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HC is a possible cause of morbidity and extended hospitalization after HSCT. Recent studies have reported the efficiency of HOT in adult patients who underwent allogeneic HSCT, but data in children are scarce. We report our single center experience with HOT in late-onset HC after HSCT. Treatment with HOT consisted of daily sessions of breathing 100% O(2) for a total of 75 min in the hyperbaric chamber with a minimum of eight sessions. HOT had been associated with a concomitant treatment with oral oxybutynin, hyperhydration and/or irrigation of the bladder through the catheter. Cidofovir had been administered based on the demonstration of viral infection. Between 2004 and 2011, 10 patients developed severe HC after a median of 26 days after HSCT. HOT was started after a median of six days since the clinical diagnosis of HC. After a median of 10 sessions of HOT, seven of 10 patients were in complete remission. HOT is a well-tolerated procedure also in the pediatric setting. The early start of HOT might be effective in the treatment of HC offering advantages in terms of duration of symptoms and hospitalization.

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among 'Nordic' origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-alpha gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90-95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL.

Hematopoietic stem cell transplantation for curing children with severe autoimmune diseases: Is this a valid option? Abstract: The cure of children with severe AD, especially patients with severe, progressive, and therapy-resistant autoimmunity, represents a challenge for current medical practice. The idea of HSCT as a promising therapeutic opportunity was borne accidentally from finding patients who, after undergoing HSCT for a hematological indication, were cured of a concomitant AD. Thus, over the last two decades, HSCT has been extensively investigated, and it has become an appealing therapy for rheumatological (juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) and hematological diseases (immune cytopenias). Recently, interesting results have been also described in type 1 diabetes mellitus and Crohns disease. Although the use of HSCT has been steadily rising in the last few years, many questions are still open, especially after the discoveries of many new biological agents. Given the low incidence of ADs in children, most of the data about the use of the HSCT for these diseases are taken from a mixed cohort of adults and children. The aim of this review is to summarize the published studies and to try to answer the question as to whether this procedure can be considered a promising approach.

Introduction and aim: Childhood cytogenetically normal acute myeloid leukemia (CN-AML) is a subgroup of pediatric AML lacking any known cytogenetic and abnormality. CN-AML accounts for 20% of pediatric AML and exhibits a very heterogeneous response to treatment and, consequently, variable outcome. With the aim of providing new insights into the molecular lesions of this subset of AML, we analyzed, through RNA-seq, 13 cases of pediatric CN-AML, corroborating our findings in an independent cohort of 152 AML patients enrolled in the AIEOP AML 2002/01 clinical trial. Methods: Paired-end RNA-seq (75×2) was performed on PoliA(+) RNA extracted from blasts at diagnosis. ChimeraScan, deFuse and FusionMap algorithms were used for chimeric transcript detection. Results: An alteration that was present in 2 out 13 cases was a chimeric transcript involving the genes nucleoporin 98kDa (NUP98) and PHD finger protein 23 (PHF23), resulting from a cryptic translocation t(11;17)(p15;p13). Both patients showed an in-frame fusion between exon 13 of NUP98 and exon 4 of PHF23 that was confirmed by RT-PCR analysis and Sanger sequencing. To date, the cryptic translocation t(11;17)(p15;p13) was never described before in pediatric AML and has been reported only once in an adult AML patient (Reader, et al. Leukemia 2007). In both our patients the same breakpoint in PHF23 gene at the beginning of exon 4 was present, which was different from that present in the adult patient. To assess the incidence of NUP98-PHF23 fusion in pediatric CN-AML, then we studied by RT-PCR and Sanger sequencing a validation cohort of 152 CN-AML children negative for the most common recurrent cytogenetic and molecular lesions, i.e. those involving MLL, CBFB, NPM1 and FLT3. Overall, 2 out of the 152 CN-AML cases were found positive for NUP98-PHF23, demonstrating that this genomic aberrancy is not rare in pediatric CN-AML (tentative frequency 2.4%). Fluorescence in situ hybridization analysis confirmed the cryptic chromosomal translocation t(7;11)(p15;p13) leading to the fusion between NUP98 and PHF23 in all cases. Conclusions: Lately, genome-wide approaches have been widely used to investigate the mutational landscape of CN-AML in adults. However, the genetic profile of childhood CN-AML still needs to be defined. Here, for the first time, we report the identification of a NUP98-PHF23 chimeric transcript in pediatric CN-AML. Together with recently published data demonstrating that NUP98-PHF23 promoted leukemogenesis and the observation that treatment with inhibitors of PHD-domain-mediated H3K4me3 binding, such as disulfiram (an FDA-approved drug), could selectively killed cells expressing NUP98-PHF23 (Gough, et al Cancer Discovery 2014), our findings enforce the role of epigenetic regulators in pediatric AML and suggest screening for this fusion gene at diagnosis in CN-AML pediatric patients. Citation Format: Marco Togni, Riccardo Masetti, Martina Pigazzi, Annalisa Astolfi, Daniele Zama, Valentina Indio, Salvatore Serravalle, Elena Manara, Valeria Bisio, Sergio Rutella, Franca Fagioli, Giuseppe Basso, Andrea Pession, Franco Locatelli. NUP98-PHF23 is a novel fusion gene in pediatric cytogenetically normal acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-211. doi:10.1158/1538-7445.AM2015-LB-211

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Background and aims: Apnoea of prematurity (AOP) is a frequent clinical issue in the management of preterm infants; its relationship with gastroesophageal reflux (GER) is widely debated. In a previous study we highlighted an increase of the frequency of AOP after GER (GER-induced AOP). The aim of the present study is to evaluate the effect of an amylopectin-thickened formula specifically designed for preterm infants on AOP and on GER-induced AOP. Materials and Methods: Eighteen preterm infants (gestational age < 32 weeks) with recurrent apnoeas underwent a six-hours simultaneous and synchronized recording of polysomnography and pH-impedance monitoring (pH-MII). Each oral/nasal flow cessation lasting at least 5 seconds was considered as apnoea. Apnoeas detected within 30 seconds after the onset of GER were defined as GER-induced. Each patient received 2 meals, one of preterm formula (PF) and the other of a thickened formula specifically designed to satisfy preterm infants' nutritional needs (TPF). AOP and GER-induced AOP detected after PF and TPF meals were compared. Results: One-hundred-twenty-seven apnoeas were recorded after TPF (mean 5/patient, range 0-21), whereas 118 apnoeas were recorded after PF (mean 4.5, range 0-27). A lower number of GER-induced AOP was detected after TPF meals (3 vs 7 after PF meals). Conclusions: Preliminary results of the present study show that a thickened formula specifically designed for preterm infants is ineffective in reducing the total number of AOP, while it could be beneficial on GER-induced AOP. Further data from a larger population are needed to confirm these results.

Background To evaluate whether physical and/or chemical features of gastro-esophageal reflux (GER) influence its relationship with apnea of prematurity (AOP). Methods Fifty-eight preterm newborns (GA ≤33 weeks) with recurrent apneas were studied by simultaneous polysomnography and combined impedance and pH monitoring, to analyze whether the correlation between GER and AOP varies according to the acidity, duration and height of GERs. Key Results The frequency of apnea (number apnea/min) occurring after-GER [median (range) 0.07 (0–0.25)] was higher than the one detected in GER-free period [0.06 (0.04–0.13), P = 0.015], and also than the one detected before-GER [0 (0–0.8), P = 0.000]. The frequency of apneas detected in the 30’’ after pH-GER [median (range), 0 min−1 (0–1.09)] was higher than the frequency detected in the 30’’ before [0 (0–0.91), P = 0.04]; even more, the frequency of apneas detected after non-acid MII-GER episodes [0 (0–2)] was significantly higher than the one detected before [0 (0–1), P = 0.000], whereas the frequency of apneas detected before acid MII-GER episodes [0 (0–0.67)] did not differ from the one detected after [0 (0–2), P = 0.137]. The frequency of pathological apneas detected in the 30’’ after-GER (0 min−1, range 0–0.55) was higher than the frequency detected before (0, range 0–0.09; P = 0.001). No difference in mean height or in mean duration was found between GERs correlated and those non-correlated to apnea. Conclusions & Inferences Non-acid GER is responsible for a variable amount of AOP detected after-GER: this novel finding must be taken into consideration when a therapeutic strategy for this common problem is planned.

Background and aims: Apnoea of prematurity (AOP) is one of the most common and frequently recurring problem in preterm infants and its relationship with gastro-oesophageal reflux (GOR) is widely debated in literature. Our previous study highlights an increase of AOP in periods after GOR. The aim of this study is to evaluate the efficacy of sodium alginate (Gaviscon®) in reducing frequency of AOP related to GOR in preterm infants by a simultaneous and synchronized pH-Intraluminal Impedance Monitoring (pH-MII) and polysomnography in preterm infants. Materials and methods: Twenty-eight preterm infants (gestational age < 33 weeks; mean birth weight 1100 gr) were studied as they had recurrent apneas. Patients who were taking drugs influencing gastrointestinal motility or gastric acidity and infants with malformations, major gastrointestinal problems or sepsis were ruled out. They underwent a six-hour simultaneous and synchronized recording of polysomnography and pH-impedance monitoring (pH-MII). Polysomnography detects apneas by recording of breathing movement, nasal airflow, electrocardiogram and pulse oximeter saturation. To avoid possible artefacts a portable camera video registered the infants during all the recording. We considered as apnoeas each oral/nasal flow cessation lasting at least 5 seconds. Apnoeas were then classified as central (CA), obstructive (OA) and mixed (MA) depending on absence or presence of obstructed respiratory efforts. pH-MII is the state-of-the-art methodology for GOR detection in preterm newborns. By pH-MII monitoring we registered both acid and non acid GORs. A standard period of 30 seconds after the onset of GOR episodes was chosen in order to test the temporal relation between GOR and apnoea. Apnoeas detected within 30 seconds after the onset of a GOR episode were defined GOR-induced. Layouts involved 2 post-prandial periods lasting 3 hours each one, characterized by presence or absence of treatment with Gaviscon® (2cc/kg) after meal. The period after Gaviscon administration was called GAV, the other No-GAV. The meal after which Gaviscon® was administered was randomly assigned in order to avoid any possible carry-over effects. During the analysis of layouts the investigator was blind to the administration of Gaviscon. pH-MII and polysomnography data were independently analyzed by two different investigators and then compared. Data obtained during these two periods were finally compared. Results: Seven-hundred-fifteen apnoeas were recorded during 165 hours of registration and then divided according to the administration of Gaviscon®. Comparing data found after the treatment with those registered during freetreatment periods, we found no differences in number of total apnoeas (AOP during GAV vs NO-GAVwas 12.4±9.5 vs 13.1±12.0 apnoeas/period, p=0.99) and related events (see Table 1).

Aim. Apnoea of prematurity (AOP) is a perplexing disorder of respiratory control that is very common in preterm infants and requires therapeutic intervention to avoid potential morbidity. The existence of a relationship between gastroesophageal reflux (GER) and AOP in preterm infants is still controversial. We aimed to evaluate the relationship between GER and apnoeas in preterm newborns, by the simultaneous and synchronized use of combined Multichannel Intraluminal Impedance and pH-monitoring (pH-MII), and polysomnography (PSG). Methods. Twenty-six preterm infants were studied as they had recurrent apnoeas. They underwent a 6-h simultaneous and synchronized recording of polysomnography and pH-MII. Each registration involved 2 post-prandial periods lasting 3 h each. Polysomnography detects and characterizes apnoeas, desaturations and bradycardia, by recording of breathing movement, nasal airflow, electrocardiogram, pulse oximeter saturation. All apnoeas lasting more than 5 s were considered, and classified as central (CA), obstructive (OA) and mixed apnoeas (MA). By pH-MII we registered acid/non acid GER. The temporal association between GER and apnoea was analysed by the frequency of apnoea in the 30 s preceding and following the onset of GER episodes. Apnoeas detected within thirty seconds after GER were defined GER-triggered. Results. One-hundred-fifty-four apnoeas out of 1136 were detected within 30 second before and/or after the onset of a GER episode. The frequency of apnoea during the 1-min time around the onset of a GER episode (mean 0.17/min; range [0–0.84/min]) was significantly different (p = 0.03) from the one detected during the GER-free period (0.12/min [0–0.43/min]), which is defined as the time difference between the total recording time and the time around all GER episodes. The frequency of apnoea before the onset of GER (0.10/min [0–0.69/min]) did not differ from the one detected during GER-free period (p = 0.17). The frequency of apnoea occurring after the onset of GER (0.25/min [0–1/min]) was higher than the one detected in the GER-free period (p = 0.02), and also than the one detected before the onset of GER (p = 0.01). A great inter-individual variability was documented in the ratio of GER-triggered apnoeas to the total number of apnoeas (median 10.34%, range: 0–20%), as well as in the ratio of GER-triggered apnoeas to the total number of GERs (median 5.77%, range: 0–50%). The increase of apnoeas after GER, defined as the difference between the number of apnoeas detected in the 30 s after GER and the one detected 30 s before GER, was calculated (median 2; range: −2/+8). A significant correlation was found between this difference and the total number of apnoeas (ρ = 0.425, p = 0.034); on the other hand, no correlation was documented between total number of GERs and GER-triggered apnoeas (ρ = 0.019; p = 0.930). Conclusion.We found that, in preterm infants with recurrent apnoeas, these events occur more frequently soon after GER than in the period immediately before GER or GERfree. This suggests that the relationship between GER and AOP is not simply by chance. The ratio of GER-triggered apnoeas to the total number of apnoeas is widely variable. Furthermore, the wide variability in the ratio of GERtriggered apnoeas to the total number of GERs documents that in some newborns a GER episode more likely evokes an apnoea. Patients who had the most significant increase of apnoeas after GER also had the highest number of total apnoeas: in other words, in the most unstable infants also GER episodes can easily act as a trigger event for apnoeas.Onthe other hand, the lack of correlation between GER-triggered apnoeas and total number of GERs highlights that the severity of GER is not predictive by itself of the risk of reflex apnoeas.