Hematology:

G protein-coupled receptor, class C, group 5, member D (GPRC5D) has emerged as a novel target for chimeric antigen receptor (CAR) T-cell therapy, demonstrating promising efficacy in multiple myeloma (MM). However, disease relapse is still common, and the mechanism of resistance remains poorly understood. In this study, we conducted whole-genome sequencing and whole-genome bisulfite sequencing on MM samples from 10 patients who relapsed after GPRC5D CAR T-cell therapy. Among these patients, 8 had GPRC5D loss, whereas 2 presented mixed expression (GPRC5D+/-). Genetic alterations were identified in 3 cases: one had a homozygous deletion in the GPRC5D gene, another had a biallelic loss in the regulatory regions of GPRC5D, and the third had homozygous deletions in both TNFRSF17 and GPRC5D after sequential anti-B-cell maturation antigen and anti-GPRC5D CAR T-cell therapies. No genetic changes were detected at GPRC5D locus in the remaining 7 cases. However, multiple hypermethylation sites were present in the transcriptional regulatory elements of the GPRC5D gene in 5 post-treatment MM samples. In MM cell lines, GPRC5D expression was inversely correlated with methylation levels in its regulatory regions. Furthermore, azacitidine treatment induced GPRC5D messenger RNA and protein expression in hypermethylated MM cell lines. Our findings highlight that biallelic genetic inactivation and hypermethylation-driven epigenetic silencing are key mechanisms contributing to GPRC5D loss and treatment resistance.

Antibiotics disrupt the delicate balance of bacteria, fungi, and viruses in the human microbiome. Growing evidence indicates a significant relationship between the intestinal microbiome and cellular therapy, which aligns with the established influence of the microbiome on immune responses. When examining the link between cellular therapy and the microbiome, it is essential to understand how disruptions in the microbiome, especially those caused by antibiotics, affect these therapies. Here, we discuss the impact of antibiotics on the intestinal microbiome, cellular therapy outcomes, and associated toxicities, particularly in the context of hematopoietic cell transplantation and chimeric antigen receptor T-cell therapy. Furthermore, we examine the mechanisms through which antibiotics affect cellular therapy, the future implications of this knowledge, and the areas that warrant further investigation.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by mitogen-activated protein kinase (MAPK) activation in hematopoietic cells. Historically, LCH has been staged according to involvement of "risk organs" (bone marrow, liver, and spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, patients with LCH now rarely die. However, most patients with LCH with multisystem disease are not cured with current front-line chemotherapy, and treatment failure is associated with long-term morbidity, including LCH-associated neurodegeneration (LCH-ND). In this study, we evaluated the impact of extent of LCH at presentation, tumor genotype, and BRAFV600E in pretherapy peripheral blood mononuclear cells (PBMCs) and bone marrow on systemic and central nervous system outcomes in a cohort of 385 pediatric patients with LCH and 115 adults with LCH, followed up for a median of 4 years (range, 0.02-18 years). Five-year event-free survival was 50.7% for pediatric patients and 32.7% for adult patients with LCH. In the pediatric cohort, presence of BRAFV600E PBMC was strongly associated with front-line treatment failure (hazard ratio [HR], 7.7). Remarkably, BRAFV600E PBMC at diagnosis also identified patients at the highest risk of developing LCH-ND (HR, 23.1). These findings support an updated model of pediatric LCH pathogenesis in which persistence of disease reservoir and cell of origin determine extent of disease and clinical risks. We, therefore, propose a major revision of pediatric LCH diagnostic staging, shifting from focus on historical risk of death to risks of systemic treatment failure and LCH-ND based on lesion location, lesion genotype, and peripheral LCH reservoir (eg, BRAFV600E PBMC).

Targeted therapy with covalent Bruton tyrosine kinase inhibitors (cBTKis) and/or the B-cell lymphoma 2 inhibitor (BCL-2i) venetoclax is now well established in the first-line management of chronic lymphocytic leukemia (CLL). However, patients with "double-refractory" disease due to the acquired resistance to both drug classes represent an increasing clinical challenge for whom few well-tolerated and effective treatment options currently exist. The highly selective, noncovalent BTKi pirtobrutinib and CD19-directed chimeric antigen receptor T-cell therapy lisocabtagene maraleucel have both recently gained US Food and Drug Administation approval for use in patients with CLL, which has progressed following ≥2 prior lines, including a cBTKi and a BCL-2i. Additionally, novel BTK-directed therapies and T-cell-engaging bispecific antibodies have achieved promising responses in pretreated CLL in early-phase clinical trials. Here, we review the mechanisms responsible for resistance to cBTKi and venetoclax in CLL, appraise recent evidence supporting the use of each of the novel and emerging agent classes, and then suggest innovative treatment strategies incorporating these in patients with double-refractory disease, remaining cognizant of the variability of access to novel therapies and clinical trials.

Lung cancer is a major malignant tumor with high morbidity and fatality rates. For many years, traditional treatments for lung cancer have struggled to achieve a favorable outlook and prognosis. It is crucial to identify and innovate novel clinical therapeutic strategies and techniques to prevent tumor progression and prolong the survival time of patients with lung cancer. Cellular immunotherapies have revolutionized the treatment of malignant tumors and have been gradually applied in clinical practice. CAR-T therapy is the best-known cellular therapy and has achieved remarkable clinical outcomes in patients with hematological malignancies, but its effect on patients with lung cancer and other solid tumors is not satisfactory, partly because of the heterogeneity and complexity of lung cancers and the sterile TMEs. To further improve the clinical effect, multiple approaches and strategies have been adopted, including discovering new tumor antigen targets, improving safety, enhancing cytotoxicity, and increasing durability. Moreover, other cell-based immunotherapies have also showed great potential for the treatment of lung cancer, including TCR-T cells, TILs, CIK cells, NK cells, macrophages, and dendritic cells, which enriched the number of treatment choices for patients with lung cancer. In summary, the present article summarizes and highlights recent advances and challenges in the use of cellular immunotherapies for the treatment of lung cancer, which might stimulate new ideas for the further development of cellular immunotherapies.

Critical bleeding in patients with immune thrombocytopenia (ITP) is a life-threatening hematologic emergency. This study aimed to describe the frequency, management, and outcomes of critical bleeds among adults and children with ITP. We conducted a retrospective cohort study of patients with ITP who presented to the emergency room with a platelet count <20 × 109/L across 7 centers in the United States and Canada between 2010 and 2019. Of 1226 patients (n = 296 adults; n = 930 children), 28 (2.3%) had critical bleeds (adults, n = 15 [median age, 68 years]; children, n = 13 [median age, 11 years]). Of patients with critical bleeds, 12 adults (80.0%) and 6 children (46.2%) had intracranial hemorrhage (ICH). For adults, the common interventions used to treat critical bleeds were platelet transfusions (n = 11 [73.3%]), corticosteroids (n = 10 [66.7%]), and IV immunoglobulin (n = 8 [53.3%]), and for children, common interventions were IV immunoglobulin (n = 10 [76.9%]), corticosteroids (n = 8 [61.5%]), platelet transfusions (n = 8 [61.5%]), thrombopoietin receptor agonists (n = 4 [30.8%]), and antifibrinolytic agents (n = 4 [30.8%]). For both adults and children, the most common treatment combination was corticosteroids, IV immunoglobulin, and platelet transfusion (n = 6 [40.0%] vs n = 6 [46.2%]). The median time from presentation to first treatment was 6.9 hours for adults and 3.5 hours for children. Overall, 9 patients (32.1%) with critical ITP bleeds died, including 7 adults (46.7%) and 2 children (15.4%). Critical bleeding in patients with ITP was rare but frequently fatal, especially among older adults with ICH and when treatments were delayed.

Allogeneic hematopoietic stem cell transplantation (HSCT) has significantly improved the outcome of children with high-risk (HR) acute myeloid leukemia (AML). Implementing allogeneic HSCT depends on numerous factors, including adverse cytogenetics, molecular abnormalities, poor response to first-line treatment, or relapsed or primary refractory disease. In HR AML, allogeneic HSCT is considered to be the consolidation strategy of choice in first complete remission (CR1) and offers the best chance of cure for patients with relapsed disease. Advances in donor/recipient typing, conditioning regimens, graft-versus-host-disease (GvHD) management, and supportive care have contributed to this improvement in overall-and transplant-outcome. This review will comprehensively discuss indications for HSCT and its modalities in pediatric AML by examining past, current, and future strategies for disease- and response-related stratification. We will examine the key importance of low/negative measurable residual disease (MRD) before transplantation and discuss conditioning regimens and graft variables, as well as novel approaches to harness the graft-versus-leukemia (GvL) effect, including targeted immunotherapy. The review will also address toxicities associated with HSCT, GvHD prophylaxis, and the management of treatment failure. Ultimately, this review seeks to inform clinical practice and highlights how improved outcomes have been achieved through the collective efforts of international study groups.

Idecabtagene vicleucel (ide-cel) was the first US Food and Drug Administration-approved chimeric antigen receptor T-cell (CAR-T) therapy for multiple myeloma (MM). However, because clinical trials are highly selective with stringent eligibility criteria, the objective of this study was to evaluate the safety and effectiveness of standard-of-care (SOC) ide-cel in the real world. Using the Center for International Blood and Marrow Transplant Research registry, we evaluated 821 patients who received SOC ide-cel. Median follow-up was 11.6 months. Median age was 66 years, and the cohort included 31% patients aged ≥70 years, with 15% Black and 7% Hispanic, and 77% of patients with ≥1 significant comorbidity. The median number of prior lines of therapy was 7, 15% patients previously received B-cell maturation antigen-directed therapy, 17% had extramedullary disease, and 27% had high-risk cytogenetics. Overall response rate was 73%, and complete response rate was 25%. Median progression-free survival was 8.8 months. Treatment-related mortality was reported in 6% of patients. Cytokine release syndrome was diagnosed in 80% of patients (grade ≥3, 3%). Immune effector cell-associated neurotoxicity syndrome was observed in 28% (grade ≥3, 5%), with no cases of Parkinsonism reported. Clinically significant infections were seen in 45% of patients. Second primary malignancies were reported in 4%, including 1% myeloid malignancies. This is, to our knowledge, the largest real-world study of ide-cel CAR-T therapy in patients with relapsed/refractory (R/R) MM. We observed a favorable safety and efficacy profile that mirrors trial experience, even in the setting of significant comorbidities in 77% of patients, many of which would have made them ineligible for the registrational KarMMa clinical trial. This trial was registered at www.clinicaltrials.gov as #NCT03361748.

Gastric cancer (GC) is one of the most common malignant tumours worldwide, and its high morbidity and mortality are closely related to insignificant early symptoms, diagnosis mostly at an advanced stage and immunotherapy resistance. In recent years, the application of immunotherapy, especially immune checkpoint inhibitors, has brought new hope for treating GC; however, the problem of drug resistance is still a major challenge. The clinical need for effective immunotherapy in GC is still unmet, as the majority of patients do not respond to current treatments or develop resistance over time. The tumour microenvironment (TME) is a key factor affecting immunotherapy resistance. It contains immunosuppressive cells, cancer-associated fibroblasts, the extracellular matrix, immunosuppressive cytokines and other components, which interact to form an immunosuppressive environment and weaken the effect of immunotherapy. In addition, tumour metabolic reprogramming further promotes immune resistance by affecting immune cell function and activity. However, the detailed mechanisms by which these components drive resistance are not fully understood, and there is a significant gap in the literature regarding comprehensive strategies to overcome this resistance. This review aims to address this gap by elucidating how key components of the TME contribute to immunotherapy resistance in GC. The study reviews the effect of key components in the TME of GC on immunotherapy resistance and its mechanism and discusses potential treatment strategies and future research directions for these mechanisms; it provides a theoretical basis for overcoming immunotherapy resistance and improving the prognosis of patients with GC.

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in treating relapsed and refractory (R/R) B-cell neoplasms, such as diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Despite its success, the long-term effects and sequelae of CAR T cells on the immune system remain underexplored. This study presents a 1-year follow-up analysis of 52 patients (42 with R/R DLBCL and 10 with R/R MM) treated with anti-CD19- and B-cell maturation antigen-targeted CAR T cells, focusing on immune reconstitution and infectious complications. Our findings reveal that CAR T-cell therapy leads to profound depletion of B and T cells. CD4+ T cells and CD19+ B cells exhibited impaired regeneration after treatment. Infections were more frequent during the first 30 days. In the short-term follow-up, density of infections within 100 days at risk was 1.8 in patients with DLBCL and 4.6 in patients with MM, with bacterial infections predominating in this early period after CAR T-cell infusion. In addition, we observed a shift to viral infections in the long-term follow-up, alongside with a decline in infection density to 0.1 in patients with DLBCL and 0.4 infections per 100 days at risk in patients with MM, respectively. Severe cytokine release syndrome was associated with a higher risk of late-onset infections. These findings highlight the importance of close monitoring and prophylactic measures in patients undergoing CAR T-cell therapy to reduce infection risks and enhance immune recovery.

This study aimed to assess the efficacy and safety of combining cemiplimab, an anti-programmed cell death protein 1 (PD-1) antibody, with isatuximab, an anti-CD38 antibody, in relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL). The hypothesis was that CD38 blockade could enhance the antitumor activity of PD-1 inhibitors. Eligible patients received cemiplimab (250 mg on days 1 and 15) and isatuximab (10 mg/kg on days 2 and 16) IV every 4 weeks for 6 cycles. Responders then received cemiplimab (350 mg) and isatuximab (10 mg/kg) every 3 weeks for up to 24 months. The primary end point was the complete response (CR) rate based on the best response. Of 37 patients enrolled, the CR rate was 51% (19/37), exceeding the primary end point of 40%, and the objective response rate was 65% (24/37). After a median follow-up of 30.2 months (95% confidence interval [CI], 25.6-34.8 months), the median progression-free survival was 9.5 months (95% CI, 1.4-17.6 months), whereas the median overall survival had not yet been reached. Patients achieving CR received a median of 28 cycles (range, 4-33 cycles), and the median duration of response for responders (n = 24) was 29.4 months (95% CI, 15.4-43.4 months). Structural variations disrupting the 3'-untranslated region of PD-L1 and high programmed death ligand 1 (PD-L1) expression were observed in responders. Most adverse events were mild (grade 1-2), with grade ≥3 events (32%) and no treatment-related deaths. The combination of isatuximab and cemiplimab demonstrated sustained antitumor activity and a manageable safety profile in R/R ENKTL. This phase 2 trial is registered at www.clinicaltrials.gov as number NCT04763616.

BACKGROUND: Gallbladder cancer (GBC) is a rare but aggressive malignancy with a poor prognosis. Its pathophysiology involves environmental, microbiological, and physiological factors. Emerging evidence highlights the role of genetic, epigenetic, and transcriptomic alterations in GBC onset. This article reviews these molecular changes in GBC patients.

Lung cancer remains a leading cause of cancer-related deaths globally, presenting significant clinical challenges despite advancements in therapeutic strategies. Recent developments have highlighted the potential of lung cancer organoids as a promising tool to bridge basic science, drug development, and clinical therapeutics. This review focuses on the innovative role of lung cancer organoids in translational research, particularly their ability to integrate and accelerate the development of personalized treatment strategies. By mimicking patient-specific tumor microenvironments, lung cancer organoids provide an unparalleled platform for drug screening, evaluation of immune therapies, and assessment of anti-angiogenesis treatments. We posit that lung cancer organoids represent a cutting-edge, multidisciplinary tool with the potential to revolutionize cancer treatment and improve patient outcomes through enhanced translational research.

The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor (TF), thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of TF or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear TF abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. Therefore, we provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects.

BACKGROUND: Vulvar Paget's disease (VPD) is an orphan neoaplasm accounting 1-2 % of vulvar malignancies. Advanced VPD is currently laking effective treatment options. Since HER2 is overexpressed in 30-40 % of VPD cases, this scoping review explores its prognostic significance and the effectiveness of HER2-targeted therapies.

While humans evolved to perform routine endurance activity, recent secular trends in the United States and globally have resulted in a dramatic rise in the amount of time spent inactive in both occupational and leisure-time settings. The high burden of physical inactivity is responsible for a high risk of preventable noncommunicable disease including cardiovascular disease, cancer, and premature death. In this review, we focus on the beneficial effects of routine physical activity (PA) on the cardiovascular system, the different ways we can achieve and measure PA, and the evidence supporting key public health guidance on optimal PA goals for promoting health. While data indicate modest improvements in leisure-time PA in the United States over the past decade, these developments are not equitably distributed across the population with racial and ethnic minorities, women, and older adults continuing to display lower PA rates. The data reviewed here demonstrate the importance of promoting PA for cardiovascular health and highlight the need to address the enormous burden of physical inactivity, especially in those affected by intersecting disparities influencing both general health and leisure-time PA.

No abstract available

Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched donors is the gold standard. However, haploidentical stem cell transplantation using posttransplant cyclophosphamide (PTCY-haplo) and cord blood transplants (CBTs) are alternatives when HLA-matched donors are not available. Using Japanese registry data, we evaluated the impact of haploidentical donor age on posttransplant outcomes by comparing PTCY-haplo and CBT. We analyzed data for 5161 patients aged 16 to 70 years who received their first HSCT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia. Haploidentical donors were categorized as "younger" (aged <40 years) or "older" (aged ≥40 years), and the patients were divided into younger (aged <50 years) and older (aged ≥50 years) cohorts. In the older cohort, PTCY-haplo from younger donors had better overall survival (OS; 55.5% vs 50.8%, P = .006), lower nonrelapse mortality (NRM; 17.3% vs 28.6%, P < .001), and higher relapse rates (33.0% vs 24.9%, P = .017) than with CBT. PTCY-haplo from older donors had comparable OS (44.1% vs 50.8%, P = 1.00), NRM (27.3% vs 28.6%, P = 1.00), and relapse (29.2% vs 24.9%, P = .90) to that with CBT. In the younger cohort, PTCY-haplo from younger and older donors showed OS, NRM, and relapse comparable with CBT. In the older cohort, cumulative incidence of acute graft-versus-host disease (GVHD) was higher with CBT than with PTCY-haplo, regardless of donor age. However, in the younger cohort, acute GVHD was lower in PTCY-haplo from younger donors than with CBT. PTCY-haplo from younger donors to older patients offers better clinical outcomes than CBT.

Megakaryocytes (MKs) serve diverse roles beyond platelet production, including hematopoietic stem cell maintenance and immune response modulation. In our mouse model of immune bone marrow failure (BMF), we observed the unexpected persistence of MKs despite thrombocytopenia. These MKs exhibited heightened expression of immune activation markers, such as IA-IE and CD53, compared with MKs from healthy controls. Single-cell RNA sequencing analysis (scRNA-seq) revealed upregulation of immune response pathways and downregulation of pathways related to platelet function and homeostasis in MKs from animals with marrow failure (BMF). Electron microscopy demonstrated that these MKs had fewer cytoplasmic extensions, reduced α-granules, and a less developed demarcation membrane system. MKs from BMF animals had reduced ability to produce platelets compared with normal control MKs. Interestingly, when cocultured with BMF-derived T cells, MKs from healthy mice acquired immune characteristics. Functionally, MKs from BMF mice suppressed hematopoietic stem cell colony formation in coculture experiments. Mechanistically, these MKs appeared to act as antigen-presenting cells, capable of T-cell activation. Notably, similar immune activation of MKs was observed in patients with aplastic anemia through scRNA-seq. These findings highlight the immune functions of mature MKs in an alloimmune model of BMF, with potential implications for human aplastic anemia and related hematologic disorders.

Subjective and objective limitations to exercise and activity are hallmarks of heart failure (HF), regardless of underlying ejection fraction (EF). These limitations relate to cardiovascular abnormalities involving the systolic and diastolic properties of the heart, venous, and arterial vasculature, as well as noncardiovascular abnormalities, including impairments in pulmonary function, autonomic regulation, anemia, metabolism, and changes in mitochondria and skeletal muscle. The contribution of these abnormalities varies between patients with HF with preserved EF and those with HF with reduced EF, but, even within each HF subtype, there is substantial individual patient pathophysiologic variability, which suggests a potentially important role for phenotyping based on exercise reserve responses to individualize treatment. In this article, we review the current understanding of exercise reserve limitation with a focus on specific organ systems involved, both in patients with HF with preserved EF and HF with reduced EF, and how these interact to lead to symptoms of exercise intolerance and objective limitations in submaximal and peak aerobic capacity across the spectrum of HF.