Showing papers by "David C. Fajgenbaum published in 2019"

Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease.

Abstract: BACKGROUND Idiopathic 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.

Predictors of response to anti-IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data

Abstract: Siltuximab is the only US Food and Drug Administration-approved treatment for idiopathic multicentric Castleman disease (iMCD), a rare haematological disorder associated with substantial morbidity and mortality Although siltuximab induces a response in a significant proportion of iMCD patients via interleukin 6 (IL6) neutralization, it is not universally effective To develop a predictive model of response, we performed an in-depth analysis of 38 baseline laboratory parameters in iMCD patients from the phase II siltuximab trial who met criteria for treatment response or treatment failure Univariate analyses identified eight baseline laboratory parameters that were significantly different between responders and treatment failures: albumin, immunoglobulin G (IgG), immunoglobulin A, C reactive protein (CRP), fibrinogen, haemoglobin, sodium and triglycerides Stepwise logistic regression analysis of these candidate parameters identified a top performing model that included fibrinogen, IgG, haemoglobin and CRP Based on cross-validation of the final multivariate logistic regression model, the model accurately discriminated responders from those who failed treatment (area under the receiver operator characteristic curve 0·86, 95% confidence interval: 0·73-0·95) All four laboratory parameters associated with response to siltuximab have biological relationships with IL6 and acute inflammation Our model suggests that iMCD patients with laboratory evidence of an inflammatory syndrome are the best candidates for siltuximab therapy

Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease.

Abstract: Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.

Renal Pathologic Findings in TAFRO Syndrome: Is There a Continuum Between Thrombotic Microangiopathy and Membranoproliferative Glomerulonephritis? A Case Report and Literature Review.

Abstract: Background: TAFRO syndrome is a clinical subtype of idiopathic multicentric Castleman disease (iMCD) that is characterized by thrombocytopenia, anasarca, fever and/or elevated serum C-reactive protein, renal dysfunction, and organomegaly. Case Presentation: A 28-year-old woman with fever, weight gain of 13 kgs, lower extremity edema, hepatosplenomegaly, and multicentric peripheral lymphadenopathy was referred to our center. Laboratory investigations revealed anemia, thrombocytopenia, creatinine at 1.19 mg/dL and hypoalbuminemia at 33 g/L. Proteinuria was measured at 2 g/day including albuminuria at 1.5 g/day. Urinary sediment examination found leukocyturia at 44,000/mL and hematuria at 645,000/mL. Vascular endothelial growth factor (VEGF) level was elevated. A cervical lymph node biopsy found features consistent with the mixed histopathological subtype of iMCD. A renal biopsy revealed a membranoproliferative glomerulonephritis (MPGN) pattern. We initiated 3 days of methylprednisolone pulse-therapy at 1,000 mg per day, followed by prednisone 1 mg/kg/day and evolution was favorable. Review of Literature: 19 iMCD patients with TAFRO syndrome had undergone a renal biopsy: 8 cases with author's diagnosis consistent with MPGN-like and 11 cases of thrombotic microangiopathy (TMA)-like glomerulopathy without fibrin thrombi in glomerular capillaries or arterioles and without typical biological signs. Clinical, biological, and outcome characteristics were similar between the cases described as having MPGN and TMA-like presentation. After a thorough review of histopathological descriptions for each case, MPGN lesions seems to be the consequences of chronic glomerular endothelial injury in persistent TMA. We suspect that VEGF and IL-6 play a key role in the physiopathology of the spectrum of renal involvement from TMA-like to MPGN observed in TAFRO syndrome. Conclusion: We present a Caucasian iMCD patient with TAFRO syndrome with renal insufficiency secondary to MPGN, which might be secondary to a chronic TMA-like disease. We suspect that there is a continuum between TMA and MPGN lesions in TAFRO syndrome favored by VEGF and IL-6.

The Collaborative Network Approach: a model for advancing patient-centric research for Castleman disease and other rare diseases.

Abstract: There are ∼7000 rare diseases affecting 30 000 000 individuals in the U.S.A. 95% of these rare diseases do not have a single Food and Drug Administration-approved therapy. Relatively, limited progress has been made to develop new or repurpose existing therapies for these disorders, in part because traditional funding models are not as effective when applied to rare diseases. Due to the suboptimal research infrastructure and treatment options for Castleman disease, the Castleman Disease Collaborative Network (CDCN), founded in 2012, spearheaded a novel strategy for advancing biomedical research, the ‘Collaborative Network Approach’. At its heart, the Collaborative Network Approach leverages and integrates the entire community of stakeholders — patients, physicians and researchers — to identify and prioritize high-impact research questions. It then recruits the most qualified researchers to conduct these studies. In parallel, patients are empowered to fight back by supporting research through fundraising and providing their biospecimens and clinical data. This approach democratizes research, allowing the entire community to identify the most clinically relevant and pressing questions; any idea can be translated into a study rather than limiting research to the ideas proposed by researchers in grant applications. Preliminary results from the CDCN and other organizations that have followed its Collaborative Network Approach suggest that this model is generalizable across rare diseases.

Letter to the editor regarding 'Non-cirrhotic portal hypertension associated with multicentric Castleman's disease: a case report'.

Abstract: Dale M. Kobrin, Ana Luisa Pinto, Sophia T. Parente, Marilia Gomes, Maria Augusta Cipriano, Maria Leticia Ribeiro and David C. Fajgenbaum Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Hematology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Pathology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

Quantitative analysis of a rare disease network’s international contact database and E-repository provides insights into biobanking in the electronic consent era

Abstract: Castleman disease (CD) describes a group of rare and poorly understood lymphoproliferative disorders that include unicentric CD (UCD), Human Herpes Virus-8 (HHV8)-associated multicentric CD (HHV8 + MCD), and HHV8-negative/idiopathic MCD (iMCD). Efforts to advance research and drug discovery for CD have been slowed by challenges shared by other rare diseases, such as collecting and centralizing data and biospecimens for research. To collect disease characteristic data and identify individuals interested in contributing biospecimens for research, a global research organization - the Castleman Disease Collaborative Network (CDCN) - established an international Contact Database and electronic repository (E-repository). Herein, we performed analyses of these datasets to further characterize CD and gain insights into research biospecimen acquisition. Descriptive statistical analyses were performed on 891 participants from the Contact Database and 166 patients in the E-repository. The median age of patients at the time of enrollment in the Contact Database and E-repository was 42 ± 15.7 and 35 ± 14.8, respectively. The E-repository had increased representation from patients with MCD and the iMCD subtype compared to other sub-groups. Though the majority of participants were from the USA, a total of 49 countries on 6 continents were represented. Several patient characteristics in the Contact Database were associated with subsequent enrollment in the E-repository. There were significantly more MCD patients (p < 0.0001) and females (p = 0.002) enrolled in the E-repository compared to the Contact Database. Patient’s year of birth, date of registration, preferred method of communication, and relationship to the patient were also significantly associated with enrollment in the e-Repository. This study of the largest- dataset of CD patients worldwide provides insights into disease phenotypes, characteristics of patients interested in contributing data and biospecimens for research, and methods for successfully acquiring data and biospecimens. Generally, the factors associated with enrollment in the E-repository represented severity of disease subtype, proximity to the research, and patient motivation. We hope that these findings and the sample documentation (e.g., electronic consent, recruitment materials) provided with this article will assist future rare disease efforts with overcoming hurdles.