Background:
Leptomeningeal enhancement (LME) is a key feature of Susac syndrome (SuS) but is only occasionally depicted on post-contrast T1-weighted images (T1-WI).
Objective:
As post-contrast ...fluid-attenuated inversion recovery (FLAIR) may be more sensitive, our aim was to assess LME in SuS on this sequence.
Methods:
From 2010 to 2020, 20 patients with definite SuS diagnosis were retrospectively enrolled in this multicentre study. Two radiologists independently assessed the number of LME on post-contrast FLAIR and T1-WI acquisitions performed before any treatment. A chi-square test was used to compare both sequences and the interrater agreement was calculated.
Results:
Thirty-five magnetic resonance imagings (MRIs) were performed before treatment, including 19 post-contrast FLAIR images in 17 patients and 25 post-contrast T1-WI in 19 patients. In terms of patients, LME was observed on all post-contrast FLAIR, contrary to post-contrast T1-WI (17/17 (100%) vs. 15/19 (79%), p < 0.05). In terms of sequences, LME was observed on all post-contrast FLAIR, contrary to post-contrast T1-WI (19/19 (100%) vs. 16/25 (64%), p < 0.005). LME was disseminated at both supratentorial (19/19) and infratentorial (18/19) levels on post-contrast FLAIR, contrary to post-contrast T1-WI (3/25 and 9/25, respectively). Interrater agreement was excellent for post-contrast FLAIR (κ = 0.95) but only moderate for post-contrast T1-WI (κ = 0.61).
Conclusion:
LME was always observed and easily visible on post-contrast FLAIR images prior to SuS treatment. In association with other MRI features, it is highly indicative of SuS.
Introduction No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate‐to‐severe relapses of multiple sclerosis (MS). Objective To compare TPE ...to sham‐TPE in patients with a recent steroid‐resistant moderate‐to‐severe MS relapse. Methods Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate‐to‐severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month. Results Thirty‐eight patients were randomized. The intention‐to‐treat analysis included 14 patients in the TPE group and 17 in the Sham‐TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham‐TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed. Conclusions A significant difference between TPE and Sham‐TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham‐TPE group.
To the Editor: Class IA phosphoinositide 3-kinases (PI3Ks) are lipid kinases that transduce signals received from receptor tyrosine kinases, resulting in activation of downstream effectors including ...AKT, mammalian target of rapamycin, and Bruton tyrosine kinase and regulation of multiple cellular processes.1 PI3K heterodimers are composed of a catalytic p110 subunit and a regulatory subunit p85.2 p110δ, 1 of 3 isoforms of the catalytic subunit, encoded by the PIK3CD gene, is preferentially expressed in leukocytes and plays a critical role in signaling via the B-cell receptor, IL-4R, and, Toll-like receptors and is therefore critical in B-cell development, activation, proliferation, differentiation, and B-cell-mediated immunity.3 Overexpression of p110δ confers oncogenic potential.4 Recently, patients were described with germline gain-of-function (GOF) mutations in PIK3CD leading to immunodeficiency, lymphoproliferation, and increased incidence of B-cell lymphomas, termed p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency5 or activated PI3Kdelta syndrome.6 Clinical and laboratory findings in these patients include recurrent sinopulmonary bacterial infections, bronchiectasis, cytomegalovirus and EBV viremia, lymphoproliferation in tissues, progressive lymphopenia in peripheral blood, autoimmune cytopenias, and variable but mostly abnormal immunoglobulin levels with reduced total and class-switched memory B cells.
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.
...We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.
We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene
lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.
Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Le travail d’Arno Gisinger, artiste-historien s’apparente à une traque obstinée et exigeante. À partir de documents d’archives qu’il associe à une réflexion sur la mémoire des lieux, le plus souvent ...traversés par la banalité tragique de l’histoire, l’artiste débusque, en les faisant advenir, les traces, les paroles d’évènements passés. Traces encore lisibles, en cours d’enfouissement, parfois même déjà fantômes ou pleinement disparues. Et dans cette filature inlassable, dans cette vision cont...
Background
Accurate disease detection is integral to risk stratification in B‐cell acute lymphoblastic leukemia (ALL). The gold standard used to evaluate response in the United States includes ...morphologic evaluation and minimal residual disease (MRD) testing of aspirated bone marrow (BM) by flow cytometry (FC). This MRD assessment is usually made on a single aspirate sample that is subject to variability in collection techniques and sampling error. Additionally, central nervous system (CNS) assessments for ALL include evaluations of cytopathology and cell counts, which can miss subclinical involvement.
Procedure
We retrospectively compared BM biopsy, aspirate, and FC samples obtained from children and young adults with relapsed/refractory ALL to identify the frequency and degree of disease discrepancies in this population. We also compared CNS FC and cytopathology techniques.
Results
Sixty of 410 (14.6%) BM samples had discrepant results, 41 (10%) of which were clinically relevant as they resulted in a change in the assignment of marrow status. Discrepant BM results were found in 28 of 89 (31.5%) patients evaluated. Additionally, cerebrospinal fluid (CSF) FC identified disease in 9.7% of cases where cytopathology was negative.
Conclusions
These results support further investigation of the role of concurrent BM biopsy, with aspirate and FC evaluations, and the addition of FC to CSF evaluations, to fully assess disease status and response, particularly in patients with relapsed/refractory ALL. Prospective studies incorporating more comprehensive analysis to evaluate the impact on clinical outcomes are warranted.
Lessons Learned
Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing.
Preclinical studies have ...suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T‐cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response.
Background
Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof‐of‐principle pilot study to evaluate the synergy between the combination of the anti–PD‐L1, avelumab, and concomitant hypofractionated radiotherapy.
Methods
This was a single‐arm phase II Simon two‐stage single center study that was prematurely terminated because of the COVID‐19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect.
Results
At a median potential follow‐up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression‐free survival (PFS) was 5.3 months (95% confidence interval CI: 2.5–7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1–2 treatment‐related adverse events.
Conclusion
Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.
Chimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional ...CRS, a comprehensive characterization of CAR T-cell-associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.
Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual ...disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined.
Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m
begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry.
Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% (
= .11), MRD-free CR rates 97% versus 24% (
< .0001, primary end point), and blood MRD-free rates 100% versus 50% (
< .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients;
= .0034) and durability (
= .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6-104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59%
9%;
< .0001) and platelet transfusions without bleeding (35%
0%;
= .0002), but higher neutrophil (
= .017) and platelet (
= .0015) counts at 4 weeks.
Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.
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