International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Plasma miR-1290 Is a Novel and Specific Biomarker for Early Diagnosis of Necrotizing Enterocolitis-Biomarker Discovery with Prospective Cohort Evaluation.

OBJECTIVE: To discover specific circulating microRNA (miRNA) biomarkers for the early differentiation of necrotizing enterocolitis (NEC) from neonatal sepsis and inflammatory conditions. STUDY DESIGN: The study comprised 3 distinct phases: differential microarray analysis to compare plasma miRNA expression profiles of NEC vs sepsis and non-NEC/nonsepsis cases, a case-control study to quantify dysregulated miRNAs as potential specific biomarkers of NEC, and a prospective cohort study to assess the diagnostic usefulness of the best miRNA biomarker(s). RESULTS: A distinct miRNA expression profile was observed in the NEC compared with the sepsis and non-NEC/nonsepsis groups. miR-1290, miR-1246, and miR-375 were discovered to be specific biomarkers of NEC in the case-control study. In the cohort study (n = 301), plasma miR-1290 (day 0; >220 copies/µL) provided the greatest diagnostic usefulness for identifying both mild medical and severe surgical NEC cases. Of 20 infants with miR-1290 >650 copies/µL, 15 were diagnosed with NEC. Incorporating C-reactive protein (day 1; >15.8 mg/L) for cases with intermediate levels (220-650 copies/µL) in a 2-stage algorithm further optimized the diagnostic profile with a sensitivity of 0.83, a specificity of 0.96, a positive predictive value of 0.75, and a negative predictive value of 0.98. Importantly, 7 of 36 infants with NEC (19.4%) could be diagnosed 7.8-32.2 hours earlier (median, 13.3 hours) using miR-1290. CONCLUSIONS: Plasma miR-1290 is a novel and specific biomarker that can effectively differentiate NEC cases from neonatal sepsis. miR-1290 facilitates neonatologists to confidently and timely reach a decision for early transfer of sick infants with NEC from community-based hospitals to tertiary surgical centers.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.