ArticleThe Journal of clinical investigation2019
Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 86 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
ACCELERATE (Advancing Castleman Care With an Electronic Longitudinal Registry, E-Repository, And Treatment/Effectiveness Research): An International Registry for Patients With Castleman Disease
A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
Who cites it
86 citing papers in PubMed, 1 synthesis or guideline pooled it, 137 citations in OpenAlex.
- Australian clinical practice guideline: diagnosis and treatment of idiopathic multicentric Castleman disease.Internal medicine journal · 2026Guideline
- A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.International journal of hematology · 2024Trial
- Response to Intravenous N-Acetylcysteine Supplementation in Critically Ill Patients with COVID-19.Nutrients · 2023Trial
- Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease.American journal of hematology · 2020Trial
- Successful treatment of idiopathic multicentric Castleman disease with TAFRO and kidney involvement: case report and literature review.Renal failure · 2026Review
- Rethinking Common Diagnoses: Idiopathic Multicentric Castleman Disease Presenting as TAFRO Syndrome: A Case Report.Clinical case reports · 2026Article
- Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease.Haematologica · 2026Article
- Comprehensive analysis of subtype-specific outcomes and management in Castleman disease: a 20-year cohort study.Blood advances · 2026Article
- Snapshot Look at Castleman Disease.Journal of cellular and molecular medicine · 2026Review
- Deciphering the Iron Metabolism and Ferroptosis in Diabetic Wound Healing.Current diabetes reviews · 2026Review
- Expert Perspective: Diagnosis and Treatment of Castleman Disease.Arthritis & rheumatology (Hoboken, N.J.) · 2026Review
- A patient-derived CABIN1 mutation recapitulates features of idiopathic multicentric Castleman disease in a mouse model.Blood advances · 2025Article
- Article
- The Evolution and Recent Advances in Diagnostic Criteria for Idiopathic Multicentric Castleman Disease.American journal of hematology · 2025Review
- Successful Treatment of Refractory TAFRO Syndrome with Cyclophosphamide: A Report of Two Cases.Internal medicine (Tokyo, Japan) · 2025Article
- The heterogeneity of thoracic Castleman disease: implications for classification and personalized management.Annals of hematology · 2025Article
- Meprin β activity modulates cellular proliferation via trans-signaling IL-6-mediated AKT/ERK pathway in IR-induced kidney injury.BMC nephrology · 2025Article
- Serum Soluble Interleukin-2 Receptor as a Potential Marker for Assessing Disease Activity in the TAFRO Subtype of Idiopathic Multicentric Castleman Disease.Internal medicine (Tokyo, Japan) · 2025Article
- The Involvement of PI3K-Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease-Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2025Article
- [Sequential treatment with siltuximab and tocilizumab for childhood idiopathic multicentric Castleman disease: a case report].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2025Article
26 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
23 authors at 9 institutions in 4 countries.
Funding
Abstract
backgroundIdiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.
methodsWe analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus.
resultsStudies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months.
conclusionThis precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).
fundingCastleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.