GMP-manufactured CRISPR/Cas9 technology as an advantageous tool to support cancer immunotherapy.

BACKGROUND: CRISPR/Cas9 system to treat human-related diseases has achieved significant results and, even if its potential application in cancer research is improving, the application of this approach in clinical practice is still a nascent technology. MAIN BODY: CRISPR/Cas9 technology is not yet used as a single therapy to treat tumors but it can be combined with traditional treatment strategies to provide personalized gene therapy for patients. The combination with chemotherapy, radiation and immunotherapy has been proven to be a powerful means of screening, identifying, validating and correcting tumor targets. Recently, CRISPR/Cas9 technology and CAR T-cell therapies have been integrated to open novel opportunities for the production of more efficient CAR T-cells for all patients. GMP-compatible equipment and reagents are already available for several clinical-grade systems at present, creating the basis and framework for the accelerated development of novel treatment methods. CONCLUSION: Here we will provide a comprehensive collection of the actual GMP-grade CRISPR/Cas9-mediated approaches used to support cancer therapy highlighting how this technology is opening new opportunities for treating tumors.

Pilot scale validation campaign of gel dosimetry for pre-treatment quality assurance in stereotactic radiotherapy.

PURPOSE: Complex stereotactic radiotherapy treatment plans require prior verification. A gel dosimetry system was developed and tested to serve as a high-resolution 3D dosimeter for Quality Assurance (QA) purposes. MATERIALS AND METHODS: A modified version of a polyacrylamide polymer gel dosimeter based on chemical response inhibition was employed. Different sample geometries (cuvettes and phantoms) were manufactured for calibration and QA acquisitions. Irradiations were performed with a Varian Trilogy linac, and analyses of irradiated gel dosimeters were performed via MRI with a 1.5 T Philips Achieva at 1 mm3 or 2 mm3 isotropic spatial resolution. To assess reliability of polymer gel data, 54 stereotactic clinical treatment plans were delivered both on dosimetric gel phantoms and on the Delta4 dosimeter. Results from the two devices were evaluated through a global gamma index over a range of acceptance criteria and compared with each other. RESULTS: A quantitative and tunable control of dosimetric gel response sensitivity was achieved through chemical inhibition. An optimized MRI analysis protocol allowed to acquire high resolution phantom dose data in timeframes of ≈ 1 h. Conversion of gel dosimeter data into absorbed dose was achieved through internal calibration. Polymer gel dosimeters (2 mm3 resolution) and Delta4 presented an agreement within 4.8 % and 2.7 % at the 3 %/1 mm and 2 %/2 mm gamma criteria, respectively. CONCLUSIONS: Gel dosimeters appear as promising tools for high resolution 3D QA. Added complexity of the gel dosimetry protocol may be justifiable in case of small target volumes and steep dose gradients.

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol.

BACKGROUND: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. METHODS: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10-4), and high (≥5∗10-4). RESULTS: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10-4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10-4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). CONCLUSION: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆.

BACKGROUND: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). PATIENTS AND METHODS: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. RESULTS: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. CONCLUSIONS: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755).

Engineered mucoperiosteal scaffold for cleft palate regeneration towards the non-immunogenic transplantation.

Cleft lip and palate (CL/P) is the most prevalent craniofacial birth defect in humans. None of the surgical procedures currently used for CL/P repair lead to definitive correction of hard palate bone interruption. Advances in tissue engineering and regenerative medicine aim to develop new strategies to restore palatal bone interruption by using tissue or organ-decellularized bioscaffolds seeded with host cells. Aim of this study was to set up a new natural scaffold deriving from a decellularized porcine mucoperiosteum, engineered by an innovative micro-perforation procedure based on Quantum Molecular Resonance (QMR) and then subjected to in vitro recellularization with human bone marrow-derived mesenchymal stem cells (hBM-MSCs). Our results demonstrated the efficiency of decellularization treatment gaining a natural, non-immunogenic scaffold with preserved collagen microenvironment that displays a favorable support to hMSC engraftment, spreading and differentiation. Ultrastructural analysis showed that the micro-perforation procedure preserved the collagen mesh, increasing the osteoinductive potential for mesenchymal precursor cells. In conclusion, we developed a novel tissue engineering protocol to obtain a non-immunogenic mucoperiosteal scaffold suitable for allogenic transplantation and CL/P repair. The innovative micro-perforation procedure improving hMSC osteogenic differentiation potentially impacts for enhanced palatal bone regeneration leading to future clinical applications in humans.

Calcium Channel-Dependent Induction of Long-Term Synaptic Plasticity at Excitatory Golgi Cell Synapses of Cerebellum.

Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here, we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca2+ channels, while LTD required uniquely activation of L-type Ca2+ channels. Notably, the voltage dependence of plasticity at the mossy fiber-Golgi cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target cell. In aggregate, this result shows that Golgi cells show cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer.SIGNIFICANCE STATEMENT This article shows for the first time a novel form of Ca2+ channel-dependent synaptic plasticity at the excitatory synapses impinging on cerebellar Golgi cells. This plasticity is bidirectional and inverted with respect to NMDA receptor-dependent paradigms, with long-term depression (LTD) and long-term potentiation (LTP) being favored at depolarized and hyperpolarized potentials, respectively. Furthermore, LTP and LTD induction requires differential involvement of T-type and L-type voltage-gated Ca2+ channels rather than the NMDA receptors alone. These results, along with recent computational predictions, support the idea that Golgi cell plasticity could play a crucial role in controlling information flow through the granular layer along with cerebellar learning and memory.

Arterial grafts for proper palmar digital artery reconstruction: An anatomical study.

Digital ischemia due to arterial defects need urgent surgical management. The traditional treatment consists of vascular reconstruction using a reversed autologous venous graft as a bypass. Very few studies have described the use of arterial grafts for digital artery reconstruction. This cadaver study characterized the forearm perforator arteries to assess the potential feasibility of using them as donor grafts for digital artery reconstruction. Eleven forearms and twenty hands were dissected from freshly injected cadavers. All clinically significant perforators (>0.5 mm) derived from radial or ulnar arteries and digital arteries were evaluated. The digital palmar arteries were measured at three points: metacarpophalangeal (MCP) joint, proximal interphalangeal (PIP) joint, and distal interphalangeal (PIP) joint. In the 11 forearms analyzed, 5.5 ± 1.3 perforators from radial or ulnar arteries with a diameter of at least 0.5 mm were found per dissection. The mean diameters were 0.9 ± 0.18 mm proximally and 0.8 ± 0.15 mm distally; the mean length was 35.6 ± 11.35 mm. The mean diameters for the dominant and non-dominant arteries were 1.5 and 1.3 mm at the MCP, 1.3 and 1.0 mm at the PIP, 0.8 and 0.7 mm at the DIP, respectively. The forearms are good donor sites as they have large-diameter arteries of suitable length for arterial grafting. These new arterial grafts may be suitable for vascular reconstruction of digital arteries starting from the PIP joint.

High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor: a study of the European Society for Blood and Marrow Transplantation.

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia.

We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective "off-the-shelf" immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation.

AIMS: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. METHODS: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. RESULTS: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. CONCLUSIONS: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.

Correction: NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL.

The original version of this Article contained an error in the spelling of the author Juan Carlos Rodriguez-Manzaneque, which was incorrectly given as J Carlos Rodríguez-Manzaneque. This has now been corrected in both the PDF and HTML versions of the Article.

Should we really STOP treating patients with IgA nephropathy with steroids?

IgA nephropathy (IgAN) is the most common primary glomerulonephritis all over the world. Once considered as a benign disease, today the scientific community is aware that a significant percentage of patients eventually progress to end-stage kidney disease (ESKD). The rate of progression is often very slow. Since 1980s, several therapeutic attempts have been made with steroids. Despite different molecules, doses, and lengths of treatment, the majority of uncontrolled and controlled studies found benefits in terms of proteinuria reduction and reduction of the risk of ESKD. This was obtained with reasonable safety and tolerability, especially when steroids are given at relatively low dose and for a period not exceeding 6 months. Recently, two randomized controlled trials have questioned the efficacy and safety of steroid therapy in IgAN. However, these trials have many drawbacks that are to be considered when interpreting the findings.

The course of asthma during pregnancy in a recent, multicase-control study on respiratory health.

BACKGROUND: Over the years it has been widely stated that approximately one-third of asthmatic women experience worsening of the disease during pregnancy. However, the literature has not been reviewed systematically and the meta-analytic reviews include old studies. This study aimed to examine whether the prevalence of worsening asthma during pregnancy is still consistent with prior estimate or it has been reduced. METHODS: A detailed Clinical Questionnaire on respiratory symptoms, medical history, medication, use of services, occupation, social status, home environment and lifestyle was administered to random samples of the Italian population in the frame of the Gene Environment Interactions in Respiratory Diseases (GEIRD) study. Only clinical data belong to 2.606 subjects that completed the clinical stage of the GEIRD study, were used for the present study. RESULTS: Out of 1.351 women, 284 self-reported asthma and 92 of them had at least one pregnancy. When we considered the asthma course during pregnancy, we found that 16 women worsened, 31 remained unchanged, 25 improved. Seven women had not the same course in the different pregnancies and 13 did not know. The starting age of ICS use almost overlaps with that of asthma onset in women with worsening asthma during pregnancy (19 years ± 1.4), unlike the other women who started to use ICS much later (30.3 years ± 12). In addition, the worsening of asthma was more frequent in women with an older age of onset of asthma (18 years ± 9 vs 13 years ± 10). Among women who completed the ACT during the clinical interview, the 50% of women who experienced worsening asthma during pregnancy (6/12) had an ACT score below 20. CONCLUSION: Asthma was observed to worsen during pregnancy in a percentage much lower to that generally reported in all the previous studies. There is still room in clinical practice to further reduce worsening of asthma during pregnancy by improving asthma control, with a more structured approach to asthma education and management prepregnancy.

The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling.

AIMS: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. METHODS: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. RESULTS: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. CONCLUSIONS: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.

Bone marrow failure may be caused by chromosome anomalies exerting effects on RUNX1T1 gene.

BACKGROUND: The majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80-85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease. RESULTS: We report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one. CONCLUSIONS: We analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003-2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients.

NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL.

Mixed-lineage leukemia (MLL)-rearranged (MLLr) infant B-cell acute lymphoblastic leukemia (iMLLr-B-ALL) has a dismal prognosis and is associated with a pro-B/mixed phenotype, therapy refractoriness and frequent central nervous system (CNS) disease/relapse. Neuron-glial antigen 2 (NG2) is specifically expressed in MLLr leukemias and is used in leukemia immunophenotyping because of its predictive value for MLLr acute leukemias. NG2 is involved in melanoma metastasis and brain development; however, its role in MLL-mediated leukemogenesis remains elusive. Here we evaluated whether NG2 distinguishes leukemia-initiating/propagating cells (L-ICs) and/or CNS-infiltrating cells (CNS-ICs) in iMLLr-B-ALL. Clinical data from the Interfant cohort of iMLLr-B-ALL demonstrated that high NG2 expression associates with lower event-free survival, higher number of circulating blasts and more frequent CNS disease/relapse. Serial xenotransplantation of primary MLL-AF4+ leukemias indicated that NG2 is a malleable marker that does not enrich for L-IC or CNS-IC in iMLLr-B-All. However, NG2 expression was highly upregulated in blasts infiltrating extramedullar hematopoietic sites and CNS, and specific blockage of NG2 resulted in almost complete loss of engraftment. Indeed, gene expression profiling of primary blasts and primografts revealed a migratory signature of NG2+ blasts. This study provides new insights on the biology of NG2 in iMLLr-B-ALL and suggests NG2 as a potential therapeutic target to reduce the risk of CNS disease/relapse and to provide safer CNS-directed therapies for iMLLr-B-ALL.

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation.

The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.

The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity.

Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.

Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol.

This corrects the article DOI: 10.1038/leu.2015.246.