INTRODUCTION:
Treatment of patients with drug resistant focal epilepsy relies upon accurate seizure localization. Ictal activity captured in intracranial EEG (iEEG) has traditionally been interpreted ...to suggest that the underlying cortex is actively seizing. On the other hand, an emerging hypothesis suggests that seizures may in fact emerge from focal regions, which emit discharges that travel over the surface of the cortex as traveling waves.
METHODS:
20 patients underwent placement of subdural electrodes for invasive monitoring at the National Instutes of Health, underwent surgical resection for epilepsy, and had at least 1 year of follow-up. Outcomes were measured by the Engel scale. In these patients, we measured the time delay in discharge receipt at adjacent electrodes to compute the location of the seizure source. This algorithm, known as multilateration, has been used for signal source localization with sparsely-spaced sensors for over a century in geophysics, radar, and acoustics, but has not been used in epilepsy until the present.
RESULTS:
In patients with good outcome, but not in patients with poor outcome, the seizure source tends to localize to the resection territory. The source is a focal, dynamic entity that moves and evolves over the time course of a seizure. Our approach also successfully localizes interictal spikes. We find that interictal spikes emerge from multiple distinct foci in each patient. Seizures either arise from or travel to interictal spike generators.
CONCLUSIONS:
The seizure source appears to be more focal than has traditionally been conceptualized. This focal source may be localized by measuring the time difference of discharge receipt in intracranial electrodes. Algorithmic source localization, as performed here, may guide pre-surgical planning for drug-resistant epilepsy and may improve outcomes.
The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational ...signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called "SBS-MM1") directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10-20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Teclistamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, is the first-in-class FDA approved treatment for relapsed/refractory multiple myeloma (RRMM). Early ...studies of teclistamab have shown high rates of response along with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) (Moreau et al. NEJM 2022). Emerging data from 28 RRMM patients treated with the bispecific antibody cevostamab (targeting FcRH5 and CD3) indicate that use of prophylactic tocilizumab, an anti-IL6 monoclonal antibody, can reduce the risk of developing CRS significantly, without impacting its anti-myeloma activity (Trudel et al. Blood 2022). Preliminary data from 14 patients treated with prophylactic tocilizumab prior to teclistamab were presented at ASCO 2023, suggested reduced CRS risk and no new safety signals (van de Donk et al. J Clin Oncol). We were motivated to administer a single dose prophylactic tocilizumab prior to the first teclistamab step-up dose in a real-world setting including 31 patients. Methods: This single-center study includes all RRMM patients treated with teclistamab in the real-world setting at the University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center between FDA approval (October 25, 2022) and data cutoff (July 21, 2023). Patients were prospectively followed for safety and efficacy outcomes. The primary aim was to investigate the effect on CRS which was assessed by the standard Lee ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Other adverse events were graded according to CTCAE V5.0. P-values were calculated using Fisher's exact test. Results: At the time of data cutoff 31 patients had received teclistamab. The median age was 71 (range 50-84) and 10 (32%) patients were 75 or older. Nine (29%) patients were black and eight (26%) were Hispanic ethnicity. A total of 24 (77%) patients had extramedullary disease, 17 (55%; p<0.01) of which had soft tissue plasmacytomas. Twenty-six (84%) met at least one exclusion criteria for the MAJESTEC-1 trial. In this population we observed a low rate of CRS (13%: binomial 95%CI 4%-30%; p<0.01) and ICANS (10%: 2%-26%); CRS was limited to grade 1 and there was 1 episode of grade 2 neurotoxicity. IgG <400 mg/dL occurred in 21 (68%) of the patients and documented infections occurred in eight (26%) of patients. Neutropenia was observed in 27 (87%) patients, including 20 (65%) with Grade 3 or higher. Among 30 patients with secretory disease, the best overall response rate (ORR) was 15/30 (50%: 31%-69%). Based on standard response criteria, we found 9 (30%: 15%-49%) complete response, 4 (13%: 4%-31%) partial response, 11 (37%: 20%-56%) stable disease, and 4 (13%: 4%-31%) progressive disease. Median follow-up was 109 days (range 9-225) and median duration of response was not reached. At time of data cutoff, 17 (55%) of patients were currently receiving teclistamab therapy. Conclusions: Our findings suggest that tocilizumab may be effective as a preventative, rather than reactive, measure for patients treated with teclistamab. Larger studies are needed to confirm and expand on our results.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Whole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and ...causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined.
In this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis.
Ninety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs.
Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis.
The changing landscape of treatment options for multiple myeloma has led to a higher proportion of patients achieving deep, long-lasting responses to therapy. With the associated improvement in ...overall survival, the development of subsequent second malignancies has become of increased significance. The risk of second malignancy after multiple myeloma is affected by a combination of patient-, disease- and therapy-related risk factors. This review discusses recent data refining our knowledge of these contributing factors, including current treatment modalities which increase risk (i.e. high-dose melphalan with autologous stem cell transplant and lenalidomide maintenance therapy). We highlight emerging data towards individualized risk- and response-adapted treatment strategies and discuss key areas requiring future research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to treatment of less complex, susceptible ...disease or inaccuracy in clinical definition of cases entered.
Here, we interrogated whole genome and whole exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480, NCT02279394).
We reveal that the genomic landscape of treated HR-SMM is generally simple as compared to Newly Diagnosed (ND)MM counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease.
Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy.
Therapy-related myeloid neoplasms (t-MN) account for approximately 10–15% of all myeloid neoplasms and are associated with poor prognosis. Genomic characterization of t-MN to date has been limited in ...comparison to the considerable sequencing efforts performed for de novo myeloid neoplasms. Until recently, targeted deep sequencing (TDS) or whole exome sequencing (WES) have been the primary technologies utilized and thus limited the ability to explore the landscape of structural variants and mutational signatures. In the past decade, population-level studies have identified clonal hematopoiesis as a risk factor for the development of myeloid neoplasms. However, emerging research on clonal hematopoiesis as a risk factor for developing t-MN is evolving, and much is unknown about the progression of CH to t-MN. In this work, we will review the current knowledge of the genomic landscape of t-MN, discuss background knowledge of clonal hematopoiesis gained from studies of de novo myeloid neoplasms, and examine the recent literature studying the role of therapeutic selection of CH and its evolution under the effects of antineoplastic therapy. Finally, we will discuss the potential implications on current clinical practice and the areas of focus needed for future research into therapy-selected clonal hematopoiesis in myeloid neoplasms.
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•Therapy related myeloid neoplasms (t-MN) make up 10–20% of myeloid malignancies•Clonal hematopoiesis (CH) occurs at high frequency in t-MN•Whole genome sequencing characterizes complexity of t-MN genetic alterations•Triad of CH, chemotherapy selection and immune response contributes to t-MN
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We introduce a secure data-independent priority queue which supports polylogarithmic-time insertion operations and constant-time deletions and read-front (aka peek) operations as opposed to the ...originally introduced queue by Toft (PODC '11). Moreover, we minimize the number of comparisons required to perform different operations on Toft's priority queue. Data-independent data structures—first identified explicitly by Toft, and further elaborated by Mitchell and Zimmerman (STACS '14)—serve the purpose of computing on encrypted data without executing branching code which can be used to avoid prohibitively expensive operations in secure computation applications. Focusing on the costly sorting operations, we show significant asymptotic improvements over prior privacy preserving dark pool applications. Dark pools are securities-trading venues which attain ad-hoc order privacy, by matching orders outside of publicly visible exchanges via the so-called dark pool operators. In this paper, we describe an efficient and secure dark pool (implementing a full continuous double auction) based on our new priority queue. Our construction's security guarantees are cryptographic based on secure multiparty computation (MPC), and do not require that the dark pool operators are trusted. Our construction improves upon the asymptotic efficiency attained by previous efforts. Existing cryptographic dark pools process new orders in time which grows linearly in the size of the standing order book; ours does so in polylogarithmic time. We describe a concrete implementation of our MPC protocol with malicious security in the honest majority setting. We also report benchmarks of our implementation and compare them to prior works. Our protocol reduces the total running time by several orders of magnitude over prior secure dark pool solutions.
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