Research

Leuk Res Rep. 2025 Aug 25;24:100540. doi: 10.1016/j.lrr.2025.100540. eCollection 2025.

ABSTRACT

OBJECTIVE: Acquired Immunodeficiency Syndrome (AIDS)-related lymphoma has diverse clinical manifestations, and its diagnosis is often challenging. Misdiagnosis can delay treatment and affect patient prognosis. We assessed the clinical data of eight patients with atypical clinical manifestations of AIDS-related lymphoma, to enhance physicians’ understanding of these patients, and reduce the potential for misdiagnosis.

METHODS: A retrospective analysis was conducted on eight patients with atypical manifestations of AIDS-related lymphoma admitted to the Department of Infectious Diseases of Yunnan Provincial Hospital between May 2017 and May 2023. They were initially misdiagnosed with opportunistic infections, and were later diagnosed with lymphoma.

RESULTS: The patients comprised five males and three females. Cluster of Differentiation 4 (CD₄) counts were lower than 200/μl for all patients, and inflammatory marker levels were elevated to varying degrees. Four patients had recurrent fever, one had bleeding, one had pulmonary infection, one had long-term diarrhoea, and one had visual impairment as the primary symptoms. Six patients were diagnosed through bone marrow cytology and biopsy, one through colonoscopy and pathological biopsy, and one through computed tomography-guided percutaneous lung biopsy. All patients had extranodal involvement, including one case in the intestine, one in the lung, and six in the bone marrow. All patients were at lymphoma stage IV, with four in Group A and four in group B.

CONCLUSION: In patients with AIDS, particularly those with low CD4 counts and unexplained fever, atypical lymphoma should be considered, and tissue biopsy should be performed to further confirm the diagnosis.

PMID:40933280 | PMC:PMC12418885 | DOI:10.1016/j.lrr.2025.100540

Immunol Res. 2025 Sep 11;73(1):129. doi: 10.1007/s12026-025-09685-8.

ABSTRACT

BACKGROUND: Variants of uncertain significance (VUS) represent a major diagnostic challenge in the interpretation of genetic testing results, particularly in the context of inborn errors of immunity such as severe combined immunodeficiency (SCID). The inconsistency among computational prediction tools often necessitates expensive and time-consuming wet-lab analyses.

OBJECTIVE: This study aimed to develop disease-specific, multi-class machine learning models using in silico scores to classify SCID-associated genetic variants and improve the interpretation of VUS.

METHODS: Genes associated with SCID were identified based on the 2024 update of the International Union of Immunological Societies. Missense variants were retrieved from ClinVar and labeled as benign, likely benign, likely pathogenic, or pathogenic. Variants classified as VUS or with conflicting interpretations were excluded. In silico functional prediction scores were collected for each variant. Multi-class classification models were developed using six machine learning algorithms: Random Forest, XGBoost, Gradient Boosting, AdaBoost, Support Vector Machine and Logistic Regression. Performance was evaluated using five-fold cross-validation with five repeats (25 folds).

RESULTS: A total of 537 variants from 71 genes were included in the final dataset. Among the models, Random Forest achieved the best performance with an accuracy of 0.70 ± 0.03 and the highest area under the receiver operating characteristic curve (AUROC: 0.90 ± 0.01). MetaRNN, BayesDel_addAF, and REVEL were the most predictive features.

CONCLUSION: This study demonstrates that disease-specific, multi-class machine learning models leveraging in silico scores can effectively support the classification of SCID-related variants, offering a promising tool for improving VUS interpretation.

KEY MESSAGES: Multi-class machine learning models can enhance the interpretation of SCID-related VUS. Random Forest showed the highest diagnostic accuracy and robustness among tested models. Disease-specific modeling improves classification performance despite limited datasets. Capsule Summary This study developed disease-specific multi-class machine learning models to classify SCID-related variants using in silico scores, with Random Forest showing the strongest performance in predicting variant pathogenicity.

PMID:40931232 | DOI:10.1007/s12026-025-09685-8

JAMA Otolaryngol Head Neck Surg. 2025 Sep 11. doi: 10.1001/jamaoto.2025.2816. Online ahead of print.

ABSTRACT

IMPORTANCE: The oral microbiome plays a critical role in cancer treatment responses, yet its influence on outcomes in patients with head and neck squamous cell carcinoma (HNSCC) undergoing (chemo)radiotherapy remains poorly understood. Identifying specific microbiome signatures associated with treatment effectiveness could provide novel prognostic biomarkers and therapeutic targets.

OBJECTIVE: To investigate the association between salivary Lachnoanaerobaculum spp abundance and treatment outcomes in patients with HNSCC undergoing (chemo)radiotherapy and to explore potential mechanisms.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study analyzed saliva samples from patients with HNSCC who were enrolled in 2 independent prospective biomarker studies (SALIVA and ZissTrans) and underwent definitive (chemo)radiotherapy. Oral microbiome composition was assessed using 16S rRNA gene sequencing. Tumor-infiltrating lymphocytes (TILs) were evaluated via immunohistochemistry in patients with available data. Findings were further assessed using data from The Cancer Microbiome Atlas and The Cancer Genome Atlas. Sample collection occurred from 2008 to 2011 (SALIVA) and from 2017 to 2022 (ZissTrans), and the data for this study were analyzed from July to December 2024.

EXPOSURE: Definitive (chemo)radiotherapy.

MAIN OUTCOMES AND MEASURES: The primary outcome was locoregional recurrence-free survival (LRFS) and a secondary outcome was overall survival (OS). Additional secondary analyses evaluated the association between Lachnoanaerobaculum spp levels and TIL levels, and the incidence of severe radiation-induced oral mucositis.

RESULTS: The analysis included 92 patients with HNSCC (mean [SD] age, 61.1 [7.9] years; 15 female [16.3%] 77 male [83.7%] individuals) and found that higher Lachnoanaerobaculum spp abundance was associated with substantially improved LRFS (median, 69 vs 11 months; hazard ratio [HR], 0.50; 95% CI, 0.29-0.86) and OS (median, 75 vs 27 months; HR, 0.54; 95% CI, 0.30-0.98). This finding was confirmed by multivariable Cox regression (LRFS: HR, 0.50; 95% CI, 0.25-1.00; OS: HR, 0.37; 95% CI, 0.16-0.85). TILs were evaluated in 76 patients (82.2%) and showed that increased Lachnoanaerobaculum spp levels were associated with higher CD4-positive and CD8-positive TIL counts. Lachnoanaerobaculum spp abundance showed no meaningful association with severe radiation-induced oral mucositis. Data from The Cancer Microbiome Atlas (n = 157) indicated that higher intratumoral Lachnoanaerobaculum spp levels were associated with improved OS (HR, 0.62; 95% CI, 0.39-0.98). Transcriptomic analyses in The Cancer Genome Atlas cohort further supported an immune-stimulated tumor microenvironment in Lachnoanaerobaculum-high tumors.

CONCLUSIONS AND RELEVANCE: This prognostic study found that higher salivary Lachnoanaerobaculum spp abundance was associated with improved tumor control and survival in patients with HNSCC undergoing (chemo)radiotherapy. These findings support further investigation into microbiome-targeted interventions to improve HNSCC treatment effectiveness.

PMID:40932704 | DOI:10.1001/jamaoto.2025.2816

Clin Case Rep. 2025 Sep 7;13(9):e70847. doi: 10.1002/ccr3.70847. eCollection 2025 Sep.

ABSTRACT

Congenital disorders of glycosylation (CDG) are a heterogeneous group of inherited metabolic diseases (IMD) characterized by defects in the synthesis and modification of glycoproteins and glycolipids. One of these disorders is ATP6AP1-CDG, a rare X-linked disease with approximately 30 cases reported so far. Symptoms associated with ATP6AP1-CDG include immunodeficiency, liver dysfunction, and neurological manifestations. This report presents the first case of ATP6AP1-CDG in Iran and the Middle East, in a 5-month-old male infant presenting with fever, vomiting, diarrhea, and poor feeding. The patient had a history of similar symptoms at three and 4 months and had been hospitalized with a diagnosis of gastrointestinal (GI) infection. In addition, he had a history of recurrent seizures, which first began at 45 days old, and was treated with phenobarbital. On physical examinations, the patient was lethargic, severely hypotonic with decreased primitive reflexes, and dehydrated with dry mucous membranes and white plaques of candidiasis. There was no tenderness, guarding, or hepatosplenomegaly in the abdominal examination. Laboratory blood tests were requested, which revealed leukocytosis and normal liver and kidney functions, with negative blood, urine, cerebrospinal fluid, and stool cultures for bacterial growth. Considering the history of recurrent infections, idiopathic seizures, suspected immunodeficiency in the patient’s deceased sibling and parental consanguinity, primary immunodeficiency was suspected as a possible diagnosis for the patient. Therefore, a panel of immune function tests was requested, all of which were within the normal range. This panel consisted of IgM, IgG, IgA, B-Cell markers (CD19), T-Cell markers (CD3, CD4, and CD8), TRECs, NK-Cell markers (CD16 and CD56), LTT-PHA, LTT-BCG, and CH50. Furthermore, whole exome sequencing (WES) was requested, which revealed a novel hemizygous deletion in the ATP6AP1 gene (NM_001183.6), designated as c.111_116del; p.Ala40_Ala41del (chrX:153657133 TGGCGGC>T, hg19 assembly).

PMID:40927402 | PMC:PMC12414802 | DOI:10.1002/ccr3.70847

JAMA Surg. 2025 Sep 10. doi: 10.1001/jamasurg.2025.3445. Online ahead of print.

ABSTRACT

IMPORTANCE: Stoma reversal is associated with few complications. However, recent studies show that 1 in 3 patients develop an incisional hernia, for which half of the patients receive surgical correction.

OBJECTIVE: To investigate whether prophylactic synthetic mesh placement in the retromuscular space during stoma reversal reduces the rate of stomal site incisional hernias.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, parallel, single-blinded randomized clinical trial was conducted between July 2018 and June 2023 and took place at 2 large teaching hospitals in the Netherlands. Data were analyzed from September 2024 and April 2025. Patients who underwent elective stoma reversal were included. Exclusion criteria included connective tissue disease, intraperitoneal dialysis, immunodeficiency, previous mesh placement within 3 cm of the stoma closure site, allergy or contraindication for mesh, pregnancy, and inflammatory bowel disease, as indication for initial stoma construction. Follow-up was at 30 days and 3, 6, 9, and 12 months postoperative.

INTERVENTION: Conventional stoma closure (n = 40) vs stoma closure with preventive synthetic mesh placement in the retromuscular space (n = 39).

MAIN OUTCOMES AND MEASURES: The primary outcome measure was radiological stoma site incisional hernia after 12 months. Secondary outcomes included postoperative complications, surgical site infections, and quality of life (measured by EuroQoL 5-Dimension, visual analog scale, 36-item short form survey, and hernia-related quality of life).

RESULTS: A total of 88 patients were randomized to either conventional stoma closure (n = 44) or synthetic mesh-reinforced stoma closure (n = 44). At 12 months, 39 patients in the control group and 40 patients in the mesh group had completed follow-up. The rate of stoma site incisional hernia was 17.9% (n = 7) in the conventional group vs 0% (n = 0) in the mesh group (relative risk, 0.18; 95% CI, 0.034-0.330; P = .02) with a number needed to treat of 6. There was no significant difference in surgical site infections or postoperative complications. Hernia-related quality of life was significantly better at 12 months follow-up in the mesh group.

CONCLUSIONS AND RELEVANCE: In this study, placement of a prophylactic synthetic mesh in the retromuscular space prevented stoma site incisional hernias. Patients receiving a synthetic mesh experienced a better hernia-related quality of life. To prevent stoma site incisional hernias, the placement of a synthetic mesh during stoma reversal should be considered.

TRIAL REGISTRATION: Dutch Trial Register: NL-OMON27268.

PMID:40928792 | DOI:10.1001/jamasurg.2025.3445

Allergol Immunopathol (Madr). 2025 Sep 1;53(5):138-142. doi: 10.15586/aei.v53i5.1437. eCollection 2025.

ABSTRACT

Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, microthrombocytopenia, and recurrent infections. Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder involving various organs. We present a 34-year-old male with WAS who developed cervical lymphadenopathy and parotid gland swelling. Initial biopsies were inconclusive and imaging suggested pleomorphic adenoma. Given the persistent cervical lymphadenopathy and the underlying immunodeficiency, lymphoma was also considered in the differential diagnosis. However, histopathological examination of excised salivary gland and lymph nodes revealed lymphoplasmacytic and eosinophilic infiltrates, numerous IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis, consistent with IgG4-RD. The patient responded well to prednisone therapy. This case emphasizes the importance of considering IgG4-RD in the differential diagnosis of lymphoproliferative lesions in immunodeficient individuals and highlights the diagnostic value of histopathological evaluation in excisional tissue specimens. To our knowledge, this represents a rare coexistence of WAS and IgG4-RD not previously reported in the literature.

PMID:40923431 | DOI:10.15586/aei.v53i5.1437

Curr Opin Pulm Med. 2025 Sep 8. doi: 10.1097/MCP.0000000000001217. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: There is a significant overlap between the diagnostic evaluation for adult and pediatric patients with bronchiectasis; however, also important age-specific unique considerations. This review focuses on these specific considerations.

RECENT FINDINGS: Bronchiectasis refers to the radiographic evidence of dilation of distal and proximal bronchi secondary to chronic infection and inflammation. Bronchiectasis can be suspected on plain chest radiograph but is confirmed and detailed through computed tomography (CT) imaging. Several different measures and descriptions of the radiographic findings of bronchiectasis exist, but the most common is a bronchial diameter equal to or greater than an adjacent blood vessel. Consideration for the presence of bronchiectasis begins with recognition of clinical symptoms of suppurative lung disease including persistent sputum producing cough and recurrent respiratory infections. Bronchiectasis etiologies include inherited forms, such as cystic fibrosis and primary ciliary dyskinesia, as well as secondary forms including chronic aspiration as well as certain infections, and immunodeficiency. Up to 40% remain idiopathic even after a comprehensive evaluation.

SUMMARY: It is important to start a bronchiectasis evaluation with a broad differential, but secondary testing should focus on etiologies specific to the patient. A thoughtful combination of testing is often required to arrive at an etiology. Patients with bronchiectasis require ongoing monitoring including longitudinal follow-up of respiratory cultures, lung function testing, and repeat CT imaging.

PMID:40916968 | DOI:10.1097/MCP.0000000000001217

Am J Hematol. 2025 Sep 8. doi: 10.1002/ajh.70061. Online ahead of print.

ABSTRACT

Loss of function mutations in the gene encoding WASP (Wiskott-Aldrich syndrome protein) result in Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia-XLT (WAS/XLT). The clinical severity of the disease can be assessed using the WAS clinical severity score. Typically, patients with a score of 3 or less at 2 years of age are considered to have mild WAS/XLT disease. However, patients with a low score in the first 2 years of life can still experience life-threatening complications, and there are no agreed guidelines for the management of these patients with mild WAS/XLT. We analyzed data on WAS/XLT patients from the French National Reference Centre for Primary Immunodeficiencies registry. At 10 December 2021, data were available for 261 patients, 170 of whom had mild WAS/XLT. The median age of these patients at last follow-up was 15.8 years (range 2.0-60.4). Overall survival at 40 years was 73% in mild WAS patients versus 65% in severe WAS patients (p = 0.43). In the mild WAS population, prior to Hematopoietic Stem Cell Transplantation or gene therapy, 38.2% of patients progressed to a WAS severity score of 4-5 after the age of 2. Remarkably, no deaths were reported in 45 HSCTs performed since 2010, regardless of initial severity, type and HLA compatibility of the transplant, and age at diagnosis, with a median follow-up of 3.2 years (0-11.5) after transplant. As complications can occur throughout life, our study supports definitive treatment for all patients when available, including those with mild forms.

PMID:40919766 | DOI:10.1002/ajh.70061

J Allergy Clin Immunol Pract. 2025 Sep 3:S2213-2198(25)00824-4. doi: 10.1016/j.jaip.2025.08.023. Online ahead of print.

NO ABSTRACT

PMID:40912613 | DOI:10.1016/j.jaip.2025.08.023

Front Immunol. 2025 Aug 20;16:1641122. doi: 10.3389/fimmu.2025.1641122. eCollection 2025.

ABSTRACT

WHIM syndrome is typically caused by C-terminal gain-of-function variants in CXCR4, yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel CXCR4 missense variant, c.1022C>A (p.S341Y), and a frameshift variant in NFKB1, c.980dup (p.A328Sfs*12). Functionally, CXCR4 p.S341Y substitution – located two residues upstream of the known pathogenic p.E343K variant – increased CXCL12-induced chemotaxis and ERK/AKT signaling while minimally affecting receptor internalization, supporting a partial CXCR4 gain-of-function. The CXCR4 variant co-segregated with mild neutropenia, recurrent respiratory infections, and cutaneous warts in the paternal lineage. In contrast, the maternal NFKB1 variant was associated with agammaglobulinemia and autoimmunity. Their co-inheritance in the proband resulted in a blended WHIM/CVID phenotype characterized by myelokathexis, B-cell maturation arrest and T-cell dysregulation. This case expands the phenotypic spectrum of CXCR4 variants and highlights how multilocus inheritance can obscure classical diagnostic boundaries and guide individualized therapy.

PMID:40909287 | PMC:PMC12405443 | DOI:10.3389/fimmu.2025.1641122