Citations

Abstract Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

Giant cell arteritis (GCA) is a relapsing large vessel vasculitis with risk of serious ischemic manifestations, including vision loss and vascular damage in the form of large artery stenosis, aneurysms, and dissections. Approximately 50% of patients treated with glucocorticoid (GC) monotherapy and 30% of patients receiving adjunctive therapy with tocilizumab experience disease relapses, often during the first 2 years after diagnosis. Although most relapses in GCA do not involve life‐ or organ‐threatening presentations and can be controlled successfully, frequent relapses may lead to increased prescription of GC and consequent treatment‐related morbidity, in addition to risk of further vascular damage. Emerging data suggest that persistent disease activity may lead to increased vascular morbidity. Additionally, although tocilizumab decreases the frequency of relapses, more than 50% of patients relapse after discontinuation of therapy. Therefore, although interleukin‐6 blockade suppresses disease activity, it does not restore tolerance. In this article, we discuss the practical diagnosis and management of GCA relapses from an expert perspective. Current treatment options for GCA relapses, including those recommended by international guidelines, and novel potential therapies are reviewed.

Abstract Vasculitic neuropathy is caused by inflammatory destruction of nerve blood vessels resulting in nerve ischaemia. Nerve vasculitis can be divided into two categories based on vessel size: large-arteriole vasculitis (≥75 µm) and microvasculitis (<75 µm). Herein, we characterize the clinical features of nerve large-arteriole vasculitis in comparison to nerve microvasculitis. This is a retrospective cohort study of patients evaluated and biopsied at Mayo sites between 2001 and 2020. We collected clinical and histopathological data from patients whose nerve biopsies were either diagnostic or highly suggestive of nerve vasculitis. Two hundred and seventy-eight cases were identified: 125 cases of large-arteriole vasculitis and 153 cases of microvasculitis. Nerve large-arteriole vasculitis presented with a more acute (50.4% versus 26.8%) versus chronic onset (33.6% versus 57.5%) than nerve microvasculitis (P = 0.0001). Nerve microvasculitis had longer mean time to diagnosis (10.5 versus 4.3 months; P < 0.0001) and longer time to plateau (8.9 versus 3.5 months; P < 0.0001). Nerve large-arteriole vasculitis typically presented as distal asymmetric polyneuropathy (48.0%), whereas nerve microvasculitis typically presented as radiculoplexus neuropathy/polyradiculoneuropathy (more proximal involvement of shoulder and thigh) (43.8%) (P < 0.0001). Systemic autoimmune disease was more common in nerve large-arteriole vasculitis (70.4% versus 22.9%, odds ratio, 8.0; 95% confidence interval, 4.7–13.7; P < 0.0001). Nerve microvasculitis was significantly related to non-systemic vasculitis (71% versus 23%, odds ratio, 7.9; 95% confidence interval, 4.6–13.6; P < 0.0001). Nerve microvasculitis had more autonomic involvement (24.2% versus 7.2%, odds ratio, 4.1; 95% confidence interval, 1.9–8.9; P = 0.0002). Nerve large-arteriole vasculitis and nerve microvasculitis have different but overlapping clinical features. Nerve large-arteriole vasculitis usually presents with acute onset, distal asymmetric polyneuropathy, associated with other autoimmune diseases and systemic involvement. In contrast, nerve microvasculitis usually presents with a subacute/chronic onset, as radiculoplexus neuropathy/polyradiculopathy (distal and proximal pattern) with autonomic involvement, and is more often a form of non-systemic vasculitis.

Abstract Adult primary leptomeningeal gliomatosis (PLG) is a rare, rapidly progressive and fatal disease characterized by prominent leptomeningeal infiltration by a glial tumor without an identifiable parenchymal mass. The molecular profile of adult PLG has not been well‐characterized. We report the clinical, pathological, and molecular findings of six adult PLG patients (five males and one female), median age 58 years. All cases exhibited pathological leptomeningeal enhancement at presentation. Leptomeningeal biopsy was diagnostic in five (of six) cases, revealing infiltration by an astrocytic glioma with mitotic activity, lacking microvascular proliferation or necrosis. One case was diagnosed at autopsy. All tumors were IDH‐wildtype, with five harboring TERT promoter mutations. Additional mutations identified were PTEN in one case, TP53 in two cases, and NF1 in two cases. A chromosome profile with +7/−10 was found in four cases, whereas the remaining two showed either chromosome 7 or 7p gain only. Four cases showed chromosome 9p loss with CDKN2A/B homozygous deletion, one case showed hemizygous CDKN2A/B loss, and one case showed intact chromosome 9 and CDK4/GLI1 amplification. DNA methylation profiling was performed in four cases and revealed a match to glioblastoma (GBM) family and mesenchymal typical class with high confidence scores in two cases; the other two cases showed only suggestive combined scores for GBM family and mesenchymal atypical class. The molecular profile of all cases closely aligned with that of adult‐type GBM, IDH‐wildtype, CNS WHO grade 4. All patients succumbed to the disease. In five cases with extensive leptomeningeal disease at diagnosis, the course was rapid, with median survival of 24 days following palliative care. Only one case, with relatively localized disease at diagnosis, received chemoradiation therapy and survived 535 days, raising the possibility that early diagnosis and timely treatment could improve outcome. A detailed list of previously reported cases is provided in a supplementary table.

Abstract Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim–Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with “idiopathic” AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases.

Objectives To reassess the role of primary retroperitoneal lymph node dissection (RPLND) in patients with marker‐negative non‐seminomatous germ cell tumour (NSGCT) clinical stage (CS) 2a, to explore results in patients with CS 2b and to evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Materials and Methods Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for CS 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and disease‐free survival (DFS). Results A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01–1.07; P = 0.03), but no association was observed with DFS. The 5‐year DFS rates in marker negative CS 2a and 2b were 79% and 76%. In men with non‐teratomatous viable cancer in the RPLND specimen, the 5‐year DFS rates for CS 2a and 2b were 95% and 87% with adjuvant chemotherapy, and 67% and 74% without adjuvant chemotherapy. We did not identify an association between the number of adjuvant chemotherapy cycles and DFS. Conclusions Our study suggests considering primary RPLND not only in marker‐negative CS 2a but also in CS 2b. Further research should determine the efficacy of primary RPLND in men with CS 2c and marker‐positive CS 2, as well as which patients may benefit from adjuvant chemotherapy and the optimal cycle number.

Objective To characterise the changing trends in the pharmacological management of SLE in the USA between 2007 and 2023 as new treatment options emerged. Methods In a retrospective cohort study using data from OptumLabs Data Warehouse, we characterised the annual prevalent (ie, all) and incident (ie, new) use of antimalarials, glucocorticoids and immunosuppressive medications among patients with SLE from 2007 to 2023 and assessed for changing trends over time. Results We identified 19 122 adults with SLE; they were 51.2 (SD 16.1) years of age, 89% were female, 61.3% were White, 18.5% were Black and 13.1% were Hispanic. The proportion of prevalent users of antimalarials has decreased from 79.4% in 2007 to 77.2% in 2023 (p=0.0055), while the proportion of incident users fluctuated between a lowest 5.8% in 2021 and a highest 8.1% in 2008 (p=0.008). The proportion of prevalent users of glucocorticoids increased from 64.6% in 2007 to 66.7% in 2023 (p=0.0132), as did the proportion of incident users (12.4% in 2007 to 21.7% in 2023; p<0.0001). The use of cyclophosphamide (2.0% in 2007 to 0.4% in 2023, p<0.0001) has decreased; the use of mycophenolate mofetil (7.7% in 2007 to 10.3% in 2023, p<0.0001), rituximab (1.4% in 2007 to 2.1% in 2023, p<0.0001) and belimumab (0.8% in 2011 to 6.1% in 2023, p=0.0001) has increased. Conclusions Despite increasing availability of alternative treatment options, patients with SLE in the USA increasingly rely on glucocorticoid-based therapy. Efforts to improve the use of antimalarials and steroid-sparing immunosuppressants are needed.

Background: Contemporary questions about treatment and outcomes of patients (pts) living with multiple myeloma (MM) demand efficient and timely evidence generation methods, where real-world/ everyday practice data can play an important role. Relevant potential applications include understanding and addressing disparities in treatment access, mitigating toxicities of novel therapies while maintaining quality of life, appropriately sequencing treatments within long-term management strategies, and disseminating and appropriately using surrogate endpoints in practice, such as minimal residual disease. However, existing real-world data (RWD) repositories are limited by an inability to implement interventions in response to issues identified through retrospective data analysis, which is pivotal for the use of newer therapies. The ASH Research Collaborative (ASH RC) MM Data Hub Program was developed to address these gaps. Methods: We developed a multicenter network of US-based tertiary academic medical centers, engaging site clinicians, patients, biostatisticians, informaticians, and data scientists. Initial activities included constructing a shared real-world MM data model comprised of consensus core data elements. Pt data from each site, dating back to at least 2019, is currently being entered through electronic case report forms, batch uploaded utilizing existing institutional data repositories, and soon direct electronic health record import in standard data acquisition formats. Data are aggregated in the Data Hub and shared in a confidential Site Portal with each site. The Portal allows sites to track their own pts, analyze outcomes, and identify ways to improve the quality of care provided to individuals living with MM. We also developed an innovative evidence generation learning community of site clinicians who meet monthly and collaborate on the “COVID-19 OutcomeS in Myeloma and the Impact of VaCcines (COSMIC)” study, a prospective, decentralized observational study that rapidly accrued pts and collects relevant practice information. The group also shares best practices in study conduct to accelerate study enrollment and execution. Results: The MM Data Hub Program now contains twelve centers: Memorial Sloan Kettering Cancer Center, Mayo Clinic, Icahn School of Medicine at Mount Sinai, University of California San Francisco, University of California Davis, Medical College of Wisconsin, Barbara Ann Karmanos Cancer Institute, University of North Carolina Medical Center at Chapel Hill, Emory University Hospital, Washington University School of Medicine in St. Louis, Dana-Farber Cancer Institute, and Atrium Health. From this Network, six centers have contributed data from 8,824 pts (2,825 with sufficiently complete data are included in this analysis). The median age at time of MM diagnosis is 63, and of the 627 deceased pts, the median age at death is 70.6 years, with median time to death from first MM diagnosis of 6 years. The proportions of pts by decade of diagnoses are 34.9% from 2020-2024; 57.6% from 2010-2019; 7.3% from 2000-2009; and 0.9% prior to 2000. 83.1% of pts had a diagnosis of plasma cell myeloma (non-light chain), and 14.4% of pts had a diagnosis of light chain myeloma. 42.3% of pts are female, and the self-reported patient races are: 85.0% white; 9.2% black or African; and 4.3% all other races (race was not documented in 1.5% of pts). 2.8% of pts are of Hispanic ethnicity. Participant data files are currently undergoing completion and cleaning procedures; the analysis will include updated results at the meeting, and a Network-wide analytic data set will be available for initial retrospective data analyses in early 2025. The COSMIC study opened for enrollment on January 22, 2024, and completed enrollment of 200 pts on May 17, 2024. Conclusions: The ASH RC Data Hub MM Program launched in 2023 and is comprised of 12 sites that collectively have contributed participant files for 8,824 pts thus far. Utilizing the structure of the Network, we successfully implemented and established the feasibility of collecting data directly from pts electronically to monitor SARS-CoV-2 vaccines and COVID-19 related outcomes. The Program serves as a successful proof-of-concept model, providing an enduring RWD resource and a prospective evidence generation platform for the myeloma community.

Aim: The definition of high-risk (HR) in Multiple Myeloma (MM) is ever evolving with the discovery of new genomic abnormalities and increasing therapeutic options. There are various stratification models incorporating laboratory and genetic features with different definitions of high-risk and varied emphasis on individual risk factors. Recognized high-risk cytogenetic abnormalities (HRCA) include t(4;14), t(14;16), t(14;20), del(17p) with recent inclusion of del(1p) and gain/amplification (amp) of 1q (+1q) . In addition to del(17p), the presence of biallelic del(1p) and ≥2 HRCAs (“double-” or “triple-hit”) appear to confer poorer outcomes. A new definition proposed by the International Myeloma society (IMS) defines HR as the presence of del(17p) and/or TP53 mutation; an IgH translocation - t(4;14), t(4;16) or t(14;20) along with +1q and/or del(1p); monoallelic del(1p32) along with +1q; bi-allelic del(1p32); or β2 microglobulin ≥5.5 with normal creatinine (&lt;1.2mg/dL). Herein, we report real-world outcomes on these HRCAs and the new IMS consensus definition of HR MM. Method: We retrospectively reviewed newly diagnosed MM patients from the Australian and New Zealand Myeloma and Related Diseases Registry across 4 Australian states. Patients with FISH and/or SNP microarray testing for IgH translocations, 1q21 (CKS1B), del(1p32) (CDKN2C) and del(17p) (TP53) were identified. Positive threshold was 30%. We used Kaplan-Meier methods to compare progression free survival (PFS) and overall survival (OS) between groups and first performed univariate analysis (UA) for each HRCA. We next analyzed patients with gain1q vs amp1q and monoallelic vs biallelic del(1p). In the final analysis, two risk groups were formed: cases meeting the new IMS-defined HR criteria were considered IMS-HR and the rest were considered standard risk (IMS-SR). Indeterminate cases with missing variables that could influence risk classification were excluded. Results: Of 839 newly diagnosed patients (pts) included, 31% had ISS (International staging system) stage 3 disease. High-risk IgH translocations t(4;14) and t(14;16) were present in 8% and 4%. Secondary HRCAs del(17p), del(1p), gain1q and amp1q were present in 9%, 14%, 30% and 11% respectively. In this cohort, 41% received ASCT. Of the transplant eligible pts, 41% received triplet therapy (PI, IMiD and corticosteroid) and 57% received PI-based induction. Of the transplant ineligible pts, 31% received triplet therapy, 47% PI-based and 19% IMiD-based therapy. Frontline Anti-CD38 antibody use was &lt;1%. Median follow up was 35 months[m] (IQR 18-60). On UA, the risk of progression and/or death was increased with ISS III vs I, amp1q, del(17p), t(14;16), del(1p) and gain1q in descending order by hazard ratio. The risk remained significant in ISS III, del(17p), amp1q and gain1q after multi-variate analysis (MVA). The risk of death was increased with ISS III vs I, del(17p), amp1q, del(1p) and t(14;16), ISS II vs I in descending order by hazard ratio. After MVA, the risk remained significant for ISS stage III, del(17p), amp1q and t(14;16). Of the 117 pts with del(1p32), 108 had monoallelic and 9 had biallelic loss. Pts with biallelic del(1p32) had an inferior PFS (median 16.3 vs 23.2m, p&lt;0.001) and OS (median 24.8m vs NR, p&lt;0.001) compared to those with monoallelic del(1p32). In pts with 1q+, pts with amp1q had an inferior PFS (median 16.3 vs 27.5m, p&lt;0.001) and OS (median 37.0m vs NR, p&lt;0.001) vs pts with gain1q. Based on the new definition of HR myeloma - 385 pts met the criteria for IMS-HR and 216 for IMS-SR. There were 238 indeterminate cases due to missing data. The IMS-HR group had an inferior PFS (median 20.2 vs 39.7m, p&lt;0.001) and OS (median 44.2m vs NR, p&lt;0.001) when compared to IMS-SR. Noting that the IMS-HR group had a higher median age, poorer performance status and lower rates of ASCT use, adjusted analysis for these variables still showed an inferior PFS (aHR 1.68; 95% CI 1.30-2.16, p&lt;0.001) and OS [aHR 1.72; 95% CI 1.21-2.44, p=0.002). Conclusion: ISS III, del(17p), amp1q are the strongest predictor of OS and PFS. Differentiating between monoallelic vs biallelic del(132p) and gain vs amp1q21 has important prognostic value. The IMS- HR definition which takes into account del(1p), “double-” and “triple-hit” disease predicts for a group of patients with a PFS of ~20 months and inferior OS, and provides a standardized approach to risk stratification in MM.

Background: The COVID-19 pandemic had an outsized impact on individuals with immune compromise, such as multiple myeloma, leading to increased rates of severe COVID, hospitalization, and death in these groups. The pandemic also demonstrated the need for rapid and efficient evidence generation to address rapidly changing medical needs and accelerated the use of innovative trial designs to accomplish this goal. Methods: We designed and established a prospective, decentralized study within a site-based provider network, COVID-19 OutcomeS in Myeloma and the Impact of VaCcines (COSMIC), for patients with multiple myeloma at ASH Research Collaborative sites to monitor outcomes related to COVID-19 infection and vaccination. The direct-to-patient approach was accomplished using a study application accessed with a QR code provided to patients during usual clinical care. All study activities occurred within the patient portal at Baseline, Day 30, and Day 180, minimizing burden on site personnel and staff. Study activities included eligibility confirmation, consenting, electronic health record (EHR) data permissions, and patient-reported outcome (PRO) surveys. PRO data (EORTC QLQ-C30, EORTC QLQ MY-20) were made available to clinicians through the portal to visualize results from their patients. Patients shared if they received a COVID-19 vaccination or booster and if they had a COVID-19 infection. Patients with a history of COVID-19 infection included method of confirmation and if hospitalization was required. Patients were provided compensation for participation. Automated text and email messages were sent at three separate intervals: 24 hours, Day 8, and Day 15 for participants who initiated but did not complete study activities. A personal email reminder per participant was sent for those whose second study visit window was approaching. ASH Research Collaborative clinicians met regularly to share best practices related to enrollment and study conduct, thereby creating an innovative evidence generation learning community. We studied the feasibility of data collection in a decentralized format by focusing on the number of participants who interacted with the system, those who consented, and those who completed baseline PRO assessments. Results: The COSMIC study rapidly accrued and consented 200 patients from eight participating ASH Research Collaborative sites over four months (1/22/2024 through 5/17/2024): 69% self-reported as non-Hispanic White (NHW). Of enrolled participants, 57.5% opted to permission sharing of their EHR data, which included disease and treatment-related clinical data, laboratory results, pathology reports, and imaging reports. A total of 196 patients (98%) provided demographic and COVID-related disease and vaccine data at baseline; nearly all of these patients (n=195) provided baseline PRO data, and 150 patients provided further information at Day 30 at the time of this analysis. Those who did not provide Day 30 data were not significantly different from those who did in terms of age (median: 68 [no Day 30 data] vs. 67 [Day 30 data] years; p=0.44), sex (41% [no Day 30 data] vs. 47% [Day 30 data] Female; p=0.47), or race (65% [no Day 30 data] vs. 71% [Day 30 data] NHW; p=0.60). A higher proportion of Hispanic patients were retained at Day 30 (13/15=87%) vs. 78% of non-Hispanic patients or those who declined reporting ethnicity (2/7=29%; p=0.007). COVID-19 vaccination data were submitted by 196 patients, 186 of whom had ever received a COVID-19 vaccination. Data on number, type, brand, and dates for these vaccinations were provided. Conclusions: The COSMIC study conducted by the ASH Research Collaborative was able to rapidly accrue a diverse cohort of patients using a decentralized workflow within a site-based provider network, with high consent and compliance rates. This platform, and the innovative evidence generation learning community of ASH Research Collaborative investigators and patients, sets a precedent to address a variety of real-world questions related to disease management, infections, vaccinations, and PROs in this population of patients with multiple myeloma.