Search Results (31)

Background and Clinical Significance: Primary Cutaneous Cribriform Apocrine Carcinoma (PCCAC) is a rare, inert low-grade cutaneous malignancy that is diagnosed on histopathologic assessment. PCCAC usually presents in middle-aged adults as a solitary, subcutaneous nodule on the extremities. Characterized by anastomosing tubules and solid/cribriform nests of atypical epithelial cells generating a sieve-like display, the tumor is a histopathological variant of apocrine metaplasia of the skin. PCCAC also follows characteristic staining patterns. It is important to distinguish PCCAC from other similar histological variants, which may hold more grievous indications. Case Presentation: A 47-year-old female presented with an enlarging, itchy growth of several months on her back. On physical exam, an indurated pink, nontender papule of 8 mm on the left lateral side wall was noted. Histopathology demonstrated a well-circumscribed, pandermal tumor composed of anastomosing solid and cribriform nests, tubules, and cords of mildly atypical, eosinophilic epithelial cells forming a glandular lumina. An immunohistochemical study revealed the tumoral epithelium to express CK7, CK5/6, BER-EP4, CD117 (C-kit), and S100. Positive EMA and CEA staining highlighted intratumoral glandular ductal differentiation and apocrine secretion. Immunohistochemical stains for CK20, GATA-3, and p63 were negative. Conclusions: We present this case to distinguish the histological attributes of PCCAC and help differentiate it from more concerning visceral metastatic malignancies. We follow with a narrative review of the histopathologic differential for PCCAC and feature reconciliation of corresponding staining patterns reported in the literature. Full article

Background: Clear cell renal cell carcinoma with rhabdoid features (ccRCC-R) is a highly aggressive variant of renal cell carcinoma that carries a poor prognosis and limited treatment options. Methods: To better define the clinicopathologic and molecular landscape of ccRCC-R, we conducted an integrated clinicopathologic and molecular study of 17 tumors of ccRCC-R, utilizing comprehensive histomorphologic evaluation, immunohistochemistry, and targeted next-generation sequencing (NGS). Results: Histologically, all tumors demonstrated classic clear cell renal cell carcinoma morphology with focal to extensive rhabdoid differentiation, characterized by eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and paranuclear intracytoplasmic inclusion. Architectural alterations, including solid/sheet-like, alveolar/trabecular, and pseudopapillary growth patterns, were frequently observed. Immunohistochemically, tumors commonly exhibited loss of PAX8 and Claudin4 expression, preserved cytokeratin AE1/AE3 staining, and diffuse membranous CAIX expression. Frequent loss of SMARCA2 with retained SMARCA4 supported aberrations in chromatin remodeling. Unsupervised hierarchical clustering based on pathway-specific somatic mutations identified four distinct molecular subgroups defined by recurrent alterations in (1) DNA damage repair (DDR) genes, (2) chromatin remodeling genes, (3) PI3K/AKT/mTOR signaling components, and (4) MAPK pathway genes. Clinicopathologic correlation revealed that each subgroup was associated with unique biological characteristics and suggested distinct therapeutic vulnerabilities. Conclusions: Our findings underscore the molecular heterogeneity of ccRCC-R and support the utility of pathway-based stratification for guiding precision oncology approaches and biomarker-informed clinical trial design. Full article

Asthma is a chronic and multifaceted respiratory condition that affects over 300 million individuals across the globe. It is characterized by persistent inflammation of the airways, which leads to episodes of wheezing, breathlessness, chest tightness, and coughing. The most prevalent form of asthma is classified as Type 2 or T2-high asthma. In this variant, the immune response is heavily driven by eosinophils, mast cells, and T-helper 2 (Th2) cells. These components release a cascade of cytokines, including interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). This release promotes several processes: the production of immunoglobulin E (IgE), which is integral to allergic responses; the recruitment of eosinophils—white blood cells that contribute to inflammation and tissue damage. Conversely, non-Type 2 or T2-low asthma is typically associated with a different inflammatory profile characterized by neutrophilic inflammation. This type of asthma is driven by T-helper 1 (Th1) and T-helper 17 (Th17) immune responses, which are often present in older adults, smokers, and those suffering from more severe manifestations of the disease. Among asthmatic patients, approximately 80–85% of cases are classified as T2-high asthma, while only 15–20% are T2-low asthma. Treatment of asthma focuses heavily on controlling inflammation. Inhaled corticosteroids remain the cornerstone therapy for managing T2-high asthma. For more severe or treatment-resistant cases, biologic therapies targeting specific inflammatory pathways, such as anti-IgE (omalizumab), anti-IL-5 (mepolizumab, benralizumab), and anti-IL-4/IL-13 (dupilumab), have shown great promise. For T2-low asthma, macrolide antibiotics like azithromycin and other novel therapies are being explored. This article reviews the safety, efficacy, and indications of the currently approved biologics and discusses potential novel biologics for asthma. Full article

The regenerative properties of platelet-rich plasma (PRP) result from the high concentration of growth factors, including transforming growth factor beta 1 (TGF-β1). Nevertheless, this form of therapy may not always be effective due to the variability in genetic factors. In this study, the association of TGFB1 gene polymorphisms with the effectiveness of lateral elbow tendinopathy (LET) treatment with PRP was investigated. The effectiveness of therapy was assessed using minimal clinically important difference (MCID) and patient-reported outcome measures (PROM), specifically visual analog scale (VAS), quick version of disabilities of the arm, shoulder, and hand score (QDASH), and patient-rated tennis elbow evaluation (PRTEE) for two years (in weeks 2, 4, 8, 12, 24, 52, and 104). The most effective therapy was noticed in CC rs2278422 genotype carriers, whereas carriers of AA, CC, and CC genotypes (rs12461895, rs4803455, rs2241717) showed more severe pain before therapy. Moreover, the analyses revealed an association of studied polymorphisms with such parameters of blood morphology as eosinophils (EOS), neutrophils (NEU), and monocytes (MONO). In conclusion, genotyping of rs2278422 variant may be a valuable diagnostic method for patient selection for PRP therapy, while genotyping of rs12461895, rs4803455, and rs2241717 polymorphisms may be used for prediction of increased risk of pain sensation. Full article

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory condition of the esophagus characterized by eosinophilic infiltration, and hallmark symptoms of esophageal dysfunction such as dysphagia and food impaction. Over the past three decades, EoE has been recognized as a distinct clinical entity, distinguished from gastroesophageal reflux disease (GERD) through advancements in diagnostic techniques, particularly endoscopy with biopsy. The rising global prevalence of EoE reflects enhanced diagnostic awareness, evolving criteria, and environmental along with lifestyle changes. The etiology of EoE is multifactorial, involving genetic predispositions, immune dysregulation, the gut microbiome, and environmental triggers, including dietary allergens and aeroallergens. Key mechanisms include a type 2 helper T-cell (Th2)-driven immune response, epithelial barrier dysfunction, and genetic variants such as CAPN14 and TSLP. Chronic inflammation leads to tissue remodeling, fibrosis, and esophageal narrowing, contributing to disease progression and complications. Management strategies have evolved to include dietary elimination, proton pump inhibitors, topical corticosteroids, biologics, and endoscopic interventions for fibrostenotic complications. Emerging therapies targeting cytokines such as interleukin (IL)-4, IL-5, and IL-13, alongside novel diagnostic tools like the esophageal string test and Cytosponge, offer promising avenues for improved disease control and non-invasive monitoring. Long-term surveillance combining endoscopic and histological evaluations with biomarkers and non-invasive tools is critical to optimizing outcomes and preventing complications. Future research should address gaps in understanding the role of the esophageal microbiome, refine therapeutic approaches, and develop personalized strategies to improve disease management and patient quality of life. Full article

Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily focused on unconjugated mAbs, which may be inadequate, especially against mast cells. Methods: Here, we used transgenic mice to raise a diverse panel of fully human mAbs that either recognize the V-set domain, membrane-distal C2-set domain, or membrane-proximal C2-set domain of full-length Siglec-8 as a basis for novel therapeutics. Results: All mAbs were efficiently internalized into Siglec-8-expressing cells, suggesting their potential to deliver cytotoxic payloads. Tool T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells using single-chain variable fragments from Siglec-8 mAbs showed highly potent cytolytic activity against Siglec-8-positive cells even in cases of very low target antigen abundance, whereas they elicited no cytolytic activity against Siglec-8-negative target cells. Siglec-8^V-set-directed T cell-engaging BiAbs and Siglec-8^V-set-directed CAR-modified NK cells induced substantially greater cytotoxicity against cells expressing an artificial smaller Siglec-8 variant containing only the V-set domain than cells expressing full-length Siglec-8, consistent with the notion that targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, unconjugated Siglec-8^C2-set mAbs, Siglec-8^C2-set-directed T cell-engaging BiAbs, and Siglec-8^C2-set-directed CAR-modified NK cells showed high antigen-specific cytolytic activity against Siglec-8-positive human cell lines and primary patient eosinophils. Conclusions: Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders. Full article

The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-β³-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01–P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-β³-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-β³-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations. Full article

Eotaxin-3 is a key chemokine with a relevant role in eosinophilic esophagitis, a rare chronic immune/antigen-mediated inflammatory disorder. Eotaxin-3 is a potent activator of eosinophil emergence and migration, which may lead to allergic airway inflammation. We investigated, using bioinformatics tools, the protein structure and the possible effects of the known variations reported in public databases. Following a procedure already established, we created a 3D model of the whole protein and modeled the structure of 105 protein variants due to known point mutations. The effects of the amino acid substitution at the level of impact on protein structure, stability, and possibly function were detected by the bioinformatics procedure and described in detail. A web application was implemented to browse the results of the analysis and visualize the 3D models, with the opportunity of downloading the models and analyzing them using their own software. Among 105 amino acid substitutions investigated, the study evidenced in 44 cases at least one change in any of the investigated structural parameters. Other six variations are also relevant, although a structural effect was not detected by our analysis, because they affected amino acids highly conserved, which suggests a possible function role. All these variations should be the object of particular attention, as they may induce a loss of functionality in the protein. Full article

The Hodgkin variant Richter syndrome (HvRS) is an infrequent complication occurring in 1% of lymphocytic lymphoma/chronic lymphocytic leukemia patients. We report a case of HvRS diagnosed in Sub-Saharan Africa. A 63-year-old patient was consulted for the investigation of an abdominal mass that had been evolving for 5 years prior to admission. His history revealed night sweats, 13% weight loss in 3 months and persistent pruritis. Examination revealed bilateral cervical axillary and inguinal macroadenopathies, painless abdominal distension, pruritic lesions and WHO 2 PS. The blood count showed anemia at 9.5 g/dL. Histology revealed a lymphomatous proliferation of diffuse architecture, nodular in places, with Hodgkin and Sternberg cells associated with small lymphocytes, histiocytes and eosinophilic polymorphs. Immunohistochemistry showed CD20, PAX5, BCL2, CD5, CD23 and MYC positivity; Ki67 at 10% and cyclin D1, BCL6 and CD10 negativity; CD30 positivity on Hodgkin and Sternberg cells that remained CD20 negative; difficulty interpreting CD15; EBV positivity (EBERs); and CD3 and CD5 positivity on reactive T cells. CD138 and kappa and lambda light chains were non-contributory. The extension work-up classified the patient as Ann Arbor stage III B with a Hasenclever score of 3/7. This case illustrates the difficulties in diagnosing HvRS in our countries, where the number of haematopathologists is insufficient and the technical facilities are limited. Full article

In this work, we present a comprehensive overview of the genetic and non-genetic complexity of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA is a rare complex systemic disease that occurs in people presenting with severe asthma and high eosinophilia. After briefly introducing EGPA and its relationship with the anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAVs), we delve into the complexity of this disease. At first, the two main biological actors, ANCA and eosinophils, are presented. Biological and clinical phenotypes related to ANCA positivity or negativity are explained, as well as the role of eosinophils and their pathological subtypes, pointing out their intricate relations with EGPA. Then, the genetics of EGPA are described, providing an overview of the research effort to unravel them. Candidate gene studies have investigated biologically relevant candidate genes; the more recent genome-wide association studies and meta-analyses, able to analyze the whole genome, have confirmed previous associations and discovered novel risk loci; in the end, family-based studies have dissected the contribution of rare variants and the heritability of EGPA. Then, we briefly present the environmental contribution to EGPA, reporting seasonal events and pollutants as triggering factors. In the end, the latest omic research is discussed and the most recent epigenomic, transcriptomic and microbiome studies are presented, highlighting the current challenges, open questions and suggesting approaches to unraveling this complex disease. Full article

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 (STAT6), CYP2C19, CYP3A4, CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. −75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants. Full article

Myocarditis is a polymorphic and potentially life-threatening disease characterized by a large variability in clinical presentation and prognosis. Within the broad spectrum of etiology, eosinophilic myocarditis represents a rare condition characterized by eosinophilic infiltration of the myocardium, usually associated with peripheral eosinophilia. Albeit uncommon, eosinophilic myocarditis could be potentially life-threatening, ranging from mild asymptomatic disease to multifocal widespread infiltrates associated with myocardial necrosis, thrombotic complications, and endomyocardial fibrosis. Moreover, it could progress to dilated cardiomyopathy, resulting in a poor prognosis. The leading causes of eosinophilic myocarditis are hypersensitivity reactions, eosinophilic granulomatosis with polyangiitis, cancer, hyper-eosinophilic syndrome variants, and infections. A thorough evaluation and accurate diagnosis are crucial to identifying the underlying cause and defining the appropriate therapeutic strategy. On these bases, this comprehensive review aims to summarize the current knowledge on eosinophilic myocarditis, providing a schematic and practical approach to diagnosing, evaluating, and treating eosinophilic myocarditis. Full article

Eosinophils in peripheral blood account for 0.3–5% of leukocytes, which is equivalent to 0.05–0.5 × 10⁹/L. A count above 0.5 × 10⁹/L is considered to indicate eosinophilia, while a count equal to or above 1.5 × 10⁹/L is defined as hypereosinophilia. In bone marrow aspirate, eosinophilia is considered when eosinophils make up more than 6% of the total nuclear cells. In daily clinical practice, the most common causes of reactive eosinophilia are non-hematologic, whether they are non-neoplastic (allergic diseases, drugs, infections, or immunological diseases) or neoplastic (solid tumors). Eosinophilia that is associated with a hematological malignancy may be reactive or secondary to the production of eosinophilopoietic cytokines, and this is mainly seen in lymphoid neoplasms (Hodgkin lymphoma, mature T-cell neoplasms, lymphocytic variant of hypereosinophilic syndrome, and B-acute lymphoblastic leukemia/lymphoma). Eosinophilia that is associated with a hematological malignancy may also be neoplastic or primary, derived from the malignant clone, usually in myeloid neoplasms or with its origin in stem cells (myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, acute myeloid leukemia with core binding factor translocations, mastocytosis, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, and myelodysplastic neoplasms). There are no concrete data in standardized cytological and cytometric procedures that could predict whether eosinophilia is reactive or clonal. The verification is usually indirect, based on the categorization of the accompanying hematologic malignancy. This review focuses on the broad differential diagnosis of hematological malignancies with eosinophilia. Full article

Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in some centers, PMBL may be treated according to a particular regimen, distinct from those used in DLBCL, emphasizing the importance of accurate identification at diagnosis. This study aimed to describe the histological and molecular characteristics of PMBL to improve the accuracy of their diagnosis. Forty-nine cases of PMBL were retrospectively retrieved. The mean age at diagnosis was 39 years (21–83), with a sex ratio of 0.88. All cases presented a fibrous background with diffuse growth of intermediate to large cells with an eosinophil (26/49, 53%) or retracted cytoplasm (23/49, 47%). “Hodgkin-like” cells were observed in 65% of cases (32/49, 65%). The phenotype was: BCL6+ (47/49, 96%), MUM1+ (40/49, 82%), CD30+ (43/49, 88%), and CD23+ (37/49, 75%). Genomic DNAs were tested by next generation sequencing of 33 cases using a custom design panel. Pathogenic variants were found in all cases. The most frequent mutations were: SOCS1 (30/33, 91%), TNFAIP3 (18/33, 54.5%), ITPKB (17/33, 51.5%), GNA13 (16/33, 48.5%), CD58 (12/33, 36.4%), B2M (12/33; 36.4%), STAT6 (11/33, 33.3%) as well as ARID1A (10/33, 30.3%), XPO1 (9/33, 27.3%), CIITA (8/33, 24%), and NFKBIE (8/33, 24%). The present study describes a PMBL cohort on morphological, immunohistochemical, and molecular levels to provide pathologists with daily routine tools. These data also reinforce interest in an integrated histomolecular diagnosis to allow a precision diagnosis as early as possible. Full article

Treatment of functional digestive disorders is not always effective. Therefore, a search for new application points for potential drugs is perspective. Our aim is to evaluate the effect of rebamipide on symptom severity, intestinal barrier status, and intestinal microbiota composition and function in patients with diarrheal variant of irritable bowel syndrome overlapping with functional dyspepsia (D-IBSoFD). Sixty patients were randomized to receive trimebutine (TRI group), trimebutine + rebamipide (T + R group), or rebamipide (REB group) for 2 months. At the beginning and end of the study, patients were assessed for general health (SF-36), severity of digestive symptoms (Gastrointestinal Symptom Rating and 7 × 7 scales), state of the intestinal barrier, and composition (16S rRNA gene sequencing) and function (short-chain fatty acid fecal content) of the gut microbiota. The severity of most digestive symptoms was reduced in the REB and T + R groups to levels similar to that observed in the TRI group. The duodenal and sigmoidal lymphocytic and sigmoidal eosinophilic infiltration was decreased only in the REB and T + R groups, not in the TRI group. Serum zonulin levels were significantly decreased only in the REB group. A decrease in intraepithelial lymphocytic infiltration in the duodenum correlated with a decrease in the severity of rumbling and flatulence, while a decrease in infiltration within the sigmoid colon correlated with improved stool consistency and decreased severity of the sensation of incomplete bowel emptying. In conclusion, rebamipide improves the intestinal barrier condition and symptoms in D-IBSoFD. The rebamipide effects are not inferior to those of trimebutine. Full article