficiency was responsible for the electrolyte imbalance, caused by tubular electrolyte losses.nnnCONCLUSIONSnOur study indicates that, despite sharing many laboratory similarities, refeeding syndrome and acute thiamine deficiency should be viewed as separate entities in which the electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency and refractory lactic acidosis may be due to renal tubular losses instead of a shifting from extracellular to intracellular compartments. In oncologic and malnourished patients, individuals at particular risk for developing refeeding syndrome, in the presence of these biochemical abnormalities, acute thiamine deficiency should be suspected and treated because it promptly responds to thiamine administration.

Genetic prothrombotic factors in children with otogenic lateral sinus thrombosis: five case reports.

Lateral sinus thrombosis (LST) is an uncommon, but life-threatening complication of both acute and chronic otitis media. There is some evidence that acquired or hereditary prothrombotic disorders are risk factors for LST. The aim of this work was to evaluate the role of thrombotic screening, anticoagulant therapy or prophylaxis in patients with either acute or chronic otitis media and LST. The medical records of five children hospitalized at Pediatric Hospital Bambino Gesù of Rome because of acute or chronic otitis media complicated by mastoiditis and LST were reviewed. All children underwent laboratory workup for hypercoagulability. All the five children were found to be heterozygote for the C677T MTHFR mutation and a child presented also heterozygosity for factor V Leiden mutation. They have been successfully treated with anticoagulant therapy without sequels. Children with acute or chronic otitis media may have a prothrombotic tendency that becomes clinically evident because of the inflammatory state. Patients with a family and/or personal history of thrombosis and/or thrombophilic conditions need anticoagulant prophylaxis also in the absence of clear signs of LST. Treatment with low molecular weight is successful in patients with LST.

Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial.

Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary‐resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high‐risk group. For the whole patient population, the probability of overall survival, event‐free survival (EFS) and disease‐free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty‐eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long‐term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long‐term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies.

Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open‐label, single‐arm study. The pharmacokinetic–pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism.

Multiple cerebral sinus thromboses complicating meningococcal meningitis: a pediatric case report

BackgroundCerebral venous sinus thrombosis (CVT) is a rare and potentially life-threatening condition in the pediatric population. The clinical presentation is frequently nonspecific; thus diagnosis is often delayed or missed.Case presentationA previously healthy 8xa0month-old boy was diagnosed with meningococcal meningitis. At hospital admission, an urgent non contrast-enhanced computed tomography (CT) of the head and neck was performed with normal results. Ceftriaxone was promptly started and the clinical condition of the patient improved. However, on the 7th day of hospitalization, the child suddenly manifested irritability and lethargy. An urgent contrast-enhanced CT of the head and neck was immediately performed, revealing thrombosis of the superior sagittal, transverse and rectus sinuses. A thrombophilic evaluation was performed, revealing hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) variants (C677T and A1298C).ConclusionsThe causes of CVT may be categorized into three main groups: hypercoagulable states, conditions causing blood flow disturbances, and all causes of inflammation or infection. In this case report, we observed more than one risk factor that predisposed the patient to CVT. Consequently, even if a causative factor is detected, a thrombophilic blood evaluation should be performed. In fact, in case of a prothrombotic condition, the patient’s family should be advised that prompt administration of anticoagulant is necessary in the event of situations that could lead to thrombosis. Finally, CVT may be considered a possible complication of infection even when recent imaging results are normal. A prompt CVT diagnosis is required to obtain a good outcome. Delayed diagnosis is mainly due to the rarity of the disease and physicians’ unawareness of this type of complication.

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism

Essentials Current standard of care (SOC) for pediatric venous thromboembolism (VTE) has limitations. Dabigatran etexilate (DE) versus SOC will be studied in children with VTE in a phase IIb/III trial. A dosing algorithm for DE in children will be assessed guiding dosing. Valuable data on the safety and efficacy of DE for VTE in children will be obtained.

Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.

Otogenic lateral sinus thrombosis in children: proposal of an experience-based treatment flowchart

PurposeTo describe the prevalent clinical, laboratory, and radiological features of otogenic lateral sinus thrombosis (OLST) in children; to identify clinical predictors of outcome; to propose a management algorithm derived from experience.MethodsA retrospective review was conducted of the clinical records of patients with OLST, treated in a single tertiary care referral center for pediatric disease from 2006 to 2017. The inclusion criteria were pediatric age (0–16xa0years) and OLST diagnosis confirmed by a pre- and post-contrast CT or venography–MRI scan. Primary outcome measures were early (1–2xa0months) and late (6xa0months) sinus recanalization assessed by means of neuroimaging.ResultsTwenty-five patients (8 females and 17 males; mean ageu2009=u20096u2009±u20093xa0years) were included. A genetic abnormality associated with thrombophilia was found in 24 (96%) patients. At diagnosis, anticoagulant treatment with low-molecular-weight heparin (LMWH) was started in all subjects, while surgical treatment (mastoidectomy and tympanostomy tube insertion) was performed in 16/25 (64%) patients. Follow-up neuroimaging showed lateral sinus recanalization in 12/25 (48%) patients after 1–2xa0months and in 17/25 (68%) after 6xa0months. At multivariate logistic regression analysis, no significant predictors of the early and late neuroradiological outcome were found.ConclusionsAll children with OLST should be screened for thrombophilia to decide on treatment duration and to assess the need for future antithrombotic prophylaxis. Immediately after diagnosis, anticoagulant treatment with LMWH should be started according to the international guidelines. Instead, our experience suggests that surgical treatment should not be indicated in all patients, but decided on a case-to-case basis.

Sometimes it is better to wait: First Italian case of a newborn with transient abnormal myelopoiesis and a favorable prognosis

Congenital leukemia is rare disease with an incidence of one to five cases per million births. Transient abnormal myelopoiesis (TAM), also called transient myeloproliferative disorder, is a pre-leukemia disorder that may occur in Down syndrome (DS) or non-DS infants. TAM may enter spontaneous remission; however, continual monitoring is required, as this disorder has been observed to develop into acute megakaryoblastic leukemia in 16–30% of cases. In the literature, 16 cases of TAM in non-DS infants have been reported. The case presented in the current study is, to the best of our knowledge, the first case of an Italian non-DS newborn presenting with clinical manifestations of acute leukemia at five days after birth, exhibiting a normal karyotype, trisomy 21 only in blast cells, and spontaneous remission. Chromosomal analyses on peripheral blood cells, bone marrow cells and dermal fibroblasts were conducted using a G-banding technique, and fluorescence in situ hybridization (FISH) was used to identify the critical regions of DS. Amplification of GATA binding protein 1 (GATA1) exon 2 genomic DNA was performed using polymerase chain reaction. Cytogenetic analysis of 50 peripheral blood cells and dermal fibroblasts from the patient revealed a normal karyotype: 46, XX. Conversely, cytogenetic analysis of the patients bone marrow revealed an abnormal karyotype 47, XX+21. In order to investigate this result, FISH was performed, which identified the presence of three signals in 70% of the cells and two signals in 30% of bone marrow cells. GATA1 sequencing revealed the substitution of a single base (c.150delG) in exon 2. Seven months after the initial analysis, FISH and cytogenetic analyses of the stimulated/unstimulated peripheral blood cells and bone marrow cells were performed, revealing that each exhibited diploid signals, as observed in a normal karyotype.

A refined approach to detect and measure minimal residual disease in childhood acute myeloid leukemia by flow cytometry

Event-free survival for children with acute myeloid leukemia (AML) ranges between 40% and 60% [1,2]. Risk stratification of patients with AML mainly relies on cytogenetic/ genetic classification and morphological response to induction therapy. However, assessment of response to chemotherapy by conventional morphology is subjective and lacks sensitivity. Thus, high-resolution methods such as real-time quantitative polymerase chain reaction (RQ-PCR) and flow cytometry (FCM) have been recently proposed to detect minimal residual disease (MRD) [3]. Notwithstanding its high sensitivity, RQ-PCR can be used only in a fraction of patients and cannot precisely calculate MRD because the amount of PCR product does not accurately reflect cell number [3]. MRD quantification by FCM has a significant prognostic value in predicting both risk of relapse and survival [4]. Recently, FCM has been successfully used for the final risk assignment determining the timing and the intensity of therapy in childhood AML [2]. The main limitation of MRD monitoring by FCM is the requirement of highly specialized skills and experience to distinguish MRD among the different populations arising in the bone marrow in the reconstitution phase following chemotherapy or transplantation [3,5,6]. Limited information is available on FCM characterization of myeloid developmental stages during normal hematopoiesis [5,6]. This knowledge is indispensable to discriminate MRD by FCM in AML [3,6]. Here, we describe a simple and most effective approach to detect MRD in AML, based on the characterization and distinction of normal precursors from leukemia cells.