Emicizumab prophylaxis in infants: Single-centre experience.

The hallmark of haemophilia A (HA) therapy is prophylaxis, aimed at spontaneous bleeding prevention. Emicizumab provides a viable alternative to intravenous factor replacement therapy. However, data on its use in infants are limited. This single-centre open arm prospective study reports on emicizumab prophylaxis in infants. We included severe HA patients under 1 year who started emicizumab prophylaxis since 2018, with longitudinal follow-up. The study collected data on demographics, clinical and laboratory variables, the occurrence of bleeding events, surgeries and treatment outcomes. Of the 27 enrolled infants, whose median age at prophylaxis initiation was 7 months, 24 primarily choose to start emicizumab therapy (3/27 switched from FVIII prophylaxis due to development of FVIII inhibitors). The median age for prophylaxis initiation decreased to 3 months in 2023. Following emicizumab initiation, the median calculated ABR decreased, and no intracranial haemorrhages were observed. Thrombin generation showed a significant improvement in peak height and endogenous thrombin potential at steady state after a loading period. Our study highlights a shift towards early prophylaxis in the era of non-replacement therapies. It underscores the need for continuous evaluation and refinement of treatment approaches, emphasizing personalized care and diligent monitoring in the evolving field of paediatric haemophilia care.

[NECROTIZING ENTEROCOLITIS - AN ONGOING CHALLENGE].

INTRODUCTION: Necrotizing enterocolitis (NEC) is a major cause for morbidity and mortality among neonates, especially among low birth weight premature infants. Even though NEC has been highly investigated during the last few decades, understanding of the pathogenesis is still relatively poor. Throughout the years protective measures, as well as risk factors, were identified, but there is still no clear prevention strategy, and the percentage of neonates suffering of NEC was not changed. Moreover, the treatment approach is controversial in many circumstances other than a few clear surgical indications. The decision between conservative and surgical treatment in many situations is in the hands of the medical staff. Herein we present the story of a premature infant who suffered from feeding intolerance since birth, with major clinical deterioration after receiving packed red blood cells (PRBCs) transfusion. She was diagnosed with NEC and was treated conservatively, with clinical improvement and worsening alternately, until a colonic stricture was identified and treated surgically. We will provide a short review on risk factors, preventive measures, as well as the research regarding PRBCS transfusion and NEC development.

A Large Cohort of RAG1/2-Deficient SCID Patients-Clinical, Immunological, and Prognostic Analysis.

INTRODUCTION: Severe combined immunodeficiency (SCID) is a fatal disorder resulting from various genetic defects. In the Middle East, where consanguineous marriage is prevalent, autosomal recessive mutations in recombination-activating genes (RAG) are a leading cause of SCID. We present a large cohort of SCID patients due to RAG1 or RAG2 mutations. METHODS: Twenty-six patients with RAG1 or RAG2 deficiency, diagnosed at Sheba Medical Center, were retrospectively investigated. Clinical presentation, immunologic phenotype, genetic analysis, treatment, and outcome were analyzed. RESULTS: Majority of patients were referred from the Palestinian Authority. Most patients were males of Muslim Arab descent, 77% were born to consanguineous parents, and 65% had family history of immunodeficiency. Nearly all patients suffered from various infections before turning 2 months old, eight patients (31%) presented with Omenn and Omenn-like syndrome, and three patients (11%) had maternal engraftment. Notably, seven patients (27%) suffered from vaccine-derived infections, including a rare case of measles encephalitis. Nineteen patients underwent hematopoietic stem cell transplantation (HSCT) at a median age of 6 months, with a successful outcome for 72% of them. Genetic analysis revealed 11 different mutations (7 RAG2, 4 RAG1), two of them novel. CONCLUSIONS: Consanguineous marriages account for a genetic "founder effect." SCID is a pediatric emergency that dictates immediate precautions and curative treatment with HSCT. Due to lack of newborn screening for SCID within the Palestinian population, most patients in this cohort were diagnosed upon clinical symptoms, which led to a delayed diagnosis, harmful administration of contra-indicated live vaccines, delay in HSCT, and poor outcome.

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects.

The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.

Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma.

Mutations in ribosomal proteins cause bone marrow failure syndromes associated with increased cancer risk, but the basis by which they do so remains unclear. We reported previously that the ribosomal protein Rpl22 is a tumor suppressor in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), and that loss of just one Rpl22 allele accelerates T-cell lymphomagenesis by activating NF-κB and inducing the stem cell factor Lin28B. Here, we show that, paradoxically, loss of both alleles of Rpl22 restricts lymphoma progression through a distinct effect on migration of malignant cells out of the thymus. Lymphoma-prone AKT2-transgenic or PTEN-deficient mice on an Rpl22(-/-) background developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22(+/+) control mice. But, unlike Rpl22(+/+) or Rpl22(+/-) tumors, Rpl22(-/-) lymphomas did not disseminate to the periphery and were retained in the thymus. We traced the defect in the Rpl22(-/-) lymphoma migratory capacity to downregulation of the KLF2 transcription factor and its targets, including the key migratory factor sphingosine 1-phosphate receptor 1 (S1PR1). Indeed, reexpression of S1PR1 in Rpl22-deficient tumor cells restores their migratory capacity in vitro The regulation of KLF2 and S1PR1 by Rpl22 appears to be proximal as Rpl22 reexpression in Rpl22-deficient lymphoma cells restores expression of KLF2 and S1P1R, while Rpl22 knockdown in Rpl22-sufficient lymphomas attenuates their expression. Collectively, these data reveal that, while loss of one copy of Rpl22 promotes lymphomagenesis and disseminated disease, loss of both copies impairs responsiveness to migratory cues and restricts malignant cells to the thymus. Cancer Res; 76(11); 3387-96. ©2016 AACR.

Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus.

Anemia of inflammation (AI) is commonly observed in chronic inflammatory states and may hinder patient recovery and survival. Induction of hepcidin, mediated by interleukin 6, leads to iron-restricted erythropoiesis and anemia. Several translational studies have been directed at neutralizing hepcidin overexpression as a therapeutic strategy against AI. However, additional hepcidin-independent mechanisms contribute to AI, which are likely mediated by a direct effect of inflammatory cytokines on erythropoiesis. In this study, we used wild-type, hepcidin knockout (Hamp-KO) and interleukin 6 knockout (IL-6-KO) mice as models of AI. AI was induced with heat-killed Brucella abortus (BA). The distinct roles of iron metabolism and inflammation triggered by interleukin 6 and hepcidin were investigated. BA-treated wild-type mice showed increased expression of hepcidin and inflammatory cytokines, as well as transitory suppression of erythropoiesis and shortened red blood cell lifespan, all of which contributed to the severe anemia of these mice. In contrast, BA-treated Hamp-KO or IL-6-KO mice showed milder anemia and faster recovery compared with normal mice. Moreover, they exhibited different patterns in the development and resolution of anemia, supporting the notion that interleukin 6 and hepcidin play distinct roles in modulating erythropoiesis in AI.

Screening tool for late-effect pediatric neuro-oncological clinics: a treatment-oriented questionnaire.

BACKGROUND: Many survivors of pediatric brain tumors (SPBTs) suffer from long-term late effects (LEs). Our aim was to create a practical screening tool for detecting LEs in this population. Such a screening tool will improve our ability to identify those patients who may benefit from treatment in LE clinics while focusing on individual relevant issues. PROCEDURE: We developed the Treatment-Oriented Screening Questionnaire (TOSQ); a self-reported, risk-based questionnaire that addresses all LEs SPBTs can potentially suffer. As a basis for the TOSQ design we used the Long-Term Follow-Up Guidelines published by the Children's Oncology Group. Output includes individual recommendations for further treatment. We prospectively assessed whether the TOSQ can accurately detect treatment targets in SPBTs by comparing patient and caregiver questionnaire scores with physician evaluations. Data are presented from 41 SPBTs. RESULTS: The TOSQ is a precise screening tool for identifying LEs in SPBTs based on the significant correlation (P < 0.05) that was found between parental scores and physician evaluations. Statistical testing proved that parents are a good source of information about child's health status, and that TOSQ accurately reflects the correlation between patient difficulties and quality of life. CONCLUSIONS: The TOSQ is the first described screening tool for identification of LEs designed specifically for SPBTs. It is simple to use and provides a valid, comprehensive and economic assessment followed by targeted treatment plan for each patient. By repeatedly using the TOSQ over the years, we can improve our ability to detect and give focused treatment to those who require assistance.

Haemophilus influenzae Type b Meningitis in the Short Period after Vaccination: A Reminder of the Phenomenon of Apparent Vaccine Failure.

We present two cases of bacterial meningitis caused by Haemophilus influenzae type b (Hib) which developed a few days after conjugate Hib vaccination. This phenomenon of postimmunization provocative time period is reviewed and discussed. These cases serve as a reminder to clinicians of the risk, albeit rare, of invasive Hib disease in the short period after successful immunization.