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Chronic anemia is commonly diagnosed in older adults and serves an important indicator of both reactive and clonal conditions. Many underlying diseases, such as myelodysplastic syndromes and multiple myeloma, are more prevalent amongst the elderly, while novel therapeutic approaches have transformed pediatric disorders of poor prognosis, such as beta-thalassemia, to a chronic disease of older adults. Thus, the increasing prevalence of chronic anemia in older ages is largely attributed to more frequent diagnostic and therapeutic evaluations and demographic changes. The etiology of anemia in adults is complex, ranging from genetic mutations to bone marrow failure syndromes, chronic kidney disease, nutritional deficiencies, and inflammatory processes, while in some cases no clear etiology is found. For this reason, extensive research is ongoing to introduce novel therapeutic targets and improve quality of life. Management of anemia in adults depends on severity and especially on the underlying conditions of each patient. Metabolic pathway analyses have revealed alterations in various pathways, including glycolysis, pyruvate, propanoate, glycerophospholipid, galactose, fatty acid, starch, and sucrose metabolism along with fatty acid elongation in mitochondria, glycerolipid, glyoxylate, and dicarboxylate metabolism in adult patients with chronic anemia compared to healthy individuals, which may serve as potential new therapeutic targets. In this review, we aim to (i) summarize current evidence regarding metabolic disturbances in diseases of age-related hematopoietic dysregulation, being represented by multiple myeloma and myelodysplastic syndromes, and in β-thalassemia, a disease model of accelerating cellular aging; and (ii) describe novel therapeutic metabolic-targeted options for the aforementioned diseases, focusing on the need for continuous research in this field.

Aplastic anemia (AA) is a rare autoimmune disease. Drugs, viruses, and radiation are among the most common etiologic factors, and most cases have immune pathophysiology. SARS-CoV-2 vaccines have been linked with rare side effects, including cases of acquired aplastic anemia. Here we review all the reported cases of new-onset AA after SARS-CoV-2 vaccination, and discuss their clinical characteristics and management. 18 patients in these case reports had a median age of 58 years. The time from vaccination to onset of aplastic anemia ranged from 1 day to 7 months, with a median of 2.5 weeks. Seventeen patients were diagnosed with severe or very severe aplastic anemia post-vaccination and all patients received standard treatments for acquired aplastic anemia. Seventeen patients achieved a complete or partial response and only 1 patient died. Aplastic anemia can be considered a very rare SARS-CoV-2 vaccine-related adverse event, although a causative relationship has not been proven. Reporting cases of such uncommon post-vaccination events could help clinicians to consider aplastic anemia when pancytopenia is observed after vaccination. The benefits of SARS-Cov-2 vaccination are established, and reports of rare events serve only to increase awareness in daily clinical practice.

Despite the significant reduction in pneumococcal disease due to pneumococcal vaccines, protection of vulnerable high-risk individuals, especially pediatric populations, remains a great challenge. In an effort to maximize the protection of high-risk children against pneumococcal disease, a combined schedule that includes both conjugate and polysaccharide vaccines is recommended by several countries in the developed world. On the other hand, middle- and low-income countries do not have in place established policies for pneumococcal immunization of children at risk. Pneumococcal conjugate vaccines, despite their benefits, have several limitations, mainly associated with serotype replacement and the wide range of serotype coverage worldwide. In addition, PPV23-impaired immunogenicity and the hyporesponsiveness effect among populations at risk have been well-documented. Therefore, the added value of continuing to include PPV23 in vaccination schedules for high-risk individuals in the years to come remains to be determined by monitoring whether the replacing/remaining serotypes causing IPD are covered by PPV23 to determine whether its benefits outweigh its limitations. In this review, we aim to describe serotype distribution and vaccine efficacy data on pneumococcal disease in the pre- and post-PCV implementation era among high-risk children in both developed and developing countries, assessing the optimization of current recommendations for their vaccination against pneumococcal disease.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell–cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell–cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway’s intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions.

Epigenetics encompasses heritable and stable changes in gene expression caused by external chromosomal modifications, without altering the underlying DNA sequence. Epigenetic modifications, established during early development and maintained through successive cell divisions, play a critical role in regulating gene expression. Post-translational modifications (PTMs) are a key aspect of epigenetics and are essential for modulating protein functionality, as well as regulatory cellular processes, including proliferation, differentiation, metabolic pathways, and tumorigenic events. Among these, the small ubiquitin-related modifier (SUMOylation) system is a reversible PTM mechanism that alters target protein interaction surfaces through covalent binding to lysine residues, thereby influencing protein structure and function. Acute myeloid leukemia (AML) is a highly aggressive malignancy characterized by the clonal expansion of primitive hematopoietic stem cells of the myeloid lineage in the bone marrow. Despite recent advancements in therapeutic strategies and an improved understanding of leukemogenic pathways, patient outcomes remain poor, particularly in elderly populations. Consequently, efforts have focused on developing novel agents, including co-targeting specific mutations or integrating targeted therapies into combinatorial chemotherapeutic regimens. Emerging evidence suggests that SUMOylation plays a significant role in AML pathogenesis and treatment response, representing a promising therapeutic target for advanced disease cases. This review provides a brief analysis of the functional role of the SUMOylation system in AML and highlights its potential as a therapeutic target. We also discuss current knowledge gaps and propose directions for future research to advance precision medicine approaches for AML treatment.

Non-transfusion-dependent (NTD) thalassaemia is characterised by ineffective erythropoiesis and haemolytic anaemia, leading to long-term complications, poor quality of life, and early mortality. No oral disease-modifying therapies are approved for β-thalassaemia and no agents are approved for α-thalassaemia. The objective of this study was to evaluate the efficacy and safety of mitapivat, an oral activator of pyruvate kinase, in adults with NTD α-thalassaemia or NTD β-thalassaemia. ENERGIZE is a phase 3, double-blind, randomised, placebo-controlled trial followed by an open-label extension conducted at 70 hospitals in 18 countries globally. Participants had to be aged 18 years or older with NTD α-thalassaemia or NTD β-thalassaemia and haemoglobin concentrations of 10 g/dL or lower. Participants were randomly assigned 2:1 to mitapivat or placebo (100 mg orally twice a day for 24 weeks) via a central interactive response technology system using block randomisation, stratified by baseline haemoglobin concentration and thalassaemia genotype. Everyone was masked to the patients' treatment assignment until the study was unblinded for the analysis of the primary endpoint. The primary endpoint was haemoglobin response (≥1·0 g/dL increase from baseline in mean haemoglobin concentration from week 12 through week 24), analysed in all patients who were randomly assigned. Safety was analysed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT04770753, and is active but not recruiting. Between Nov 8, 2021, and March 31, 2023, 235 patients were screened, of whom 194 were enrolled (123 [63%] were female and 71 [37%] were male). 130 patients were randomly assigned to mitapivat and 64 patients to placebo and formed the full analysis set. One patient in each group was randomly assigned but not given treatment and was therefore excluded from the safety analysis set (mitapivat 129 patients and placebo 63 patients). Seven patients in the mitapivat group and one patient in the placebo group discontinued treatment before the end of the 24-week double-blind period. 55 (42%) of 130 patients in the mitapivat group had a haemoglobin response versus one (2%) of 64 in the placebo group (least-squares mean difference 41% [95% CI 32–50], two-sided p<0·0001). Adverse events were reported in 107 (83%) of 129 patients who received mitapivat and 50 (79%) of 63 patients who received placebo. The most commonly reported adverse events with mitapivat were headache (29 [22%] of 129 patients in the mitapivat group vs six [10%] of 63 in the placebo group), initial insomnia (18 [14%] vs three [5%]), nausea (15 [12%] vs five [8%]), and upper respiratory tract infection (14 [11%] vs four [6%]). No deaths were reported. Mitapivat could be a new oral treatment for adults with NTD α-thalassaemia or NTD β-thalassaemia by increasing haemoglobin concentration and improving fatigue. Agios Pharmaceuticals.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) are prevalent conditions that have been correlated with infertility through overlapped pathophysiological mechanisms. MASLD is associated with metabolic syndrome and is considered among the major causes of chronic liver disease, while PCOS, which is characterized by ovulatory dysfunction and hyperandrogenism, is one of the leading causes of female infertility. The pathophysiological links between PCOS and MASLD have not yet been fully elucidated, with insulin resistance, hyperandrogenemia, obesity, and dyslipidemia being among the key pathways that contribute to liver lipid accumulation, inflammation, and fibrosis, aggravating liver dysfunction. On the other hand, MASLD exacerbates insulin resistance and metabolic dysregulation in women with PCOS, creating a vicious cycle of disease progression. Understanding the intricate relationship between MASLD and PCOS is crucial to improving clinical management, while collaborative efforts between different medical specialties are essential to optimize fertility and liver health outcomes in individuals with MASLD and PCOS. In this review, we summarize the complex interplay between MASLD and PCOS, highlighting the importance of increasing clinical attention to the prevention, diagnosis, and treatment of both entities.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.