Search Results (2,751)

Background: Systemic mastocytosis (SM) with associated non-mast cell myeloid neoplasm is a rare condition, defined by the presence of both SM and a clonal non-mast cell neoplasm. Due to its rarity, the demographic and molecular characteristics are poorly understood. This study investigated seven patients diagnosed with this condition at our institution. Methods: Our institutional database was searched for “systemic mastocytosis” from 1 January 2020, to 31 December 2025. Each case was annotated to identify the primary cohort of this study, systemic mastocytosis with associated non-mast cell myeloid neoplasm (SM-AHN). Demographic characteristics, outcome, hematologic features at diagnosis, cytogenetics, and molecular characteristics were annotated. Eight cases of isolated SM diagnosed during the same period were also analyzed for comparison. All patients in the database were followed until their death or until 31 December 2025. All data were exported to SPSS v. 28 (IBM, Armonk, NY, USA^®). Results: A total of seven patients were diagnosed with SM-AHN. Compared to isolated SM, SM-AHN patients showed older age at presentation, poorer hematologic values (increased anemia and thrombocytopenia), higher mutational burden, and poorer outcomes. KIT mutations were most common, predominantly D816V, with other variants like D816Y and L576F also observed. Additional frequent mutations included DNMT3A, TET2, ASXL1, SF3B1, EZH2, JAK2, NRAS, and SRSF2. Conclusions: Our findings, though limited by a small sample size, suggest that SM with associated myeloid neoplasm presents with distinct clinical and molecular features compared to isolated SM. This combined disorder is associated with older age, worse hematologic parameters, a higher mutational burden, and poorer prognosis. The frequent co-occurrence of mutations in other genes, in addition to KIT mutations, highlights the complex molecular landscape. Full article

Central nervous system (CNS) relapse remains a major cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL). Repeated isolated CNS relapse is particularly rare and associated with poor prognosis, while optimal therapeutic strategies remain insufficiently defined. Intensified CNS-directed therapy may improve disease control but is also associated with substantial long-term neurotoxicity and survivorship burden. We present the case of a boy with favorable-risk B-cell ALL who developed two isolated CNS relapses despite a good initial response to frontline therapy and absence of classical CNS relapse risk factors. The second relapse was associated with extensive meningeal involvement and optic nerve infiltration. The patient underwent intensive multimodal CNS-directed therapy, including repeated intrathecal chemotherapy, liposomal cytarabine administered according to the IntReALL 2010 protocol, cranial irradiation, and allogeneic hematopoietic stem cell transplantation (alloHSCT) from a matched sibling donor. Durable long-term remission was achieved despite the extremely unfavorable prognosis that is associated with a second isolated CNS relapse. A twenty-year follow-up extending into early adulthood revealed substantial late complications, including epilepsy, transient ischemic attack, optic nerve injury, endocrinopathies, obesity, secondary thyroid malignancy, neurocognitive difficulties, and depression requiring long-term psychiatric and psychological support. The present case illustrates the complex balance between effective CNS disease control and cumulative treatment-related neurotoxicity in pediatric ALL survivors. It also highlights the cumulative CNS injury and long-term survivorship burden that is associated with repeated CNS relapse and multimodal CNS-directed therapy. Full article

Background: Interleukin-24 (IL-24) is expressed in synovial myofibroblasts and has been associated with pain severity in female patients with knee osteoarthritis (OA). However, the direct effects of IL-24 on inflammatory responses in synovial fibroblasts and the signaling pathways involved remain unclear. This study investigated IL-24-induced transcriptional and inflammatory responses in fibroblast-enriched synovial cells and examined the effects of STAT3 and p38 mitogen-activated protein kinase (MAPK) inhibition. Methods: Fibroblast-enriched synovial cells isolated from synovial tissue obtained from patients with knee OA undergoing total knee arthroplasty were stimulated with IL-24 for 6 and 24 h. RNA sequencing (RNA-seq) was performed using cells from two patients, and overlapping upregulated genes were subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The concentration- and time-course experiment used samples from nine patients; the HJC0152 and SB203580 experiments used ten specimens from eight patients and ten specimens from nine patients, respectively. Selected inflammatory cytokines and chemokines were subsequently evaluated by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay in concentration- and time-course experiments using nine specimens from nine patients. To investigate signaling involvement, cells were treated with IL-24 in the presence or absence of the STAT3 inhibitor HJC0152 or the p38 MAPK inhibitor SB203580, each at 5 or 10 μM. Results: RNA-seq identified 27 and 34 overlapping upregulated genes that independently met the DEG criteria in both patients at 6 and 24 h, respectively. These genes were enriched in inflammatory pathways, including TNF, IL-17, NF-κB, chemokine, cytokine–cytokine receptor interaction, Toll-like receptor, and NOD-like receptor signaling pathways. IL-24 significantly increased the mRNA expression of CCL2, CXCL1, CXCL3, IL6, and IL8. HJC0152 and SB203580 at 10 μM both significantly reduced IL-24-associated CCL2, CXCL1, and IL6 expression. At the protein level, both inhibitors attenuated CCL2, CXCL1, and IL-6 concentrations in IL-24-stimulated cells. HJC0152 also reduced CXCL3 expression at the mRNA level, although its protein-level effect was less pronounced. In contrast, the effects of both inhibitors on CXCL3, CXCL10, and IL-8 were limited or inconsistent. Conclusions: IL-24 induces an inflammatory response in fibroblast-enriched synovial cells characterized by increased chemokine and cytokine expression. STAT3 and p38 MAPK inhibition preferentially attenuated IL-24-associated CCL2, CXCL1, and IL-6 responses, suggesting the possible involvement of these pathways in selected IL-24-associated inflammatory responses. These findings provide a basis for further investigation of IL-24-related signaling in OA synovitis. Full article

Primary and isolated secondary central nervous system lymphomas are aggressive malignancies requiring effective central nervous system–directed therapy. Intensive high-dose methotrexate–based regimens may be difficult to deliver, particularly in older or functionally impaired patients. Berubicin is a doxorubicin analog developed to cross the blood–brain barrier. We report a prospective case series of five adults with primary or isolated secondary CNS lymphoma treated within the BER-PUM phase Ib/II study (EudraCT 2021-006028-41), evaluating berubicin as part of the investigational MBTRIX regimen. Patients received up to four 21-day cycles of rituximab, high-dose methotrexate, berubicin, and thiotepa, with between-patient and intrapatient berubicin dose escalation. Four out of five patients completed all planned cycles, even though most of the patients had an ECOG score of 2. After two cycles, four achieved partial response, and one had progressive disease. Two patients underwent autologous stem-cell transplantation; one achieved complete response maintained at 12 months, whereas the other died from severe infectious and multiorgan complications. All patients experienced at least one grade ≥ 3 adverse event, predominantly hematologic. No protocol-defined dose-limiting toxicity or berubicin dose reduction occurred. Recruitment ended prematurely because berubicin became unavailable. This case series demonstrates the feasibility of MBTRIX, although the small sample and incomplete dose escalation preclude definitive conclusions regarding safety and efficacy. Full article

Extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae causes difficult-to-treat bloodstream infections in patients with haematological malignancies, particularly after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Carbapenems remain reliable, but their anti-anaerobic activity may aggravate intestinal dysbiosis and increase selection pressure for carbapenem resistance. Cefepime–enmetazobactam is a novel fourth-generation cephalosporin/β-lactamase inhibitor combination active against many class A ESBL-producing Enterobacterales. We describe a profoundly immunocompromised patient with acute myeloid leukaemia after allo-HSCT, grade III steroid-refractory gastrointestinal graft-versus-host disease, and intestinal colonization by an ESBL-producing K. pneumoniae isolate resistant to ceftolozane–tazobactam. The patient developed persistent bacteraemia and right pyelonephritis with small renal abscess-like lesions. Meropenem was rapidly de-escalated to cefepime–enmetazobactam, with temporary adjunctive fosfomycin and subsequently tigecycline. Blood-culture time to positivity progressively lengthened from 1.18 h to 16 h before cultures became negative. Serial cefepime therapeutic drug monitoring permitted repeated assessment of exposure and neurological toxicity risk. Whole-genome sequencing identified K. pneumoniae ST307 carrying bla_CTX-M-15, bla_TEM-1, bla_SHV-28, and bla_OXA-1, together with multiple resistance determinants and a large conjugative plasmid. This case describes the use of cefepime–enmetazobactam as part of a targeted carbapenem-sparing strategy for invasive ESBL-producing K. pneumoniae infection in a highly immunocompromised allo-HSCT recipient. Full article

Pulmonary hypertension (PH) is a well-recognized complication of chronic hemolytic anemias such as sickle cell disease and thalassemia, yet the relative contributions of hypoxia and cell-free hemoglobin (Hb) to disease progression remain incompletely understood. Patients with hemolytic anemia experience a lifelong cycle of chronic and inter bitten hypoxia that compounds vascular injury driven by extracellular Hb and its degradation products, heme and iron. While the effects of hypoxia and Hb exposure have historically been studied in isolation, the combined impact of sustained, low-level plasma Hb together with chronic hypoxia—more representative of steady-state hemolysis—has been largely overlooked. A rat model incorporating chronic hypoxia with continuous low-dose Hb infusion via an implanted pump demonstrates that even modest plasma Hb concentrations (10–20 µM heme) exert an additive effect on hypoxia-induced PH. This effect is associated with increased adventitial macrophage accumulation, oxidative stress, and inflammation, driving more severe pulmonary vascular remodeling. Building on this model, therapeutic strategies targeting Hb-mediated vascular injury are evaluated, with particular focus on repeated-dose haptoglobin (Hp) therapy, given that Hp is often severely depleted in sickle cell disease. Restoring circulating Hp sequesters plasma Hb into a non-reactive, compartmentalized Hb–Hp complex, limiting NO scavenging and oxidative damage. These mechanistic findings are further linked to functional outcomes through studies of skeletal muscle microvascular oxygen tension and exercise capacity in Berkeley sickle cell disease mice. This review synthesizes findings across these studies to clarify the interplay between hypoxia, macrophage biology, and extracellular Hb in driving pulmonary vascular remodeling and to highlight emerging Hb-targeted therapeutic strategies for hemolysis-associated PH. Full article

Diabetes mellitus prevalence is rising globally, linked to persistent hyperglycemia and endothelial dysfunction. Extracellular vesicles (EVs) play a role in diabetes pathology, involving complex intercellular communication that influences endothelial response. However, the mechanisms by which EVs contribute to endothelial dysfunction under hyperglycemia remain unknown. To investigate the effect of glucose-altered EVs on endothelial cells, we isolated EVs from HBMECs and THP-1 cells under normal- and high-glucose conditions (5.5 and 33 mM). We used NTA, electron microscopy, and LC-MS/MS for EV characterization. HBMECs in RPMI’s default glucose (11 mM) were exposed to 100 ng/mL of each EV condition, and adherent THP-1 CFSE+ cells were quantified. Long-term high glucose activated HBMECs without altering cell viability. Glucose level altered EV secretion, content, and function. For HBMECs, high glucose decreased EV release but shifted their cargo toward metabolism, barrier disruption, and neuronal protein content. For THP-1 cells, high glucose kept the EV release rate and shifted the cargo toward an inflammatory activation profile. Functionally, high-glucose EVs (mainly THP-1-derived) showed a pro-adhesive effect on endothelial cells. Here, we describe the impact of glucose on EV biology and how glucose-altered EVs can influence inflammation and endothelial responses, highlighting the importance of glycemic control in diabetic patients. Full article

Background/Objectives: MEK inhibitors (selumetinib, mirdametinib) are the only approved class of targeted therapy for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN), producing partial responses in a substantial proportion of patients (up to 63.6% in adults; objective response rate 19.7% versus 5.4% with placebo in the KOMET trial). Responses, however, are rarely complete or durable, and in malignant peripheral nerve sheath tumor (MPNST) single-agent MEK inhibition is clinically ineffective. Mechanisms of escape from MEK inhibition in these tumors remain poorly characterized and are reported in the literature as isolated primary studies without an integrative analysis. The aim of this review was to systematize both the established molecular mechanisms of resistance to MEK inhibitors in PN and MPNST and the biologically plausible candidate mechanisms extrapolated from other RAS-driven malignancies. Methods: This is a narrative review. A structured search was performed in PubMed, PubMed Central, NCBI Bookshelf, and Scopus, supplemented by clinical practice guidelines and regulatory documents; it covered publications up to 31 May 2026 and was updated in August 2026. Ninety-six sources are cited, and their composition by publication type is reported; record counts at the intermediate screening steps were not maintained, and no PRISMA flow diagram is presented. Results: Mechanisms were classified within a convergent framework into six categories: reactivation of MAPK signaling within the cascade; parallel (bypass) reactivation through receptor tyrosine kinases and adjacent inputs; epigenetic and transcriptional rewiring; cell survival programs; the tumor microenvironment and immune evasion; and intratumoural heterogeneity. Each mechanism was then graded along two independent axes—the strength of evidence that it confers resistance in PN or MPNST (E1–E3) and its therapeutic tractability (T1–T3)—and annotated with the entity and model constituting its evidence source. Conclusions: Resistance to MEK inhibition in PN and MPNST is convergent rather than mechanism-unique. The principal limitation of the field is the near-absence of clinical resistance data from patients progressing on MEK inhibitors; prospective molecular monitoring, rational combination trials, and mechanism-stratifying biomarkers are the priorities. Full article

Background/Objectives: Perioperative chemoimmunotherapy has become an important curative-intent strategy for selected patients with resectable non-small cell lung cancer (NSCLC). However, most pivotal trials evaluate neoadjuvant therapy, surgery, and postoperative immune checkpoint inhibitor (ICI) treatment as an integrated regimen. Whether continued postoperative immunotherapy provides independent incremental benefit for all patients after effective neoadjuvant chemoimmunotherapy and complete resection remains unresolved. This review focuses on the adjuvant-phase dilemma and discusses how postoperative treatment may be refined according to response and residual risk. Methods: We performed a narrative review of major neoadjuvant and perioperative chemoimmunotherapy trials, indirect comparative analyses, pathological-response studies, circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) evidence, immune biomarker studies, and emerging data in driver-positive and real-world populations. Particular attention was given to evidence informing postoperative continuation, de-escalation, or intensification after neoadjuvant chemoimmunotherapy. Results: Current phase III perioperative trials demonstrate clinically meaningful activity but do not isolate the independent contribution of the adjuvant ICI phase. Pathological response provides the most accessible postoperative risk signal: pathologic complete response identifies the deepest-response group, major pathologic response represents an intermediate state, and non-major pathologic response or persistent nodal disease suggests higher relapse risk. ctDNA-based MRD offers dynamic risk refinement and may help identify patients with residual systemic disease, although prospective validation is required before it can guide routine treatment omission or escalation. Programmed death-ligand 1 (PD-L1), tumor mutational burden, tertiary lymphoid structures, B-cell signatures, radiomics, and pathomics may provide complementary information but are not sufficient as standalone decision tools. Driver-positive disease requires molecularly stratified perioperative strategies rather than unselected extrapolation from epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative trials. Conclusions: The key question in resectable NSCLC is shifting from whether perioperative immunotherapy is active to which patients truly require postoperative immunotherapy. Future trials should prospectively test response-guided strategies integrating pathological response, ctDNA-based MRD, immune contexture, baseline risk, and treatment feasibility. Full article

Background: Bone marrow abnormalities in people living with HIV may reflect infectious, neoplastic, or inflammatory processes, particularly in advanced disease presenting with fever of unknown origin or unexplained cytopenias. In Latin America, contemporary data on the causes and diagnostic contribution of bone marrow evaluation remain limited, especially in resource-constrained settings. Aim: To characterize the etiologies, histopathological patterns, and diagnostic contribution of bone marrow evaluation in adults living with HIV at a tertiary referral center in Venezuela. Methods: We conducted a cross-sectional study with retrospective and prospective case ascertainment among adults with confirmed HIV infection who underwent bone marrow aspiration, biopsy, or both for suspected infiltrative disease between January 2019 and April 2024. We analyzed clinical, laboratory, histopathological, microbiological, and molecular data at the index bone marrow evaluation. Test-specific denominators are reported because diagnostic investigations were not uniformly available. Results: Forty-two patients were included (35 retrospectively and 7 prospectively); 59.5% were male and the median age was 39 years (IQR: 31.75–50.0). At presentation, 67% were newly diagnosed with HIV and 79% were ART-naive; the median CD4+ T-cell count was 98.5 cells/mm³. Histopathology was evaluable in 37/42 patients; 31/37 (83.8%) showed findings compatible with infectious involvement and 6/37 (16.2%) showed malignancy. Histoplasma capsulatum was isolated in 17/35 fungal cultures (48.6%), Mycobacterium tuberculosis in 13/33 mycobacterial cultures (39.4%), and CMV PCR on bone marrow aspirate was positive in 2/3 patients tested. The final etiologic classification was infectious in 36/42 patients (85.7%) and neoplastic in 6/42 (14.3%). Conclusions: In this highly selected cohort of adults with advanced HIV disease, infectious etiologies-particularly histoplasmosis and tuberculosis-predominated. Bone marrow aspiration and biopsy, interpreted together with microbiological and molecular testing, provided clinically relevant diagnostic information in patients with prolonged fever, cytopenias, or otherwise inconclusive investigations. The findings support earlier HIV diagnosis and ART initiation and improved access to fungal, mycobacterial, and molecular diagnostics in resource-limited settings. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) treated with high-dose-rate (HDR) surface brachytherapy using patient-specific 3D-printed applicators lacks a validated non-invasive follow-up modality capable of resolving microscopic residual disease. Line-field confocal optical coherence tomography (LC-OCT) provides real-time, cellular resolution, three-dimensional imaging of the epidermis and superficial dermis and has been proposed as a candidate tool for post-radiotherapy monitoring. We evaluated the feasibility of LC-OCT for pre- and post-treatment imaging of cSCC and assessed whether an LC-OCT-defined remission phenotype, operationally defined a priori as the absence of all malignancy-associated LC-OCT criteria, can be documented after 3D-printed HDR surface brachytherapy. Methods: Eight consecutive patients with histologically confirmed cSCC, unsuitable for surgery, were treated with HDR surface brachytherapy delivered through patient-specific 3D-printed applicators. LC-OCT imaging was performed immediately before brachytherapy and at short-term follow-up (six months). Nineteen pre-treatment LC-OCT criteria derived from the Cinotti 2021 descriptive criterion set for cSCC were scored: seventeen malignancy-associated criteria, plus elastosis (scored as a background photodamage covariate, not counted towards remission) and fibrosis (scored post-treatment only). Presence/absence of each criterion was rated by two blinded dermatologists; inter-assessor agreement was quantified using percentage agreement and Cohen’s kappa. Results: Baseline LC-OCT showed a rich malignant signature: hyperkeratosis, parakeratosis, disarranged epidermal architecture, dyskeratotic keratinocytes, atypical and crowded nuclei, and dermoepidermal junction alterations were present in eight out of eight lesions (100%) under an inclusive two-reader rule. At short-term follow-up, six months after the final brachytherapy fraction, all seventeen malignancy-associated criteria constituting the pre-specified remission set were absent in all eight patients under the decision rule described in the article—which classifies isolated dilated linear vessels occurring in an otherwise criterion-negative, fibrotic dermis as post-radiation telangiectasia rather than residual tumour, yielding an LC-OCT-defined remission phenotype rate of 100% (eight out of eight; 95% exact binomial [Clopper–Pearson] CI 63.1–100%). Post-radiation fibrosis was observed in 8/8 patients (100%), and dilated linear vessels were observed in six out of eight patients (75%, evaluated under the same decision rule (Observer 1: 4/8; Observer 2: 6/8). Elastosis, a marker of background actinic photodamage present in eight out of eight lesions at baseline and excluded from the malignancy-associated criterion count, is distinct from post-treatment fibrosis, a radiation-induced dermal remodelling feature scored only at follow-up; the two should not be conflated. Conclusions: In this proof-of-concept cohort, LC-OCT was feasible for pre- and post-treatment imaging of cSCC after 3D-printed HDR surface brachytherapy, produced highly reproducible dual-observer readings (κ = 0.903), and documented, at a single short-term time point six months after the final fraction, an LC-OCT-defined remission phenotype in every treated lesion, with a consistent fibrosis signature. Persistent dilated linear vessels in a fibrotic, otherwise criterion-negative dermis were classified as a non-specific post-radiation vascular change and did not preclude LC-OCT-defined complete remission. Because this remission phenotype rests on a pre-specified but not externally validated imaging definition and was not anchored to post-treatment histopathology or reflectance confocal microscopy, it constitutes an imaging surrogate rather than a confirmed complete remission, and microscopic residual disease below the resolution limit of LC-OCT cannot be excluded. These hypothesis-generating findings support LC-OCT as a candidate non-invasive monitoring modality, requiring confirmation in larger, biopsy-anchored prospective studies with longer follow-up. Full article

Background: Pineal region tumors (PRTs) are rare and biologically heterogeneous neoplasms with overlapping clinical and radiological features. Low-level cerebrospinal fluid (CSF) beta-human chorionic gonadotropin (β-hCG) may support a clinical diagnosis of germinoma (GE); however, its pathological specificity remains uncertain. Methods: We retrospectively reviewed four patients with low-level CSF β-hCG elevation whose available tissue specimens demonstrated pineal parenchymal tumors (PPTs). Tissue was obtained before systemic treatment in two patients and after platinum-based chemotherapy in two. Results: All four patients were male and aged 8 to 19 years. Pretreatment specimens from two patients demonstrated pineal parenchymal tumors of intermediate differentiation (PPTID), whereas postchemotherapy specimens from the other two demonstrated pineoblastoma (PB). Serum β-hCG was <0.1 IU/L in all patients, while CSF β-hCG ranged from 2.86 to 18.29 IU/L; serum and CSF alpha-fetoprotein (AFP) levels were normal. Two patients received platinum-based chemotherapy for presumptive intracranial germ cell tumors before tissue diagnosis, achieving stable disease or partial response. Because their specimens were obtained after chemotherapy, an occult pretreatment germ cell component could not be excluded. Conclusions: Although contemporary diagnostic protocols allow a clinical diagnosis of GE with characteristic imaging findings and low-level β-hCG elevation, isolated low-level CSF β-hCG immunoreactivity may also coexist with tissue specimens demonstrating PPT and should therefore not be considered pathognomonic for GE or interpreted in isolation. Early tissue acquisition with integrated histopathological and molecular evaluation is essential to avoid diagnostic misclassification and ensure appropriate treatment. Full article

Background/Objectives: Chronic lymphocytic leukemia (CLL) is characterized by marked clinical heterogeneity, underscoring the need for reliable biomarkers to improve diagnosis and risk stratification. Extracellular vesicles (EVs) represent promising liquid biopsy candidates because they reflect the molecular profile of their cells of origin. In CLL, CD200 is a well-established marker of tumor cells; its expression on EVs and its role as a CLL biomarker were poorly characterized. This study investigated the diagnostic and prognostic value of serum EVs in CLL. Methods: Serum EVs were isolated from 83 patients with CLL and 20 healthy subjects (HS). EV morphology, size, and concentration were assessed by transmission electron microscopy and nanoparticle tracking analysis. Flow cytometry was used to evaluate the expression of CD19, CD20, and CD200 on EVs, while digital PCR quantified EV-associated miR-93-5p, miR-125b-5p, miR-150-5p, and miR-484. Results: Compared with HS, CLL patients showed increased total EV counts and higher levels of CD19⁺, CD20⁺, CD200⁺, and CD19⁺/CD20⁺ EVs, together with enhanced CD20 and CD200 expression and reduced miR-93-5p, miR-125b-5p, and miR-484 levels. In contrast, EV-associated miR-150-5p levels were comparable between CLL patients and HS. EV features were correlated with clinical and biological characteristics, including disease stage, cytogenetic abnormalities, treatment, and time to treatment (TTT). Older age was associated with lower EV concentrations but higher CD20 and CD200 expression. Advanced-stage disease was characterized by smaller EVs with increased CD200 expression. Notably, elevated CD200⁺ EV levels and reduced CD19 expression were associated with shorter TTT and earlier treatment initiation. Conclusions: Multiparametric profiling identified distinct quantitative, phenotypic, and molecular features of CLL-derived EVs and revealed CD200 as a novel EV-associated biomarker. These findings support the clinical utility of serum EVs as a new valuable approach for CLL diagnosis, prognosis, and treatment prediction. Full article

Juvenile colorectal polyps (JP) are the most common polypoid lesions of the colon in children and the leading cause of lower gastrointestinal bleeding in pediatric patients. Although histologically classified as benign hamartomatous lesions, they arise in a context of allergic sensitization and IgE-mediated inflammation, suggesting that the epithelial compartment may play an active role in their pathogenesis. To date, most studies have focused on the immune cell infiltrate, leaving the molecular programs operating within the epithelium largely unexplored. Whole-transcriptome RNA sequencing (RNA-seq) was performed on epithelial cells isolated from pediatric JP (n = 8) and paired tissue circumjacent to polyp (TCP) (n = 7) obtained from children with a history of rectal bleeding and IgE sensitization to food allergens. Differential expression, functional enrichment (GO, KEGG, GSEA), and cross-dataset comparison with TCGA colorectal adenocarcinoma (CRC) was conducted. Candidate genes were validated by RT-qPCR in independent samples, including colorectal cancer (CRC) and inflammatory bowel disease (IBD) tissue. Differential expression analysis identified 3273 differentially expressed genes (2342 upregulated, 931 downregulated in JP vs. TCP), with 220 genes exceeding 32-fold change, including SERPINB3 (log2FC = 12.16), MMP1 (log2FC = 10.19), NMUR2 (log2FC = 10.08) and CHI3L1 (log2FC = 8.87). JP epithelium displayed a coherent type 2 inflammatory signature, encompassing upregulation of the alarmin IL33, eosinophil-attracting chemokines (CCL11, CCL24), IgE receptor subunits (FCER1A, FCER1G), and a coordinately activated leukotriene and prostaglandin biosynthetic program (ALOX5, ALOX5AP, PTGS2). Concurrent alterations in epithelial identity were observed, including downregulation of absorptive enterocyte and intestinal stem cell markers (CDX2, LGR5, ASCL2) alongside upregulation of secretory and regenerative programs, including the ectopic gastric-type mucin MUC5AC. Tight junction dysregulation—notably upregulation of the pore-forming claudin CLDN2 and loss of barrier-sealing claudins (CLDN3, CLDN4, CLDN23)—was consistent with impaired epithelial permeability. Pathway analyses confirmed activation of type 2 immune and extracellular matrix remodeling programs, with concurrent suppression of mitochondrial oxidative phosphorylation. Cross-dataset comparison with TCGA CRC data identified 381 co-upregulated and 87 co-downregulated genes shared between JP and CRC, including SERPINE1, CXCL8, ICAM1, and MMP3, several of which were associated with poorer disease-specific survival in CRC patients. RT-qPCR validation confirmed elevation of CHI3L1 and SERPINE1 in both JP and CRC, while SERPINB4 appeared JP-specific. Epithelial cells from pediatric juvenile colorectal polyps associated with allergic sensitization display a comprehensive type 2 inflammatory transcriptome alongside profound alterations in lineage identity, barrier integrity, and metabolic programming. Partial convergence with CRC-associated gene expression programs—in the absence of histological dysplasia—suggests that chronic allergic inflammation activates conserved epithelial remodeling pathways shared across mucosal tissues. CHI3L1, SERPINE1, and SERPINB4 are candidate biomarkers warranting validation in larger cohorts. Full article

Uhthoff’s phenomenon (UP) is a transient, fully reversible exacerbation of pre-existing neurological deficits in multiple sclerosis (MS) patients, triggered by minor elevations in core body temperature. In clinical practice, UP is a frequent source of distress, often misidentified as an acute inflammatory disease relapse. This narrative review provides a critical analysis of UP, addressing methodological heterogeneity in its epidemiological estimates, its clinical presentation, and its differential diagnosis from true relapses. Mechanistically, we synthesize traditional concepts of temperature-dependent conduction block with modern insights into neuroenergetic failure, mitochondrial dysfunction, inflammatory mediators, and autonomic dysregulation. Furthermore, this work delineates current management strategies, establishing a clear distinction between robust evidence-based interventions and expert-informed practical guidance for patient education, physical rehabilitation planning, targeted active/passive cooling, and pharmacological approaches. Characterized as a pseudo-relapse, UP occurs independently of novel focal neuroinflammation. In conclusion, an isolated episode of Uhthoff’s phenomenon (UP) represents a transient, functional conduction block and does not inflict acute, permanent structural damage to the axon. However, emerging frameworks suggest that frequent, repeated episodes subject the already demyelinated axon to recurrent metabolic strain. Over time, these successive neuroenergetic crises do not directly destroy the fiber, but they may gradually exhaust the cell’s metabolic reserve. This cumulative stress potentially increases long-term secondary axonal vulnerability, making the axon more susceptible to the progressive neurodegenerative processes inherent to multiple sclerosis. Full article