A growing role of Immune Checkpoint Therapy (ICT) in pediatric and adolescent lymphoma. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1 (PD-1) inhibitors are the most commonly utilized ICTs which enhance anti-tumor immunity. ICT has demonstrated efficacy in both high-risk and relapsed disease with ongoing investigations into low-risk disease. Given the success of ICT in pediatric Hodgkin Lymphoma (pHL), there is promise for the use of ICT in multiple subtypes of pediatric Non-Hodgkin Lymphoma with increased expression of programmed death ligand 1 (PD-L1), especially after the FDA approval of cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibitor ipilimumab in 2011, and PD-L1 inhibitors nivolumab and pembrolizomab in 2014. CTLA-4 inhibitors increase T-cell expansion by interrupting the inhibitory interaction of CTLA-4 on T-cells, whereas PD-1 inhibitors prevent T-cell exhaustion by interrupting the inhibitory interaction of PD-L1 and PD-L2 on tumor cells with PD-1 receptors on T-cells. Through both mechanisms, anti-tumor immunity is enhanced. Other immune regulatory pathways are also being explored. Other variables that support the implementation of ICT have come to light such as the increased quantity of tumor neoantigens that have been identified as positive predictors of response to ICT, high tumor mutation burden of >10 mutations per Mb, and high microsatellite instability of >2 of 5 microsatellite repeats determined by PCR, are additional tumor agnostic companion biomarkers that support the use of ICT leading to broad-ranging applications of ICT across a multitude of subtypes of lymphoma. Furthermore, combination therapy with ICT and various forms of cytotoxic chemotherapy, small molecule inhibitors, radiotherapy, antibody-drug conjugates, and cancer vaccines are being investigated. However, it should be emphasized that further research is needed to determine the safety and efficacy of ICT and CTLA-4 inhibitors as treatments in different histological subtypes of pediatric and adolescent lymphomas. While ICT have shown efficacy, it can cause immune-related adverse events (irAEs) in children and adolescents like liver toxicity, pediatric endocrine AEs such as thyroid dysfunction, adrenal insufficiency, hypophysitis, acute Type 1 diabetes, severe high-grade 3 pneumonitis, neuritis, and pancreatitis. The use of ICT must be carefully weighed against toxicities in pediatric and adolescent patients who are a particularly vulnerable and fragile population. haematologica.org/article/vi…

The 2026 Nobel Prize in Physiology or Medicine has been awarded to Karl Deisseroth, Peter Hegemann, and Georg Nagel for their discoveries concerning light-gated ion channels and optogenetics. The laureates are honored for laying the foundation of a new era in neuroscience. Optogenetics has fundamentally altered our understanding of brain activity. Deisseroth introduced the gene for channelrhodopsin into neurons from rats by illuminating the cells with a blue light, triggering a nerve signal. Optogenetics helps in mapping and understanding retinal circuitry. Among the clinical applications of optogenetics is helping in the restoration of degenerative retinal diseases such as Retinitis Pigmentosa and Age-Related Macular Degeneration. Previously blind patients regained the ability to perceive light, identify shapes, and locate objects. Optogenetics is mutation-agnostic: It helps to treat different inherited retinal diseases regardless of the underlying genetic mutation.

Circulating extracellular vesicles (EVs) as drivers of innate immune dysregulation in Multi-system Inflammatory Syndrome in Children (MIS-C). MIS-C is associated with humoral and cytokine responses and EV-associated viral/inflammatory signatures. Compared with acute COVID-19, MIS-C is distinguished by delayed onset, pronounced cytokine storm-like inflammation, and multiorgan involvement, rather than primary respiratory disease. Autoantibodies against endothelial, immune, and GI targets in pathogenesis are implicated. Endothelium-reactive bodies promote vascular inflammation and a prothrombotic state, whereas antibodies targeting intestinal tissues amplify SARS-CoV-2-triggered injury and systemic inflammation. Humoral responses in children with MIS-C frequently exhibit elevated IgA, anti-spike (S) IgG, and anti-receptor-binding domain (RBD) IgG, consistent with a dysregulated or exaggerated antibody response. Patients MIS-C have higher anti-spike/RBD IgG at hospital admission and sustained titers over follow-up, consistent with prolonged antigenic exposure. MIS-C also shows a distinct inflammatory profile with prominent IL-17A and IL-22 elevation relative to severe COVID-19. MIS-C is also distinguished by convergent signal EV cargo and TH 17p-associated signature pathways. These particular characteristics support EV cargo, IL-17, and integrin/adhesion pathways as candidate biomarkers and therapeutic targets to curb hyperinflammation in MIS-C. MIS-C is a rare, severe systemic illness affecting multiorgan systems that occurs 2-6 weeks post SARS-CoV-2 (COVID-19) infection. It causes persistent fever with GI symptoms like abdominal pain, vomiting, and diarrhea, with strawberry-tongue, and mucocutaneous symptoms. It progressively leads to toxic shock, cardiac failure, coronary artery aneurysm, acute kidney injury (AKI), coagulopathy and DIC. It is associated with cytokine storm, and macrophage activation syndrome (MAS). MIS-C mostly affects school-aged children and adolescents 5-13 years and must be differentiated from Kawasaki Disease and bacterial sepsis caused by staphylococcus and streptococcus infections. Standard treatments rely on IVIG, corticosteroids, and cytokine blockers as supplementary therapy.

Wishing you my friends a happy Saturday✨️ "Philosopher Reading" Rembrandt van Rijn

Late cytopenia is a significant complication after CD19-directed CAR T-cell therapy in patients with Relapsed/Refractory Large B-cell Lymphoma (R/R LBCL). Neutropenia consistent with late immune effector cell-associated hematotoxicity was identified in 30% of patients between 30 to 100 days. High CAR-HEMATOTOX score of >2 was a predictor of cytopenia at 3 months, whereas receipt of bridging chemotherapy and axicabtagene ciloleucel was associated with cytopenia at 6 months after CAR T-cell therapy. Late cytopenia was associated with a higher 1-year non-relapse mortality and worse 2-year progression-free survival. CAR T-cell therapy, although highly effective, is associated with siginficant toxicities, most notable are immune-mediated adverse events (AEs), particularly Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Other delayed toxicities include cytopenias, secondary malignancies, and infections. Late cytopenia can be severe and persistent for a long duration indicating delayed bone marrow recovery which complicates post-treatment recuperation, with increased susceptibility to infections and bleeding further affecting post-CAR T-cell therapy outcomes, contributing to morbidity, and decreased overall survival. Identifying patients at risk with meticulous and prompt surveillance may alleviate toxicities and AEs of late cytopenias post CD19 CAR T-cell therapy in R/R LBCL.

A review of POEMS syndrome: 2026 update on diagnosis, risk stratification, and management. POEMS syndrome is a rare, life-threatening syndrome due to a rare underlying plasma cell neoplasm. There is a Castleman Disease variant of POEMS syndrome that may be associated with clonal plasma cell disorders (PCD). The acronym refers to polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. Important features not included in the POEMS acronym include: papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis (P.E.S.T.), elevated vascular endothelial growth factor (VEGF), predisposition towards thrombosis, and abnormal pulmonary function tests. Major criteria for diagnosis include polyneuropathy, PCD, sclerotic bone lesions, elevated VEGF, and presence of Castleman Disease. Minor criteria include organomegaly, endocrinopathy, skin changes, papilledema, extravascular volume overload, and thombosis. Diagnosis is made with three of the major criteria, two of which must include polyneuropathy and PCD, and at least one of the minor criteria. VEGF is the cytokine that correlates most with disease activity. About 95% of plasma cells in POEMS syndrome are lambda chains. A good history and physical examination followed by radiographic assessment of bones, VEGF, and bone biopsy can differentiate POEMS from chronic inflammatory demyelinating polyneuropathy (CIDP), immunoglobulin light- chain amyloidosis, and MGUS. For patients with dominant plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic bone lesions or disseminated BM involvement should undergo systemic therapy. Corticosteroids, alkylating agents, and lenalidomide are the mainstay of treatment. Benefit from neurotoxic drugs such as bortezomib and thalidomide must be weighed against the risk of exacerbating peripheral neuropathy and should be adimistered carefully in relapsed/refractory disease. Hematopoietic stem cell transplantation (HSCT) may be beneficial for eligible R/R patients.

The U.S. Food and Drug Administration (FDA) has approved Atebrioz (zilurgisertib) for the treatment of adults and pediatric patients aged 12 years and older suffering from Fibrodysplasia Ossificans Progressiva (FOP). Atebrioz is an oral activin receptor-like kinase 2 (ALK2) inhibitor that reduces the volume of total heterotopic ossification, the bone formation outside skeleton, with a recommended dose of 100 mg orally once per day. FOP is an ultra rare, genetic, connective tissue disorder caused by autosomal dominant allele on chromosome 2q23-24. A mutation in the ACVR1 gene, also known as activin-like kinase 2 (ALK2), which encodes activin receptor type-1 (ACVR1) is responsible for the disease. It causes the body to misinterpret tissue repair signals, instead of healing soft tissues normally after injury, the body responds by building new bone, creating extra bone layers impacting joints, muscles, tendons, and ligaments resulting in progressive ossification. FOP has an onset in early childhood causing limited movement, skeletal deformities, severe disability, difficulties eating, swallowing, and speaking. Pathological bone growth around ribs result in restricted lung expansion leading to restrictive lung disease with severe complications and early death. FOP flare-ups are triggered by physical trauma, invasive medical interventions and procedures like injections, punctures, surgeries, and biopsies associated with pain and inflammation. Atebrioz has received first track, priority orphan drug designation offering improved overall survival and better quality of life for patients with Fibrodysplasia Ossificans Progressiva.

A review of cancer vaccines and their role in stimulating adaptive immunity against neoantigens, nonmutated tumor proteins, or tumor-derived antigens. Antigen-based cancer vaccine strategies are designed to stimulate the adaptive immune system by helping patients develop immunity to cellular proteins expressed by their cancer. Eventually, cancer vaccines may be integrated into treatment regimens with chemotherapy and immunotherapy. Cancer vaccines work by stimulating immune cells to recognize proteins or mutations on or within cancer cells, allowing immune cells to recognize and destroy cancer cells. Therapeutic cancer vaccines for melanoma, prostate, and bladder cancer have been approved, and newer ones are currently undergoing late-stage clinical trials and regulatory reviews. Other cancer vaccines are undergoing clinical testing and trials to target different types of cancer such as breast, ovarian, lung, pancreatic, and colon cancer, as well as several hematologic malignancies. Cancer vaccines have an important role in prevention and treatment of many malignancies, in the era of tremendous advances in tumor immunology, antigen discoveries, and novel vaccine deliveries which are reshaping the scientific fields of immunology and cancer.