Citations

ObjectiveAutoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA‐associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.MethodsSequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)–ANCA–positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long‐term follow‐up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3‐specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/μl after RTX treatment.ResultsAt B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05).ConclusionThe composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.

Histological transformation (HT) to an aggressive lymphoma results from a rare evolution of Waldenström macroglobulinemia (WM). A higher incidence of transformation events has been reported in MYD88 wild-type WM patients. HT in WM can be histologically heterogeneous, although the diffuse large B-cell lymphoma of activated B-cell subtype is the predominant pathologic entity. The pathophysiology of HT is largely unknown. The clinical suspicion of HT is based on physical deterioration and the rapid enlargement of the lymph nodes in WM patients. Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) and extranodal disease. A histologic confirmation regarding the transformation to a higher-grade lymphoma is mandatory for the diagnosis of HT, and the choice of the biopsy site may be dictated by the findings of the 18fluorodeoxyglucose-positron emission tomography/computed tomography. The prognosis of HT in WM is unfavorable, with a significantly inferior outcome compared to WM patients without HT. A validated prognostic score based on 3 adverse risk factors (elevated LDH, platelet count < 100 × 109/L and any previous treatment for WM) stratifies patients into 3 risk groups. The most common initial treatment used is a chemo-immunotherapy (CIT), such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The response duration is short and central nervous system relapses are frequent. Whether autologous stem cell transplantation could benefit fit patients responding to CIT remains to be studied.

AbstractHow to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

OBJECTIVE The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I–II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%–93%) and 105/110 low-grade (95%, 95% CI 90%–98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%–18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%–28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%–9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 (ClinicalTrials.gov)

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Abstract Case reports of patients infected with COVID-19 and influenza virus (“flurona”) have raised questions around the prevalence and severity of coinfection. Using data from HHS Protect Public Data Hub, NCBI Virus, and CDC FluView, we analyzed trends in SARS-CoV-2 and influenza hospitalized coinfection cases and strain prevalences. We also characterized coinfection cases across the Mayo Clinic Enterprise from January 2020 to April 2022. We compared expected and observed coinfection case counts across different waves of the pandemic and assessed symptoms and outcomes of coinfection and COVID-19 monoinfection cases after propensity score matching on clinically relevant baseline characteristics. From both the Mayo Clinic and nationwide datasets, the observed coinfection rate for SARS-CoV-2 and influenza has been higher during the Omicron era (2021 December 14 to 2022 April 2) compared to previous waves, but no higher than expected assuming infection rates are independent. At the Mayo Clinic, only 120 coinfection cases were observed among 197,364 SARS-CoV-2 cases. Coinfected patients were relatively young (mean age: 26.7 years) and had fewer serious comorbidities compared to monoinfected patients. While there were no significant differences in 30-day hospitalization, ICU admission, or mortality rates between coinfected and matched COVID-19 monoinfection cases, coinfection cases reported higher rates of symptoms including congestion, cough, fever/chills, headache, myalgia/arthralgia, pharyngitis, and rhinitis. While most coinfection cases observed at the Mayo Clinic occurred among relatively healthy individuals, further observation is needed to assess outcomes among subpopulations with risk factors for severe COVID-19 such as older age, obesity, and immunocompromised status.

Abstract The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.