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Febrile neutropenia (FN) represents one of the main complications of pediatric patients with oncological and hematological diseases. In these patients, it is crucial to identify bacterial infections. The aim of this study is to evaluate presepsin as an early biomarker of bacterial infections during FN. We compared patients with oncological and hematological diseases and a 2:1 age-matched healthy control group. In the FN group, we evaluated 4 biomarkers, namely, C reactive protein (CRP), procalcitonin (PCT), interleukin 6 (IL6) and presepsin at the onset of fever (T0) and 48 h after T0 (T1). In the control group, we only evaluated presepsin. We enrolled a total of 41 children with oncological and hematological diseases disease experiencing 50 FN episodes and 100 healthy patients in the control group. In patients with FN, we found that presepsin was significantly higher than in the control group (p p = 0.989 at T0, p = 0.619 at T1). Presepsin values at T1 were higher in patients experiencing an unfavorable outcome (p = 0.025). This study shows that presepsin increases in neutropenic patients, but it only revealed useful in predicting an unfavorable outcome 48 h from the onset of fever.

Immediate breast reconstruction is recommended for eligible patients undergoing mastectomy, raising the issue of economic sustainability of both mastectomy and breast reconstruction performed within the same hospitalization, as opposed to two surgical procedures in two different hospitalizations.A retrospective analysis was conducted to compare economic sustainability of mastectomies with or without immediate breast reconstruction.Economic data on hospitalizations for mastectomy in a Teaching Hospital between 1 January 2019 and 31 March 2021 were analyzed to assess their sustainability.338 admissions were selected (63.9% with immediate breast reconstruction (CI 99%: 57.2% to 70.6%). Compared to mastectomy alone, mastectomy with immediate breast reconstruction had higher cost of € 2,245 (p0.001), with operating rooms and devices as main cost drivers. Current reimbursements rates (which are the same for mastectomy alone and for mastectomy with immediate breast reconstruction) led to an average loss of € 1,719 for each mastectomy with immediate breast reconstruction.Current DRGs reimbursement rates for hospital admissions for breast cancer surgery do not guarantee immediate breast reconstruction's economic sustainability. DRGs system should be revised, or other solutions as bundled payment should be implemented in the light of the costs of innovation in healthcare, considering mastectomy and breast reconstruction steps in a path of linked actions aimed at improving patients' health.

Additional file 1: Supplementary Figure S1. Photographs of patient III-3; Supplementary Figure S2. Bone marrow aspirate smear from patient III.2; Supplementary Figure S3. Sanger sequencing validations of CBL c.1141T>C (A) and SH2B3 c.1697G>A (B) mutations performed on peripheral blood cells of II.2 and III.2; Supplementary Table S1. Immunoglobulin (Ig) levels and antibody responses.

Nipple-sparing mastectomy is an oncologically validated technique for selected breast cancer patients and allows to improve aesthetic results and patients' quality of life. Conventional skin incisions are often a suboptimal solution due to the visibility of the scars. Aim of this work is to show our innovative technique, which allows to perform nipple-sparing mastectomy, lymph-node surgery, and endoscopic immediate prosthetic breast reconstruction using a single cosmetic axillary incision.Between June 2016 and October 2019, 14 consecutive patients underwent therapeutic nipple- sparing mastectomy with endoscopic immediate reconstruction via axillary incision; inclusion criteria were cup A or B breasts and tumors less than 3 cm in diameter. Data were recorded in order to evaluate reproducibility, feasibility, safety, aesthetic outcomes and patients' quality of life.Mean age was 46 years old (range: 34-54 years); median tumor size was 1.7 cm; average follow-up time was 11 months (range 3-42); median operation time was 340 minutes; mean hospital stay was 4,1 days. Tumor-free margins were obtained in all 14 cases. No local-regional recurrence occurred during follow-up. No major complications were experienced. No systemic complications were observed. All patients were satisfied with their aesthetic results, especially the absence of visible scars.Therapeutic nipple-sparing mastectomy with endoscopic immediate prosthetic reconstruction via axillary incision is a safe and appropriate procedure in cup A and B breasts, alternative to conventional techniques. It allows to improve aesthetic outcomes and patients' quality of life thanks to a single well-hidden axillary scar.Axillary Incision, Breast Cancer, Endoscopic Breast Reconstruction, Nipple-Sparing Mastectomy, Oncological and Aesthetic Outcomes, Quality of Life.Oggi, la chirurgia conservativa (BCS) associata alla radioterapia adiuvante è stata definitivamente convalidata come il trattamento standard delle pazienti con carcinoma mammario in fase iniziale. La mastectomia rimane una valida alternativa chirurgica in casi selezionati ed è generalmente associata a procedure ricostruttive immediate. Quando la BCS non può garantire un adeguato controllo locale e buoni risultati estetici, è necessario optare per una mastectomia totale. Varie tecniche chirurgiche possono essere adottate quando si pianifica una mastectomia, ma negli ultimi anni sono emerse nuove procedure chiamate “mastectomie conservative”. La più innovativa di queste procedure è la mastectomia “nipple-sparing” (NSM) che consente di rimuovere l’intero tessuto ghiandolare preservando l’involucro cutaneo e il complesso capezzolo-areola (NAC). La NSM è oncologicamente sicura e consente di ottenere un elevato grado di soddisfazione da parte delle pazienti con risultati estetici migliori rispetto ad altre mastectomie tradizionali. Le incisioni cutanee più comunemente utilizzate nella NSM sono quella laterale-radiale, inframammaria, periareolare con estensione laterale e transareolare con estensione laterale. Tuttavia, queste incisioni convenzionali sono una soluzione cosmetica non ottimale e imperfetta a causa della visibilità delle cicatrici, del “deposizionamento” dei capezzoli e del rischio di danni vascolari al NAC. Lo scopo di questo lavoro è mostrare la nostra innovativa tecnica chirurgica, che consente di eseguire contestualmente una NSM in sicurezza, il trattamento chirurgico dei linfonodi ascellari ed una ricostruzione protesica endoscopica immediata del seno utilizzando un’unica incisione ascellare cosmetica.

Interstitial lung disease is a rare disorder that has various etiologies and clinical presentations. Some interstitial lung diseases are more common in infancy period, which is not similar to interstitial lung disease in childhood or adult. Every infant presenting with early respiratory distress/failure or chronic respiratory symptoms without reasonable cause together with diffuse pulmonary infiltration should be sought out for interstitial lung diseases after excluding other common conditions of diffuse lung disease. This review focuses on interstitial lung disease in infant or in first year of life in the scope of classification system, systematic approach, investigations, clinical presentations, imaging findings, pathological findings, managements and prognosis. Early recognition of clinical and characteristic of imaging findings of ILD in infants can lead to prompt diagnosis and proper management.

Freeze drying (Lyophilization) performed at temperature and pressure below the triple point is being practiced for the preservation of virus stocks for longer periods. The present study is aimed to lyophilize influenza virus strain to study its effects on infectivity and viral load.

Additional file 1. Composition of the enteral nutrition formula.

Additional file 1. The altered transcriptome of pediatric myelodysplastic syndrome revealed by RNA sequencing.

Figure S1. PCoA based on Bray-Curtis distances of genus-level relative abundance profiles of the samples sequenced in the present study using Illumina HiSeq and those from the study of Biagi et al. [7] sequenced by Roche 454 pyrosequencing. Figure S2. PCoA based on Bray-Curtis distances of genus-level relative abundance profiles of samples taken from patients aged 12 years, before, 12–28 days after, and > 30 days after HSCT. Figure S3. PCoA based on Bray-Curtis distances of genus-level relative abundance profiles of samples taken from patients hospitalized in the four centers before, 12–28 days after, and > 30 days after HSCT. Figure S4. Box and whiskers distribution of the relative abundance (%) of OTUs assigned to the genera Enterococcus, Citrobacter and Erwinia, in samples grouped as pre-HSCT, engraftment and post-HSCT, for the four enrollment centers. Figure S5. Box and whiskers distribution of the Simpson diversity index calculated for the genus-level microbiota profiles in samples taken before HSCT from subjects who did not develop aGvHD, who developed aGvHD (I-II grade) at a skin level, and who developed gastrointestinal aGvHD (II-IV grade). Figure S6. Box and whiskers distribution of the Bray-Curtis distances calculated using the genus-level gut microbiota profiles of samples taken before HSCT from subjects who did not develop aGvHD, who developed aGvHD (I-II grade) at a skin level, and who developed gastrointestinal aGvHD (II-IV grade). Figure S7. PCoA based on Bray-Curtis distances of genus-level relative abundance profiles of samples taken > 30 days after HSCT from patients who did not develop aGvHD, who developed aGvHD (I-II grade) at a skin level, and who developed gastrointestinal aGvHD (II-IV grade). (PDF 305 kb)

Tables S1. Average relative abundances in pre-HSCT and engraftment samples, of the main discriminant genera between the two time points in subjects who did not develop aGvHD (non-aGvHD), who developed aGvHD (I-II grade) at a skin level (Skin aGvHD), and who developed gastrointestinal aGvHD (II-IV grade) (Gut aGvHD) (Wilcoxon test, P ≤ 0.05, in bold, in at least one group of subjects). P values between 0.05 and 0.1 are reported in italics, whereas P values > 0.1 are reported as “ns”, not significant. (PDF 257 kb)

Tables of linear regression analysis and multivariate analysis. Due to the large amount of data which would have been impractical to attach to the end of this manuscript, the authors provides this file with seventeen detailed tables (from “Table 10” to “Table 26”) supporting the results of the analysis. (DOCX 46 kb)

Tables of t-test analysis between patient’s cohort subgroups. Due to the large amount of data which would have been impractical to attach to the end of this manuscript, the authors provides this file with eight detailed tables (from “Table 2” to “Table 9”) supporting the results of the analysis. (DOCX 145 kb)

Materials and methods. (DOCX 22Â kb)

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631.

Oncoplastic surgery of the breast has generated great excitement over the past years and has become an integrated component of the surgical treatment of breast cancer. Oncoplastic procedures (OPP) associate the best surgical oncologic principles to achieve wide tumor-free margins with the best principles of plastic surgery to optimize cosmetic outcomes. Thanks to oncoplastic techniques, the role of breast conserving surgery (BCS) has been extended to include a group of patients who would otherwise require mastectomy to achieve adeguate tumor clearance. However, even with the use of OPP, cosmetic outcomes may result unsatisfying when a large volume of parenchyma has to be removed, particularly in small-medium size breasts. Recently, it has been proposed the use of ORC (Oxidized Regenerated Cellulose) as a reconstructive biomaterial to optimize the aesthetic results after OPP. The aim of this article is to describe the standard pattern of an innovative surgical oncoplastic technique with ORC, that we have called "QUORC" (QUadrantectomy with Oxidized Regenerated Cellulose), to improve cosmetic results and minimize the possible postoperative complications.Breast cancer, Cosmetic results, Oncoplastic surgery results, Oxidized regenerated cellulose, QUORC.La chirurgia oncoplastica della mammella ha generato grande entusiasmo negli ultimi anni ed è diventata una componente integrante ed essenziale del trattamento chirurgico dei tumori del seno. Le tecniche oncoplastiche associano i migliori principi della chirurgia oncologica con i migliori principi della chirurgia plastica per ottenere margini indenni da malattia ed al tempo stesso ottimizzare i risultati estetici. Grazie a queste procedure, il trattamento conservativo della mammella è stato esteso ad includere un gruppo di pazienti che altrimenti richiederebbero una mastectomia per ottenere radicalità oncologica. Tuttavia, anche con l’uso delle procedure oncoplastiche, gli esiti cosmetici possono risultare insoddisfacenti nei tumori di voluminose dimensioni in cui è necessario eseguire ampie exeresi parenchimali in particolare in seni di medio-piccole dimensioni. Recentemente, è stato quindi proposto l’uso di Cellulosa Ossidata Rigenerata come biomateriale ricostruttivo per ottimizzare i risultati estetici dopo chirurgia oncoplastica. Lo scopo di questo articolo è quello di descrivere il modello standard di una innovativa tecnica oncoplastica con cellulose ossidata, che abbiamo denominato “QUORC“ (QUadrantectomy with Oxidized Regenerated Cellulose), grazie alla quale sembra possibile migliorare i risultati estetici e ridurre al minimo le possibili complicanze post-operatorie.

Oncoplastic surgery of the breast has generated great excitement over the past years and has become an integrated component of the surgical treatment of breast cancer. Oncoplastic procedures (OPP) associate the best surgical oncologic principles to achieve wide tumor-free margins with the best principles of plastic surgery to optimize cosmetic outcomes. So, a number of conventional mammoplasty techniques have been adapted to allow reconstruction of resection defects with parenchymal flaps using a variety of different approaches. Thanks to these oncoplastic techniques, the role of breast conserving surgery (BCS) has been extended to include a group of patients who would otherwise require mastectomy to achieve adeguate tumor clearance. However, even with the use of therapeutic mammoplasties, cosmetic outcomes may result unsatisfying when a large volume of parenchyma has to be removed, particularly in medium size breasts and for tumor localized in unfavourable location as central, inner-upper and lower quadrants. Recently, it has been proposed the use of oxidized regenerated cellulose (ORC) as a reconstructive biomaterial to optimize the aesthetic results after OPP. The aim of this article is to describe the standard pattern of an innovative surgical oncoplastic technique with ORC, that we have called "QUORC" (QUadrantectomy with Oxidized Regenerated Cellulose), to improve cosmetic results and minimize the possible postoperative complications after therapeutic mammaplasties.Breast cancer, Cosmetic results, Oncoplastic surgery, Oxidized regenerated cellulose, QUORC technique.La chirurgia oncoplastica della mammella ha suscitato grande interesse negli ultimi anni ed è progressivamente divenuta una componente integrante ed essenziale del trattamento chirurgico conservativo dei tumori del seno. Le tecniche di chirurgia oncoplastica combinano i migliori principi della chirurgia oncologica con in migliori principi della chirurgia plastica con lo scopo di ottenere margini indenni da malattia ed al tempo stesso ottimizzare i risultati estetici. In particolare le tecniche di mastoplastica riduttiva sono state applicate in pazienti con seni medio-grandi e ptosici per ottimizzare i risultati oncologici ed estetici. Grazie a queste procedure il trattamento conservativo della mammella è stato esteso ad includere un gruppo di pazienti che altrimenti avrebbero richiesto una mastectomia associata a complessi interventi di ricostruzione mammaria. Tuttavia anche con l’applicazione delle tecniche di mastoplastica riduttiva gli esiti cosmetici possono risultare insoddisfacenti, in particolar modo in pazienti con seni medi che richiedono ampie resezioni parenchimali per tumori di voluminose dimensioni, localizzati nei quadranti supero-interni o inferiori. Recentemente è stato quindi proposto l’utilizzo della cellulosa ossidata rigenerata come biomateriale ricostruttivo per ottimizzare i risultati estetici nella chirurgia oncoplastica. Lo scopo di questo articolo è quello di descrivere il modello standard di una innovativa tecnica oncoplastica con cellulosa ossidata rigenerata che abbiamo denominato “QUORC” (QUadrantectomy with Oxidized Regenerated Cellulose) grazie alla quale sembra possibile migliorare i risultati estetici e ridurre al minimo le possibile complicanze post-operatorie, come infezioni ed ematomi, nella chirurgia oncoplastica con tecnica di mastoplastica riduttiva.

e12618 Background: Conservative mastectomy with immediate prosthetic breast reconstruction (IPBR) is an oncologically accepted technique that allows to improve aesthetic results and patient quality of life. Traditionally, implants have been placed in a submuscolar (SM) plane beneath the pectoralis major muscle (PMM). Recently, prepectoral (PP) placement of prosthesis is increasingly used in order to avoid morbidities related to manipulation of PMM. The aim of this study was to compare outcomes of SM vs PP IPBR after conservative mastectomy in patients with histologically proven breast cancer treated with neoadjuvant chemotherapy (NAC). Methods: In this retrospective observational study we analyzed two cohorts of patients that underwent mastectomy with IPBR after NAC in our Istitution from January 2018 to December 2021. Conservative mastectomy was performed in 155 of the 400 patients that underwent NAC during the study period. Patients were divided in 2 groups based on the positioning of implants: 60 SM versus 95 PP. Results: The two cohorts were similar for age (mean age 45 and 42 years in the SM and PP group respectively) and follow‐up (32 and 21 months, respectively). Mean operative time was 55 minutes shorter in the PP group (298 and 243 minutes in the SM and PP group). No significant differences were observed in overall major complication rates. Implant loss occurred was observed in 1.6% of patients (1/60) in the SM group and 1,05% of patients (1/95) in PP group. No differences were observed among the two groups in local or regional recurrence. Conclusions: Our preliminary experience, that represents one of the largest series of PP-IPBR after NAC at a single Institution documented in the Literature, seems to confirm that PP - IPBR after NAC is a safe, reliable and effective alternative to traditional SM - IPBR with excellent aesthetic and oncological outcomes; it is easy to perfom, reduces operative time and minimizes complications related to manipolation of PPM. However this promising results need to be confirmed in prospective trials with longer follow-up.

The surgical management of breast cancer has been undergoing continuous and profound changes over the last 40 years. The evolution from aggressive and mutilating treatment to conservative approach has been long but constant, despite the controversies arising every time a new procedure came to light. Today, the esthetic satisfaction of breast cancer patients coupled with oncological safety is the goal of the modern breast surgeon. Breast-conserving surgery with adjuvant radiotherapy is considered the gold standard approach for patients with early stage breast cancer and the recent introduction of "oncoplastic techniques" has furtherly increased the use of breast-conserving procedures. Mastectomy still remains a valid surgical alternative in selected cases and is usually associated with immediate reconstructive procedures. New surgical procedures called "conservative mastectomies" are emerging as techniques that combine oncological safety and esthetic outcome by entirely removing the breast parenchyma sparing the breast skin and nipple-areola complex. Staging of the axilla has also gradually evolved toward less aggressive approaches with the adoption of sentinel node biopsy and new therapeutic strategies are emerging in patients with a pathological positivity in sentinel lymph node biopsy. The present special article will highlight the new surgical treatment options, which are more and more effective and respectful of breast cancer patients.

MYCN is an oncogene frequently overexpressed in pediatric solid tumors whereas few evidences suggest his involvement in the pathogenesis of haematologic malignancies. Here we show that MYCN is overexpressed in a relevant proportion (40 to 50%) of adult and pediatric T-cell acute lymphoblastic leukemias (T-ALL). Focusing on pediatric T-ALL, MYCN-expressing samples were found almost exclusively in the TAL1-positive subgroup. Moreover, TAL1 knockdown in T-ALL cell lines resulted in a reduction of MYCN expression, and TAL1 directly binds to MYCN promoter region, suggesting that TAL1 pathway activation could sustain the up-regulation of MYCN. The role of MYCN in T-ALL was investigated by peptide nucleic acid (PNA-MYCN)-mediated transcriptional silencing of MYCN and by siRNAs. MYCN knockdown in T-ALL cell lines resulted in a reduction of cell viability, up to 50%, while no effect was elicited with a mismatch PNA. The inhibitory effect of PNA-MYCN on cell viability was due to a significant increase in apoptosis. PNA-MYCN treatment in pediatric T-ALL samples reduced cell viability of leukemic cells from patients with high MYCN expression, while no effect was obtained in MYCN-negative blast cells. These results showed that MYCN is frequently overexpressed in pediatric T-ALL and suggested his role as a candidate for molecularly-directed therapies.

The brown marmorated stink bug (BMSB), Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is an Asian invasive plant-feeding insect and an emerging kiwifruit pest. Knowledge about the BMSB dynamics and damage to kiwifruit outside the bug native range is scarce. This 2-yr study was aimed at describing phenology and infestation dynamics of BMSB in green-fleshed and yellow-fleshed kiwifruits. Natural enemies were investigated as well. Field surveys were performed weekly in two sites in Northern Italy by pheromone-baited traps and visual samplings, from early Spring to mid-Autumn. All BMSB life stages were collected and kept under observation to assess occurrence of parasitoids. A sample of fruit was dissected weekly to detect BMSB feeding injuries. In 2018–2019, BMSB was found throughout the growing season with two generations per year with a large overlapping of all life stages. Pheromone-baited traps and visual samplings gave consistent results and can be both considered effective sampling methods on kiwifruit. Fruit injuries were significantly related to kiwifruit development stage, weekly captures of BMSBs by traps, and cultivar. Several BMSB egg masses were found on kiwifruit leaves. Anastatus bifasciatus Geoffroy (Hymenoptera: Eupelmidae), a native egg parasitoid with Palearctic distribution, emerged from 20.14% of eggs in 2018, but the percent parasitism dropped to 0.47% in 2019. In both years, other natural enemies were found exerting negligible pressure on BMSB populations. The determination of reliable economic thresholds for BMSB on kiwifruit is urgently needed to develop a robust and sustainable integrated pest management (IPM) strategy, and this study provides data towards that direction.

BackgroundCBL syndrome is a RASopathy caused by heterozygous germline mutations of the Casitas B-lineage lymphoma (CBL) gene. It is characterized by heterogeneous clinical phenotype, including developmental delay, facial dysmorphisms, cardiovascular malformations and an increased risk of cancer development, particularly juvenile myelomonocytic leukemia (JMML). Although the clinical phenotype has been progressively defined in recent years, immunological manifestations have not been well elucidated to date.MethodsWe studied the genetic, immunological, coagulative, and clinical profile of a family with CBL syndrome that came to our observation after the diagnosis of JMML, with homozygous CBL mutation, in one of the members.ResultsVariant analysis revealed the co-occurrence of CBL heterozygous mutation (c.1141 T > C) andSH2B3mutation (c.1697G > A) in two other members. Patients carrying both mutations showed an ALPS-like phenotype characterized by lymphoproliferation, cytopenia, increased double-negative T-cells, impaired Fas-mediated lymphocyte apoptosis, altered cell death in PBMC and low TRECs expression. A coagulative work-up was also performed and showed the presence of subclinical coagulative alterations in patients carrying both mutations.ConclusionIn the reported family, we described immune dysregulation, as part of the clinical spectrum of CBL mutation with the co-occurrence of SH2B3.

Simple Summary Nutritional management is an underestimated issue in treating pediatric cancer, since a systematic approach is currently lacking. In this consensus statement, a cohort of 12 experts selected from four different tertiary pediatric oncology centers formulated 21 clinical questions regarding the identification and treatment of nutritional issues in children with cancer. These questions were discussed, and practical recommendations were provided. With this paper, we aimed to give consensus-based guidance for addressing the nutritional needs of children with cancer, filling a gap in the field. Malnutrition, intended as both overnutrition and undernutrition, is a common problem in children with cancer, impacting quality of life as well as survival. In addition, nutritional imbalances during childhood can significantly affect proper growth. Nevertheless, there is currently a lack of a systematic approach to this issue in the pediatric oncology population. To fill this gap, we aimed to provide practice recommendations for the uniform management of nutritional needs in children with cancer. Twenty-one clinical questions addressing evaluation and treatment of nutritional problems in children with cancer were formulated by selected members from four Italian Association of Pediatric Hematology and Oncology (AIEOP) centers and from the Survivorship Care and Nutritional Support Working Group of Alliance Against Cancer. A literature search in PubMed was performed; during two consensus meetings, all recommendations were discussed and finalized using the nominal group technique. Members representing every institution voted on each recommendation. Finally, recommendations were approved by all authors.

Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06–1.24; P = 0.0006) and disease-free survival (relative risk, 1.31; 95% CI, 1.17–1.47; P = 0.0001) in the allo-HSCT group, with increased relapse rate in the chemotherapy group (relative risk, 1.26; 95% CI, 1.07–1.49; P = 0.006). Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring.

The gut microbiome (GM) has emerged in the last few years as a main character in several diseases. In pediatric oncological patients, GM has a role in promoting the disease, modulating the effectiveness of therapies, and determining the clinical outcomes. The therapeutic course for most pediatric cancer influences the GM due to dietary modifications and several administrated drugs, including chemotherapies, antibiotics and immunosuppressants. Interestingly, increasing evidence is uncovering a role of the GM on drug pharmacokinetics and pharmacodynamics, defining a bidirectional relationship. Indeed, the pediatric setting presents some contrasts with respect to the adult, since the GM undergoes a constant multifactorial evolution during childhood following external stimuli (such as diet modification during weaning). In this review, we aim to summarize the available evidence of pharmacomicrobiomics in pediatric oncology.

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS® results in Italy and its impact on treatment decisions. Physicians’ treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2− early BC population studied (N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.

In neonatal period, tumours, although very rare, represent an important cause of morbidity and mortality. The prevalence of neoplasms, within the first month after birth, occurs once in every 12,500–27,500 live births, and malignant tumours develop in approximately 40–50% of them. Diagnosis often occur during prenatal screening or during follow-up for a known cancer predispo- sition syndrome; in fact the presence of congeni- tal anomalies, multifocal or bilateral diseases and cancer in close relatives is suggestive for an underlying cancer predisposition syndrome, and genetic counselling and testing should be consid- ered to investigate these possibilities.

Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.

Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3α (GSK-3α) and GSK-3β dependency leads to aggressive AML. Although GSK-3α deletion alone has no effect, GSK-3β deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3β and GSK-3α uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3β provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3α- and GSK-3β-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution. Guezguez et al. show that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling by Gsk3b allelic deletion results in an MDS state that, when combined with Gsk3a deletion, leads to AML. A molecular signature derived from Gsk3b-null cells has prognostic potential for MDS patients.

Background Cardiotoxic effects of anthracycline therapy are a major cause of morbidity for childhood cancer survivors. The aim of this retrospective evaluation is to assess the efficacy of Tissue Doppler Imaging in the early detection of myocardial alterations in these patients. Methods A population of 50 childhood cancer survivors (32 males and 18 females) who have been treated with anthracyclines was evaluated by standard and TDI echocardiographic examination of the basal and median region of the interventricular septum (IVSb, IVSm), of the left ventricular posterior wall (LVPWb, LVPWm), and of the mitral annulus; the results were compared with those obtained from a population of 50 healthy age-matched and sex-matched controls by using the Student test. The clinical and echocardiographic data of the two groups were compared also with the independent samples t-test. All data were expressed as mean ± standard deviation. A two-tailed P-value

Posterior reversible encephalopathy syndrome (PRES) is a clinical neuroradiologic entity that is becoming increasingly well known and documented in pediatrics. It is characterized by a variable association of seizures, headache, vomiting, altered mental status, visual disturbances, and seizures, as well as imaging suggesting white-gray matter edema involving the posterior regions of the central nervous system in most cases. The pathophysiology of PRES remains unclear. Although PRES has been associated with a widespread range of clinical conditions, namely infections, adverse drug events, autoimmune diseases, and many others, its onset after hematopoietic stem cell and solid organ transplantation remains the most commonly reported. Historically, PRES has proved to be generally reversible and associated with good clinical outcomes; however, severe complications, sometimes life-threatening, can also occur. Most reported cases of childhood PRES after hematopoietic stem cell or solid organ transplantation have been case reports or series across a broad spectrum of different transplant settings, and no clear consensus exists regarding how best to manage the syndrome. Thus, in this article, we provide a comprehensive review of the pathophysiological, clinical, and diagnostic aspects of PRES in children, with a specific focus on the transplant scenario. Differential diagnoses with other neurologic complications after pediatric transplantation are reviewed, and crucial issues in the management of PRES and the development of future research are ultimately addressed.

Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.

To the editor: DNA methyltransferase-inhibiting azanucleosides have become a mainstay of treatment of myeloid neoplasms in adult patients,[1][1] with 5-azacytidine (azacitidine) being the agent in broadest clinical use. Although not curative, treatment with azacitidine achieves hematologic

Oral chronic graft versus host disease (cGVHD) is often refractory to systemic therapies. Additional topical treatment is commonly required. The potency of the agent, the vehicle and formulation in which it is delivered are all critical factors in determining the effectiveness of topical therapies. High potency of budesonide, combined with its very low bioavailability when absorbed through mucosal surfaces, increased the potential role in topical application for oral cGVHD. Viscous formulation increases mucosal contact time resulting in a greater decrease in mucosal inflammation. This short communication suggests that oral viscous budesonide should be considered as a potential new therapy in the management of oral cGVHD.

In children with acute myeloid leukaemia (AML), assessment of initial treatment response is an essential prognostic factor; methods more sensitive than morphology are still under evaluation. We report on the measurement of minimal residual disease (MRD), by multicolour flow-cytometry in one centralized laboratory, in 142 children with newly diagnosed AML enrolled in the Associazione Italiana di EmatoOncologia Pediatrica-AML 2002/01 trial. At the end of the first induction course, MRD was 1% in 51 patients. The 8-year disease-free survival (DFS) of 125 children in morphological complete remission and with MRD

// Riccardo Masetti 1, * , Ilaria Castelli 1, * , Annalisa Astolfi 2 , Salvatore Nicola Bertuccio 1 , Valentina Indio 2 , Marco Togni 1, 3 , Tamara Belotti 1 , Salvatore Serravalle 1 , Giuseppe Tarantino 2 , Marco Zecca 4 , Martina Pigazzi 5 , Giuseppe Basso 5 , Andrea Pession 1, # , Franco Locatelli 6, 7, # 1 Department of Pediatrics “Lalla Seragnoli”, Hematology-Oncology Unit, University of Bologna, Bologna, Italy 2 Interdepartmental Centre of Cancer Research “G. Prodi”, University of Bologna, Bologna, Italy 3 Current address: Stem Cell Group, University College London Cancer Institute, University College London, London, United Kingdom 4 Department of Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 5 Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy 6 Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesu, Rome, Italy 7 University of Pavia, Pavia, Italy * These authors have contributed equally to this work # Both authors have shared co-senior authorship Correspondence to: Riccardo Masetti, email: riccardo.masetti@gmail.com Keywords: pediatric acute myeloid leukemia, acute myeloid leukemia relapse, whole-exome massively parallel sequencing, SETD2 mutation, FLT3-TKD mutation Received: April 19, 2016 Accepted: July 10, 2016 Published: July 22, 2016 ABSTRACT Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B over expression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in JMML.

Genetic abnormalities and early treatment response are the main prognostic factors in acute myeloid leukemia (AML). Acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML. Deep sequencing has identified CBFA2T3/GLIS2 and NUP98/KDM5A as recurrent aberrations, occurring in similar frequencies as RBM15/MKL1 and KMT2A-rearrangements. We studied whether these cytogenetic aberrations can be used for risk group stratification. To assess frequencies and outcome parameters of recurrent cytogenetic aberrations in AMKL, samples and clinical data of patients treated by the Associazione Italiana Ematologia Oncologia Pediatrica, Berlin-Frankfurt-Munster Study Group, Children's Oncology Group, Dutch Childhood Oncology Group, and the Saint Louis Hôpital were collected, enabling us to screen 153 newly diagnosed pediatric AMKL cases for the aforementioned aberrations and to study their clinical characteristics and outcome. CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive. RBM15/MKL1-rearranged patients were significantly younger. No significant differences in sex and white blood cell count were found. NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions. NCK-7-patients (n = 61) showed a 4-year probability of overall survival of 35 ± 6% vs 70 ± 5% in the RBM15/MKL1-other groups (n = 92, P < .0001) and 4-year probability of event-free survival of 33 ± 6% vs 62 ± 5% (P = .0013), the 4-year cumulative incidence of relapse being 42 ± 7% and 19 ± 4% (P = .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring.

Children aged 0–2 years (i.e., infants) with acute myeloid leukemia (AML) are a peculiar subgroup of patients in the childhood AML scenario. They present with distinctive biological and clinical characteristics, including a high prevalence of prognostically unfavorable risk factors and an increased susceptibility to therapy-related toxicity. Remarkable improvements have been achieved over the last two decades in the treatment of these patients and their outcome is becoming superimposable to that of the older age groups. In this review, we will focus on peculiarities of this young subgroup of children with AML, describing their clinical presentation, the biology of disease, and factors influencing outcome. Treatment results and toxicity data reported by major collaborative groups are also summarized and compared.

Overexpression of antiapoptotic proteins occurs frequently in cancer, resulting in defective apoptosis that may contribute to a poor chemosensitivity of tumor cells. B-cell lymphoma (BCL) 2–associated AthanoGene-1 (BAG-1) is a prosurvival chaperone recently found involved in the maintenance of acute myeloid leukemia (AML) cells survival in vitro. Here we reported BAG-1 upregulation in 87 of 99 analyzed AML patients with respect to healthy control samples applying reverse phase protein assay. Silencing of BAG-1 expression confirmed a decreased BCL-2 protein level but, in addition, provoked the increased transcription of GADD34 stress sensor. Furthermore, a dephosphorylation of eIF2α, as well as alteration of expression of IRE-1 and CHOP proteins, were documented, suggesting that a disruption of the endoplasmic reticulum stress/unfolded protein response was provoked by downregulation of BAG-1. A similar phenomenon was triggered after addition of Thioflavin S, which was shown to block BAG-1/BCL-2 interaction and to increase cell death, enforcing a prosurvival role of the BAG-1 protein in AML. Interestingly, synergic cytotoxic effects of doxorubicin, VP16 drugs, and ABT-737 compound were observed when Thioflavin S was coupled with these drugs. Taken together, our results gave further proof that upregulation of BAG-1 plays a critical role in AML and that BAG-1 targeting might be considered for a combined therapeutic strategy with conventional chemotherapy drugs in the treatment of AML patients.