small molecules

2026-08-17 | Early longitudinal proteomic changes during sirolimus therapy in tocilizumab-refractory idiopathic multicentric Castleman disease.

To characterise early treatment-associated changes in circulating immune mediators following sirolimus initiation in patients with tocilizumab-resistant idiopathic multicentric Castleman disease (iMCD). As a predefined translational sub-analysis of a placebo-controlled exploratory trial, we performed longitudinal serum proteomic profiling using a RayBiotech L-1000 antibody array (∼1,000 proteins) in a sirolimus-treated patient with tocilizumab-resistant iMCD. Serum samples were obtained at baseline and at weeks 8, 12, and 16. Protein expression levels were normalised, log₂-transformed, and analysed for stepwise temporal changes. Pathway-level effects were assessed using gene set enrichment analysis (GSEA). Six immune mediators-CCR5, ICAM-1, RANTES, S100A8/A9, CD40 ligand, and OX40 ligand-showed consistent monotonic decreases from baseline through week 12. Heatmap visualisation of the top 80 dynamically regulated proteins confirmed a broader suppression of immune activation signatures. GSEA demonstrated significant negative enrichment of coagulation, complement, IFN-γ response, IL-6-JAK-STAT3 signalling, TNFα signalling via NF-κB, and MMP-driven extracellular matrix remodelling. Temporal analysis confirmed sustained downregulation of IFN-γ-inducible chemokines (CXCL9, CXCL10, CXCL11) and a broad panel of interferon-response mediators through weeks 12 and 16. Early and coordinated decreases in immune-inflammatory mediators were observed during sirolimus therapy in tocilizumab-resistant iMCD, extending beyond the IL-6 axis to encompass IFN-γ, TNF-α, and chemokine signalling. These findings are hypothesis-generating and provide a mechanistic rationale for mTOR inhibition as a potential disease-modifying strategy warranting evaluation in future controlled studies.

Open article ↗

2026-08-10 | Human Herpesvirus 8 Causes a Wide Spectrum of Disease in Liver Transplant Recipients and May be Donor Derived: Case Series and Systematic Review of an Emerging Challenge.

Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma (KS)-associated herpesvirus, can cause severe disease in liver transplant (LT) recipients, be donor-derived, and present variably. We describe HHV8 disease post-LT. HHV8 disease was identified post-LT in New South Wales (NSW), 2017-2024, and from systematic review. Reports were compared by suspected donor-derived infection (DDI) and disease manifestation, using chi-square and t-tests. Survival was investigated with Cox proportional hazards. Of 188 records, 79 publications (131 cases) were included, plus four NSW cases (n = 135). Median onset was 7 months posttransplant (IQR: 5-13), with 33% suspected DDI. After median 12 months of follow-up, 68/125 had disease remission/regression; 59/135 died (49 HHV8-related). In NSW, Case 1 was proven DDI: visceral KS, 6 months post-LT; complete remission occurred with immunosuppression modification and chemotherapy. Case 2 was probable DDI: KS, multicentric Castleman's disease, and hemophagocytic lymphohistiocytosis, 3 months post-LT; the patient died despite immunosuppression modification, hydrocortisone and rituximab. Case 3 was possible DDI: KS-herpesvirus-induced cytokine syndrome, 6 months post-LT; died despite immunosuppression modification and ganciclovir. Case 4 was unlikely DDI: visceral KS, 5 months post-LT; complete remission occurred with surgery and immunosuppression modification. Survival was worse with visceral KS and non-KS disease (aHR 5.83 and 4.32, p = 0.002). Reduced immunosuppression, mTORi, and chemotherapy improved survival (aHRs 0.53, 0.36, 0.43; p = 0.006, 0.044, and 0.030). Treatment effects diverged by KS and non-KS disease. Donor screening identified more KICS and DDI, with improved non-KS disease survival. Post-LT HHV8 disease is heterogeneous, with high mortality. Targeted treatments and possibly donor screening improve survival.

Open article ↗

2026-07-31 | Castleman disease: clinical features, pathology, and treatment outcomes in 12 cases.

To conduct a retrospective descriptive analysis of the clinical manifestations, pathological characteristics, diagnostic approaches, and treatment outcomes of Castleman disease (CD) in a Chinese regional population, thereby contributing real-world evidence to improve clinical management of this rare disorder. A retrospective analysis was performed on 12 patients with CD diagnosed via a rigorous three-step differential diagnosis protocol at Linyi People's Hospital between February 2020 and February 2024. The cohort included 10 males and 2 females, age range 20-67 years (median, 45 years). Tumor locations involved retroperitoneum, pelvis, neck, supraclavicular region, axilla, and inguinal region. According to the Frizzera classification, 7 patients were diagnosed with unicentric CD (UCD; 5 hyaline vascular type, 2 mixed type) and 5 with multicentric CD (MCD; 4 plasma cell type, 1 mixed type). All patients tested negative for HHV-8 and HIV. Treatment modalities included surgical resection alone (7 UCD cases), surgical resection followed by systemic therapy (1 MCD mixed-type case), and primary R-CHOP chemotherapy (4 MCD plasma cell type cases). All 12 patients were alive at follow-up. The 7 UCD patients treated with complete surgical resection alone experienced no recurrence. The MCD mixed-type patient (Case 8) initially received rituximab for 3 months postoperatively, but interleukin-6 (IL-6) levels remained elevated; the regimen was switched to oral thalidomide-cyclophosphamide-dexamethasone (TCD) for 2 months, leading to complete remission. The 4 MCD patients treated with primary R-CHOP achieved favorable outcomes with no recurrence during follow-up (range, 10-45 months). In this small cohort, CD was associated with a favorable short-term prognosis following individualized treatment. Complete surgical resection is curative for resectable UCD, whereas MCD typically requires systemic therapy. In resource-limited settings where anti-IL-6 monoclonal antibodies are not readily accessible, R-CHOP represents an effective first-line alternative for idiopathic multicentric Castleman disease (iMCD), and the oral TCD regimen is a valuable option for refractory cases. These findings provide practical evidence to guide clinical decision-making for CD in regional medical centers.

Open article ↗

2026-07-27 | Castleman Disease: Updated Pathophysiology, Diagnostic Approach and Therapeutic Strategies

Objective: Castleman disease (CD) comprises a heterogeneous spectrum of uncommon lymphoproliferative disorders characterised by diverse clinical presentations, distinct biological mechanisms and highly variable prognoses. During the past decade, major advances in molecular immunology, cytokine biology, spatial transcriptomics and targeted therapeutics have fundamentally reshaped current concepts regarding disease pathogenesis, diagnosis and management. This review provides a contemporary synthesis of these developments with particular emphasis on idiopathic multicentric Castleman disease (iMCD), emerging molecular endotypes and mechanism-based therapeutic strategies. [8–12,27–32] Methods: A comprehensive narrative review was conducted following the Scale for the Assessment of Narrative Review Articles (SANRA) recommendations. Publications indexed in PubMed/MEDLINE, Scopus, Web of Science and ClinicalTrials.gov between 1954 and July 2026 were critically evaluated. Evidence from basic science, translational research, clinical trials, international consensus guidelines and observational studies was integrated to provide a clinically relevant and biologically updated perspective. Results: Recent discoveries have transformed Castleman disease from a clinicopathological entity largely defined by interleukin-6 excess into a complex disorder of immune–stromal dysregulation. Single-cell transcriptomics and spatial biology have identified fibroblastic reticular cells, endothelial dysfunction and dysregulated immune-cell communication as central pathogenic components. These findings explain the biological heterogeneity observed among patients and provide mechanistic support for emerging molecular endotypes characterised by differential activation of IL-6, CXCL13, TNF and PI3K/AKT/mTOR signalling pathways. Therapeutically, anti-IL-6 monoclonal antibodies remain the standard of care for idiopathic multicentric disease, whereas rituximab-based strategies have substantially improved outcomes in HHV-8-associated disease. Novel therapies targeting intracellular signalling pathways, particularly mTOR and JAK/STAT inhibition, represent promising alternatives for refractory disease and illustrate the progressive transition towards precision medicine. Conclusions: Castleman disease should no longer be regarded as a single cytokine-mediated disorder but rather as a biologically heterogeneous group of immune-mediated lymphoproliferative syndromes. Integration of molecular pathology, spatial biology and biomarker-guided therapeutic selection is expected to redefine disease classification and clinical management over the coming decade. Continued international collaboration and translational research will be essential to realise the full potential of precision medicine for patients with Castleman disease.

Open article ↗

2026-07-09 | Definitive Radiotherapy for Unresectable Unicentric Mediastinal Castleman Disease: A Case Report.

Castleman disease is a rare nonclonal lymphoproliferative disorder with heterogeneous clinical presentations and therapeutic approaches. Surgery remains the standard treatment for unicentric Castleman disease, while radiotherapy may represent an alternative option in unresectable cases. We report the case of a 17-year-old female who presented with exertional dyspnea related to a right hilar mediastinal mass. Chest computed tomography revealed a well-circumscribed lesion closely related to adjacent vascular and bronchial structures. Histopathological examination demonstrated abnormal lymphoid follicles with atrophic germinal centers producing the characteristic "onion-skin" appearance. Immunohistochemical analysis showed a CD3-, CD20+, CD21+, Bcl2-, and CD5- profile consistent with the hyaline vascular subtype of unicentric Castleman disease. Positron emission tomography/computed tomography demonstrated localized hypermetabolic mediastinal lymphadenopathy without distant involvement. Due to close vascular relationships and high hemorrhagic risk, the lesion was considered unresectable after multidisciplinary discussion. The patient underwent definitive volumetric modulated arc therapy (VMAT) delivering 39.6 Gy in 22 fractions. Treatment was well tolerated without significant acute or late toxicity. After 13 months of follow-up, clinical and radiological evaluation demonstrated a favorable response, with approximately 50% tumor reduction according to RECIST v1.1 criteria, improvement in dyspnea from New York Heart Association (NYHA) class III to class II, and normalization of pulmonary function tests. This case highlights the potential role of definitive radiotherapy as an effective and well-tolerated therapeutic alternative in unresectable unicentric mediastinal Castleman disease.

Open article ↗

cell therapies

2026-06-24 | Sustained Complete Response in Refractory Idiopathic Multicentric Castleman Disease Following a Single CD19 CAR T-Cell Infusion: A Case Report With Mechanistic Insight.

Idiopathic multicentric Castleman disease (iMCD) is rare and life-threatening; although siltuximab is standard first-line therapy, a substantial proportion of patients are refractory or experience relapse. We report a 31-year-old woman with HHV-8-negative iMCD with idiopathic plasmacytic lymphadenopathy (IPL; iMCD-IPL), intractable to five prior lines of therapy, who declined siltuximab and enrolled in ChiCTR1900025419. After fludarabine/cyclophosphamide lymphodepletion, she received 1 × 106 CAR + T cells/kg of autologous CD19 CAR T cells on day 0. Grade 1 cytokine release syndrome (Tmax 38.2°C) resolved with supportive care; no ICANS occurred. CAR transgene levels expanded (peaking on day +11) and remained detectable through day +58, and flow cytometry showed CD19+ B-cell depletion from day +7 to day +198. By day +198, she met CDCN criteria for complete biochemical and clinical response with normalization of inflammatory markers and hematologic recovery. Panhypogammaglobulinemia was managed with intravenous immunoglobulin replacement. At > 12 months post-infusion, she remains in complete, treatment-free remission. This observation supports a B-cell-centric model for refractory iMCD-IPL and motivates prospective evaluation of CD19 CAR T-cell therapy.

Open article ↗

2026-02-04 | Successful Bilateral-Lung Transplantation With Long Survival Time for Multicentric Castleman Disease With Fatal Pulmonary Involvement.

We present a rare case of multicentric Castleman disease (MCD) complicated by severe respiratory failure, which was successfully managed through bilateral lung transplantation. A 31-year-old male patient exhibited progressive dyspnea attributed to MCD associated with bronchiolitis obliterans. Pretransplant evaluations indicated severe hypercapnia and markedly impaired pulmonary function. Despite the administration of steroid therapy, the patient's respiratory status continued to decline. Consequently, he underwent bilateral lung transplantation, which resulted in significant alleviation of hypercapnia and considerable improvement in pulmonary function. Four years posttransplant, the patient remains alive and does not require supplemental oxygen. This case highlights the potential efficacy of bilateral lung transplantation in addressing severe respiratory complications associated with MCD.

Open article ↗

2025-10-20 | Bronchiolitis Obliterans in Unicentric Castleman Disease Without Paraneoplastic Pemphigus Requiring Bilateral Lung Transplantation.

Bronchiolitis obliterans (BO) is an uncommon but life-threatening complication of unicentric Castleman disease (UCD), typically linked to paraneoplastic pemphigus. We report a 25-year-old woman who developed progressive dyspnea and severe, irreversible airflow obstruction in the absence of clinical or serologic evidence of paraneoplastic pemphigus. Unresponsive to inhaled triple therapy and systemic corticosteroids, she progressed to end-stage respiratory failure. She underwent living-donor bilateral lung transplantation with subsequent excision of the retroperitoneal UCD lesion. Explanted lungs confirmed concentric obliteration of small airways consistent with BO. Post-transplant, she demonstrated marked functional improvement with no recurrence of BO or UCD. This case highlights that BO can occur without detectable paraneoplastic pemphigus autoantibodies and that lung transplantation remains the only curative option for the end-stage disease.

Open article ↗

2025-08-18 | Lung transplantation in a patient with severe bronchiolitis obliterans secondary to Castleman disease.

Castlemann disease (CD) is a rare but often benign condition of the lymph nodes. Seldomly coinciding with CD are other conditions, such as paraneoplastic phemhigus (PMP) and bronchiolitis obliterans (BO). When these occur, patients are at risk of developing severe complications, such as respiratory failure, which may subsequently result in death. Diagnosing and managing conditions related to CD poses a challenge and may cause diagnostic delay. In this case report, we describe the course of illness in a 31-year-old female diagnosed with CD. Prior to the diagnosis of CD, the patient had been diagnosed with both paraneoplastic phemfigus and an irreversible airway obstruction. Standard surgical treatment for CD, as well as standard medical treatment for airway obstruction, had little effect. Radiologic findings supported the diagnosis of bronchiolitis obliterans. A progressive decline in pulmonary function eventually led to the patient being evaluated for and undergoing lung transplantation. The co-occurrence of CD and PMP has previously been described as increasing the risk of developing BO, irreversible pulmonary function restrictions and poor prognosis. Lung transplant may be a possible treatment for some patients with terminal respiratory failure.

Open article ↗

2025-04-11 | Unicentric Castleman disease complicated with bronchiolitis obliterans: A single-centre retrospective study from China.

Bronchiolitis obliterans (BO) is a rare and life-threatening complication of unicentric Castleman disease (UCD), which is considered the leading cause of death in UCD. However, few studies focused on the characteristics of UCD patients complicated with BO. This single-centre, retrospective study of 281 patients diagnosed with UCD identified 18 patients (6.4%) with BO. UCD-BO patients had a significantly lower age at UCD diagnosis than the UCD without BO group. 94.4% of UCD-BO patients had deep lymph nodes involvement and 83.3% of them had paraneoplastic pemphigus, which were both significantly higher than UCD without BO. Median forced expiratory volume in 1 s of predicted was 20.9% (10%-41.9%) and 83.3% patients had severe BO. All patients underwent complete resection for UCD. 61.1% patients developed BO after surgery. UCD-BO patients had a poorer overall survival than UCD without BO. Among severe BO, 11 patients did not receive lung transplantation and two of them died, with 62.5% (95% CI, 20.8%-100%) of estimated 5-year overall survival. Four patients underwent lung transplantation and they all survived. UCD-BO patients had distinct clinical identity. Complete resection could neither alleviate BO nor prevent BO progression. Lung transplantation is a vital treatment for improving prognosis for patients with severe BO.

Open article ↗

proteins

2026-06-09 | PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.

Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several malignancies, including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease, harbors a DNA replication helicase encoded by ORF44 that is crucial for viral replication and pathogenesis. In this study, we identified the host PFN1 (profilin 1), a well-known actin-binding factor, as an inhibitor of KSHV lytic replication functioning via the macroautophagy/autophagy-lysosomal degradation pathway targeting ORF44. Mechanistic analyses revealed that PFN1 interacts with ORF44, leading to enhanced polyubiquitination of PFN1. Notably, the E3 ubiquitin ligase TRIM37 (tripartite motif containing 37) facilitates the polyubiquitination of lysine residues at position 116 of PFN1, which serves as a critical recognition motif for the cargo receptor SQSTM1/p62 (sequestosome 1), which is pivotal for the subsequent autophagic degradation of ORF44. Overall, our findings revealed a previously uncharacterized antiviral function of PFN1, highlighting its potential as a novel therapeutic avenue for the treatment of KSHV-associated malignancies.Abbreviations: ALS: amyotrophic lateral sclerosis; Baf A1: bafilomycin A1; co-IP: co-immunoprecipitation; KSHV: Kaposi sarcoma-associated herpes virus; LIR: LC3-interacting region; PFN1: profilin 1; SQSTM1/p62: sequestosome 1; TRIM37: tripartite motif containing 37; UBA: ubiquitin-associated domain.

Open article ↗

2026-05-05 | Effective Use of Subcutaneous Tocilizumab in a Case of Castleman Disease Progressing From Unicentric to Multicentric Form.

Castleman Disease can progress from a unicentric to a multicentric form in children. Subcutaneous tocilizumab is a safe and effective therapy for patients with Castleman Disease, improving quality of life and eliminating the need for frequent hospital admissions for intravenous infusions.

Open article ↗

2026-02-28 | Effectiveness of tocilizumab for IgA vasculitis associated with idiopathic multicentric Castleman's disease: Two cases and literature review.

Idiopathic multicentric Castleman's disease (iMCD) is a systemic lymphoproliferative disorder characterised by interleukin (IL)-6 overproduction. To date, several cases of iMCD with autoimmune features have been reported, and cases of iMCD complicated by IgA vasculitis have also been reported. IL-6 is reported to promote the production of galactose-deficient IgA1, a key pathogenic factor in IgA vasculitis. Therefore, IL-6 overproduction in iMCD may contribute to the development of IgA vasculitis in these cases. Here, we present two cases of iMCD complicated by IgA vasculitis, both successfully treated with tocilizumab, an IL-6 receptor blockade. Furthermore, our literature review identified two reported cases of iMCD complicated by IgA nephropathy, and one case of iMCD complicated by IgA vasculitis, all of which responded favourably to tocilizumab. Our cases and literature review suggest the pathogenic role of IL-6 in the development of IgA vasculitis in iMCD and the effectiveness of tocilizumab as a potential therapeutic option not only for iMCD itself, but also for IgA vasculitis in the setting of iMCD.

Open article ↗

2025-08-14 | Successful tocilizumab monotherapy for multicentric Castleman disease complicated by rheumatoid arthritis and Sjögren's disease: a case-based literature review.

Multicentric Castleman disease (MCD) is a rare and complex lymphoproliferative disorder marked by multiple lymph node enlargement, characteristic histopathological features, and systemic inflammation driven by excessive interleukin-6 (IL-6) production. MCD can occasionally coexist with other autoimmune diseases, but the therapeutic approach in such cases remains poorly defined. Here, we present the first documented case of MCD complicated by both rheumatoid arthritis (RA) and Sjögren's disease (SjD), where all conditions were successfully treated with tocilizumab (TCZ) monotherapy, an IL-6 receptor antagonist. Furthermore, a literature review identified two previously reported cases of MCD with either RA or SjD, all of which showed favorable responses to TCZ. Our findings highlight the potential of TCZ as an effective therapeutic option for patients with MCD in the context of coexisting autoimmune disorders, offering new hope for managing these challenging clinical scenarios.

Open article ↗

2025-05-15 | Efficacy of High-Dose Intravenous Anakinra in Pediatric TAFRO Syndrome: Report of Two Cases and Literature Review.

TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly) syndrome is a rare, life-threatening inflammatory condition linked to infections, neoplasms, and idiopathic multicentric Castleman disease. Interleukin (IL)-6 inhibitors are the primary treatment, but refractory cases require alternatives. This study reports the first two pediatric TAFRO cases successfully treated with anakinra, an IL-1 receptor antagonist. Both patients had severe, rapidly progressing disease with multiorgan involvement. Anakinra, combined with corticosteroids, led to significant improvement and remission. We provide a literature review of pediatric TAFRO, confirming its rarity and the partial efficacy of IL-6 inhibitors in many cases.

Open article ↗

antibodies

2026-09-25 | Turkish Journal of Hematology

Objective: TAFRO syndrome, entailing thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly, was previously considered a subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO), with the diagnosis requiring pathology supporting Castleman disease.However, lymph node biopsies may be difficult for TAFRO patients (TAFRO without pathological evidence: TAFRO-w/op-iMCD), and sometimes these biopsies do not confirm iMCD (TAFRO-w/o-iMCD).We aimed to compare the clinical features and prognosis of TAFRO subgroups. Materials and Methods:We retrospectively analyzed the cases of 50 iMCD-TAFRO and 11 TAFRO-w/o-iMCD patients treated from May 2015 to April 2024. Results:The groups showed no significant differences in clinical presentation or laboratory data.Both groups of patients were treated with iMCD-targeted strategies addressing cytokine storms.With a median follow-up of 21.4 (range: 0.5-107.0)months, there were no significant differences between iMCD-TAFRO and TAFRO-w/o-iMCD patients in 3-month response rate (72.1% vs. 88.9%,p=0.525), 6-month response rate (70.0% vs. 83.3%,p=0.849), or best overall response rate (77.6% vs. 90.0%,p=0.645).The estimated 3-year progression-free survival rate (65.8% vs. 90.0%,log-rank p=0.163) and the estimated 3-year overall survival rate (77.0% vs. 100%, log-rank p=0.145) were also not significantly different.Cox univariate analysis showed that decreased estimated glomerular filtration rate (<60 mL/min/1.73m 2 ) was associated with an increased risk of disease progression (hazard ratio: 4.133, 95% confidence interval: 1.561-10.940,p=0.004).Conclusion: iMCD-TAFRO and TAFRO-w/o-iMCD could be considered overlapping entities and these patients should be treated promptly, targeting cytokine storms with similar strategies for each group of patients.Amaç: Trombositopeni, anazarka, ateş, retikülin fibrozu ve organomegaliyi içeren TAFRO sendromu, daha önce idiyopatik multisentrik Castleman hastalığının (iMCD-TAFRO) bir alt tipi olarak kabul ediliyordu ve tanı için Castleman hastalığını destekleyen patoloji gerekiyordu.Ancak, lenf nodu biyopsileri TAFRO hastaları için zor olabilir (patolojik kanıt olmayan TAFRO: TAFRO-w/op-iMCD) ve bazen bu biyopsiler iMCD'yi doğrulamaz (TAFRO-w/o-iMCD).TAFRO alt gruplarının klinik özelliklerini ve prognozunu karşılaştırmayı amaçladık. Gereç veYöntemler: Mayıs 2015 ile Nisan 2024 tarihleri arasında tedavi edilen 50 iMCD-TAFRO ve 11 TAFRO-w/o-iMCD hastasının olguları retrospektif olarak analiz edildi.Bulgular: Gruplar klinik sunum veya laboratuvar verilerinde anlamlı bir fark göstermedi.Her iki hasta grubu da sitokin fırtınalarını ele alan iMCD hedefli stratejilerle tedavi edildi.21,4 (aralığı: 0,5-107,0) aylık medyan takip süresiyle iMCD-TAFRO ve TAFRO-w/o-iMCD hastaları arasında 3 aylık yanıt oranında (%72,1'e karşı %88,9, p=0,525), 6 aylık yanıt oranında (%70,0'a karşı %83,3, p=0,849) veya en iyi genel yanıt oranında (%77,6'ya karşı %90,0, p=0,645) anlamlı bir fark görülmedi.Tahmini 3 yıllık ilerleme içermeyen sağkalım oranı (%65,8-%90,0, logrank p=0,163) ve tahmini 3 yıllık genel sağkalım oranı (%77,0-%100, logrank p=0,145) da anlamlı şekilde farklı değildi.Tek değişkenli Cox analizi, glomerüler filtrasyon hızının (<60 mL/dk/1,73 m 2 ) düşük olmasının, hastalık progresyonu riskinde artış ile ilişkili olduğunu göstermiştir (hazard oranı: 4,133, %95 güven aralığı: 1,561-10,940, p=0,004).Sonuç: iMCD-TAFRO ve TAFRO-w/o-iMCD örtüşen durumlar olarak kabul edilebilir ve bu hastalar hemen tedavi edilmeli, her hasta grubu için benzer stratejilerle sitokin fırtınaları hedeflenmelidir.

Open article ↗

2026-09-24 | The Spectrum of Human Herpesvirus 8/Epstein-Barr Virus-Co-Positive Lymphoproliferations and Lymphomas.

Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is a gamma-2 herpesvirus implicated in a distinctive group of lymphoproliferative disorders (LPDs) and lymphomas. In some of these entities, lesional cells are concurrently infected with Epstein-Barr virus (EBV), a gamma-1 herpesvirus, raising important questions regarding viral cooperation in lymphomagenesis. This narrative review summarizes the clinicopathological spectrum and biological significance of HHV-8/EBV co-positive lymphoproliferations. We provide a narrative synthesis of the biology of HHV-8 and EBV, including latent, abortive lytic, and productive lytic infection programmes and viral mechanisms involved in cell-cycle deregulation, apoptosis inhibition, immune evasion, and B-cell transformation. Major HHV-8-associated lymphoproliferative entities are reviewed within the current WHO-HAEM5 and International Consensus Classification frameworks, with particular attention to patterns of EBV co-infection and diagnostically atypical or overlapping lesions. Primary effusion lymphoma, including its extracavitary presentation, is frequently EBV-positive, whereas HHV-8-positive germinotropic lymphoproliferative disorder is characteristically HHV-8/EBV dual-positive. In contrast, HHV-8-positive lesional cells in multicentric Castleman disease and HHV-8-positive diffuse large B-cell lymphoma are typically EBV-negative. True dual positivity requires demonstration of HHV-8 latency-associated nuclear antigen and EBV-encoded RNA within the same morphologically defined lesional cell population. Rare atypical cases show overlapping clinicopathological features among established entities. HHV-8/EBV co-positive lymphoproliferations comprise a biologically and diagnostically heterogeneous group. Although unusual overlapping cases suggest potential relationships among HHV-8-associated disorders, current evidence does not support a single continuous disease spectrum or a uniform mechanism of HHV-8/EBV cooperation.

Open article ↗

2026-09-01 | New Paradigms in the Management of Castleman Disease.

Castleman disease (CD) comprises a heterogeneous group of rare lymphoproliferative disorders unified by characteristic lymph node histopathology but with substantial clinical, biologic, and therapeutic diversity. Over the past decade, major advances in disease classification, pathophysiologic understanding, and targeted therapy have reshaped the management of CD, particularly idiopathic multicentric CD (iMCD). The introduction of IL-6-directed therapy has transformed the management of iMCD by shifting treatment from empirical immunosuppression or cytotoxic chemotherapy toward a biologic-based approach, achieving durable disease control in most patients. Progress has also been made over the past several years in the anatomic, etiologic, and clinical classification of CD, enabling more individualized, severity-adapted treatment approaches across the disease spectrum. Emerging paradigms in CD management include the recognition of oligocentric CD (OligoCD) as an intermediate anatomic entity with distinct therapeutic implications, as well as the validation of idiopathic plasmacytic lymphadenopathy (IPL) as a clinically distinct subtype of iMCD. These developments underscore the importance of integrating disease distribution, subtype, and severity into therapeutic decision-making. In addition, the recent paradigm of CD management emphasizes early identification of refractory disease and timely escalation beyond biologic therapy. This review provides an updated overview of CD management, drawing on recent advances to discuss practical considerations in treatment selection across disease subtypes, as well as ongoing challenges and future directions.

Open article ↗

2026-08-07 | Evolving understanding of Kaposi sarcoma and associated diseases in the ART era.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV), otherwise known as HHV-8, causes KS and several lymphoproliferative disorders including KSHV-associated multicentric Castleman disease, KSHV-associated inflammatory cytokine syndrome, primary effusion lymphoma, and KSHV-positive diffuse large B-cell lymphoma not otherwise specified. KS represents a substantial burden of disease in sub-Saharan Africa and in people with HIV worldwide. Diagnosis relies on pathology, but quantitative KSHV DNA measurements can help identify multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome and monitor treatment response. Alongside antiretroviral therapy, a stage-stratified approach to KS treatment indicates systemic therapy for advanced disease or to mitigate the risk of the related immune reconstitution inflammatory syndrome. The latter condition constitutes a therapeutic challenge, as do multicentric Castleman disease and KSHV-associated inflammatory cytokine syndrome, which are likely to be underdiagnosed. Research on novel treatment approaches, such as immunomodulatory regimens, as well as diagnostic and monitoring strategies, is underway.

Open article ↗

2026-07-25 | HIV-negative KSHV/HHV8-associated multicentric Castleman disease with concurrent Kaposi sarcoma and POEMS-like manifestations.

Castleman disease (CD) is a heterogeneous lymphoproliferative disorder with unicentric and multicentric forms. Multicentric CD (MCD) is etiologically classified into idiopathic MCD (iMCD), POEMS-associated MCD, and Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8)-associated MCD, and it typically presents with systemic inflammation. KSHV/HHV-8-associated MCD is most commonly seen in HIV-positive patients, although it may rarely occur in HIV-negative individuals. We report a case of a 65-year-old HIV-negative woman diagnosed with mixed-type KSHV/HHV-8-associated MCD accompanied by Kaposi sarcoma and POEMS-like clinical features. The patient presented with generalized lymphadenopathy, splenomegaly, cytopenias, hypercalcemia, and monoclonal IgG lambda gammopathy. PET-CT revealed widespread hypermetabolic lymphadenopathy and a sclerotic bone lesion in the left humerus. Bone marrow examination was normocellular and showed polytypic plasma cell proliferation. Lymph node biopsy demonstrated HHV-8 (LANA-1) positivity consistent with mixed-type MCD and Kaposi sarcoma. HHV-8 DNA positivity was also confirmed. The patient was treated with a regimen including daratumumab, bortezomib, cyclophosphamide, and dexamethasone, achieving a clinical and hematologic response after the third cycle. This case highlights that KSHV/HHV-8-associated MCD may occur in HIV-negative individuals and may present concurrently with Kaposi sarcoma and POEMS-like manifestations, representing a rare diagnostic challenge.

Open article ↗

other

2026-07-29 | Targeting soluble immunoglobulins ameliorates idiopathic multicentric Castleman disease in a mouse model

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder that affects lymph nodes at multiple sites and can progress to life-threatening organ dysfunction. While curative therapies remain unavailable, largely due to a critical gap in understanding the disease’s underlying etiology, the cytokine interleukin-6 (IL-6) is recognized as a major pathogenic driver, particularly in iMCD patients with plasmacytic lymphadenopathy. Here, we demonstrate the presence of Foxp3-expressing cells alongside plasma cells within germinal centers of lymph nodes from such iMCD patients. Based on this observation, we directed IL-6 overexpression specifically to Foxp3 + Treg cells and established a novel preclinical mouse model of iMCD. This targeted approach successfully recapitulated the key characteristics of iMCD in mice, including multifocal lymphadenopathy, splenomegaly, anemia, thrombocytopenia, marked plasmacytosis, and mortality in young adults. Advanced disease was characterized by renal pathology, including proteinuria and elevated creatinine levels. In this model, IL-6 directly promoted plasmacytosis, resulting in profound IgG1 hyperimmunoglobulinemia. Genetic ablation of soluble immunoglobulin production ameliorated iMCD symptoms, prevented renal dysfunction, and significantly extended survival. Our findings identify IL-6-driven IgG1 plasmacytosis as a critical pathogenic factor in iMCD, shedding light on the mechanisms underlying its development. Key points Transgenic IL-6 expression in Foxp3 + cells models iMCD in mice and drives lethal IgG1 plasmacytosis Loss of soluble immunoglobulins prevented renal impairment and prolonged survival in iMCD-like mice

Open article ↗

2026-01-21 | KSHV and cancer: understanding the oncogenic machinery for next-generation diagnostic tools and therapies.

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8), is an oncogenic virus responsible for Kaposi's sarcoma (KS) and lymphoproliferative disorders like primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). This review explores KSHV's oncogenic mechanisms, focusing on its ability to manipulate host cell signaling, evade immune detection, and promote tumorigenesis through latent and lytic viral proteins. Key oncoproteins, such as LANA, vCyc, vFLIP, and vGPCR, activate cancer hallmarks, as sustained proliferation, immune evasion, angiogenesis, and resistance to cell death, by modulating pathways such as PI3K/AKT/mTOR and NF-κB. While histopathology and LANA staining remain diagnostic standards, emerging technologies, including advanced imaging and new molecular biomarkers, assay improved early detection. Of KSHV current therapies face challenges, especially in immunocompromised patients, highlighting the need for targeted treatments addressing viral infection. Next-generation approaches, such as CRISPR-Cas9 and therapeutic aptamers, aim to inhibit viral replication, modulate oncogenic pathways, and enhance immune responses. Current diagnosis of KS still relies primarily on histopathology and LANA immunostaining, which remain the gold standard but present important limitations, particularly in early or atypical lesions and in distinguishing latent from lytic infection. Despite advances in conventional chemotherapy and antiretroviral therapy, KSHV-associated malignancies lack virus-specific targeted treatments, and clinical outcomes remain suboptimal, especially in immunocompromised patients. By integrating emerging diagnostic biomarkers, such as viral microRNAs, with next-generation therapeutic strategies-including gene editing and synthetic biology-based approaches-this review highlights opportunities for precision medicine to improve disease detection, therapeutic specificity, and patient outcomes. Collectively, we provide a comprehensive framework for understanding KSHV-driven oncogenesis while outlining critical directions for future diagnostic and therapeutic innovation.

Open article ↗

2025-03-03 | Design, development, and evaluation of gene therapeutics specific to KSHV-associated diseases.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and two human lymphoproliferative diseases: primary effusion lymphoma and AIDS-related multicentric Castleman's disease. KSHV-encoded latency-associated nuclear antigen (LANA) is expressed in KSHV-infected cancer cells and is responsible for maintaining viral genomes in infected cells. Thus, LANA is an attractive target for therapeutic intervention for KSHV-associated diseases. Here, we devised a cancer gene therapy vector using the adeno-associated virus (AAV), which capitalizes the LANA's function to maintain terminal repeat (TR) containing circular genome in latently infected cells and the TR's enhancer function for KSHV inducible gene promoters. By including two TR copies with a lytic inducible gene promoter (TR2-OriP), we prepared an AAV vector, which expresses an engineered thymidine kinase (TK) selectively in KSHV-infected cells. Ganciclovir (GCV), an anti-herpesvirus drug, effectively eradicated multiple KSHV-infected cells that include iPSC-derived epithelial colony-forming cells, but not non-KSHV-infected counterparts in the presence of AAV8-TR2-OriP-TK. In addition, AAV8-TR2-OriP-TK prevents KSHV virion production from reactivated cells, spreading KSHV infections from reactivated cells. Anti-cancer drugs, known to reactivate KSHV, stimulated TK expression from the vector and, therefore, synergized with AAV8 TR2-OriP-TK to induce KSHV-infected cancer cell death. Finally, the AAV8-TR2-OriP-TK with GCV completely diminished KSHV-infected cancer cells in the xenograft tumor model. The new cancer gene therapeutics should augment the current clinical protocol for KS.

Open article ↗

2023-09-15 | Modulation of Pro-Inflammatory IL-6 Trans-Signaling Axis by Splice Switching Oligonucleotides as a Therapeutic Modality in Inflammation

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a crucial role in maintaining normal homeostatic processes under the pathogenesis of various inflammatory and autoimmune diseases. This context-dependent effect from a cytokine is due to two distinctive forms of signaling: cis-signaling and trans-signaling. IL-6 cis-signaling involves binding IL-6 to the membrane-bound IL-6 receptor and Glycoprotein 130 (GP130) signal-transducing subunit. By contrast, in IL-6 trans-signaling, complexes of IL-6 and the soluble form of the IL-6 receptor (sIL-6R) signal via membrane-bound GP130. Various strategies have been employed in the past decade to target the pro-inflammatory effect of IL-6 in numerous inflammatory disorders. However, their development has been hindered since these approaches generally target global IL-6 signaling, also affecting the anti-inflammatory effects of IL-6 signaling too. Therefore, novel strategies explicitly targeting the pro-inflammatory IL-6 trans-signaling without affecting the IL-6 cis-signaling are required and carry immense therapeutic potential. Here, we have developed a novel approach to specifically decoy IL-6-mediated trans-signaling by modulating alternative splicing in GP130, an IL-6 signal transducer, by employing splice switching oligonucleotides (SSO), to induce the expression of truncated soluble isoforms of the protein GP130. This isoform is devoid of signaling domains but allows for specifically sequestering the IL-6/sIL-6R receptor complex with high affinity in serum and thereby suppressing inflammation. Using the state-of-the-art Pip6a cell-penetrating peptide conjugated to PMO-based SSO targeting GP130 for efficient in vivo delivery, reduced disease phenotypes in two different inflammatory mouse models of systemic and intestinal inflammation were observed. Overall, this novel gene therapy platform holds great potential as a refined therapeutic intervention for chronic inflammatory diseases.

Open article ↗

2022-02-28 | Hematologic cancers in individuals infected by HIV.

HIV infection increases cancer risk and is linked to cancers associated to infectious agents classified as carcinogenic to humans by the International Agency for Research on Cancer. Lymphomas represent one of the most frequent malignancies among individuals infected by HIV. Diffuse large B-cell lymphoma remains a leading cancer after the introduction of combined antiretroviral therapy (cART). The incidence of other lymphomas including Burkitt lymphoma, primary effusion lymphomas, and plasmablastic lymphoma of the oral cavity remain stable, whereas the incidence of Hodgkin lymphoma and Kaposi sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman disease has increased. The heterogeneity of lymphomas in individuals infected by HIV likely depends on the complexity of involved pathogenetic mechanisms (ie, HIV-induced immunosuppression, genetic abnormalities, cytokine dysregulation, and coinfection with the gammaherpesviruses Epstein-Barr virus and KSHV) and the dysregulation of the immune responses controlling these viruses. In the modern cART era, standard treatments for HIV-associated lymphoma including stem cell transplantation in relapsed/refractory disease mirror that of the general population. The combination of cART and antineoplastic treatments has resulted in remarkable prolongation of long-term survival. However, oncolytic and immunotherapic strategies and therapies targeting specific viral oncogenes will need to be developed.

Open article ↗