Citations

Targeting the main protease of SARS-CoV-2 Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al . identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice. —VV

Abstract In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10−5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

Abstract Photodynamic therapy (PDT) offers localized focal ablation in unresectable pancreatic tumors while tissues surrounding the treatment volume experience a lower light dose, termed photodynamic priming (PDP). While PDP does not cause tissue damage, it has been demonstrated to promote vascular permeability, improve drug delivery, alleviate tumor cell density, and reduce desmoplasia and the resultant internal pressure in pre-clinical evaluation. Preclinical data supports PDP as a neoadjuvant therapy beneficial to subsequent chemotherapy or immunotherapy, yet it is challenging to quantify PDP effects in clinical treatment without additional imaging and testing. This study investigated the potential of radiomic analysis using CT scans acquired before and after PDT to identify areas experiencing PDT-induced necrosis as well as quantify PDP effects in the surrounding tissues. A total of 235 CT tumor slices from seven patients undergoing PDT for pancreatic tumors were examined. Radiomic features assessed included intensity metrics (CT number in Hounsfield Units) and texture analysis using several gray-level co-occurrence matrix (GLCM) parameters. Pre-treatment scans of tumor areas that resulted in PDT-induced necrosis showed statistically significant differences in intensity and texture-based features that could be used to predict the regions that did respond (paired t-test, response versus no response, p < 0.001). Evaluation of PDP effects on the surrounding tissues also demonstrated statistically significant differences, in tumor mean value, standard deviation, and GLCM parameters of contrast, dissimilarity and homogeneity (t-test, pre versus post, p < 0.001). Using leave-one-out cross validation, six intensity and texture-based features were combined into a support-vector machine model which demonstrated reliable prediction of treatment effects for six out of seven patients (ROC curve, AUC = 0.93). This study provides pilot evidence that texture features extracted from CT scans could be utilized as an effective clinical diagnostic prediction and assessment of PDT and PDP effects in pancreatic tumors. (clinical trial NCT03033225)

Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.

Abstract Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET−) (P &lt; .0001). The median OS in the PET+ group was 46 months compared with 99 months in the PET− group (P &lt; .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.

Abstract Purpose: Structural variants (SV) of the MYC gene region are common in multiple myeloma and influence disease progression. However, the prognostic significance of different MYC SVs in multiple myeloma has not been clearly established. Experimental Design: We conducted a retrospective study of multiple myeloma comparing MYC SV subtypes identified by next-generation sequencing (NGS) and FISH to MYC expression and disease survival using 140 cases from Mayo Clinic and 658 cases from the MMRF CoMMpass study. Results: MYC SVs were found in 41% of cases and were classified into nine subtypes. A correlation between the presence of a MYC SV and increased MYC expression was identified. Among the nine MYC subtypes, the non-immunoglobulin (non-Ig) insertion subtype was independently associated with improved outcomes, while the Ig insertion subtype, specifically involving the IgL gene partner, was independently associated with poorer outcomes compared with other MYC SV subtypes. Although the FISH methodology failed to detect approximately 70% of all MYC SVs, those detected by FISH were associated with elevated MYC gene expression and poor outcomes suggesting a different pathogenic role for FISH-detected MYC subtypes compared with other MYC subtypes. Conclusions: Understanding the impact of different MYC SVs on disease outcome is necessary for the reliable interpretation of MYC SVs in multiple myeloma. NGS approaches should be considered as a replacement technique for a more comprehensive evaluation of the multiple myeloma clone.

Background: Noninvasive fractional flow measures with CT angiography (CTA) have revolutionized cardiology, yet the complex anatomy of the cerebral circulation and boundary conditions challenge the study of intracranial atherosclerosis. We developed a framework for systematic computational fluid dynamics (CFD) of middle cerebral artery (MCA) stenosis with CTA in SAMMPRIS. Methods: A 3D geometric mesh was generated from CTA source images, followed by CFD processing in Ansys (ICEM, CFX) on a Cray supercomputer. Reference boundary conditions were applied with an ICA inlet and outlets at the ACA and distal MCA to yield quantitative maps of intraluminal pressure drops (ΔP or fractional flow), blood flow velocity (V) and turbulent kinetic energy (TKE) with wall shear stress (WSS) mapped along the arteries. CFD parameters were then compared with SAMMPRIS angiography variables. Results: Of 451 SAMMPRIS (70-99% symptomatic stenosis) subjects, CTA was acquired at enrollment in 41 MCA cases. CFD results were successfully attained in 30, limited by anatomy (e.g. across branch points) in 7/11 and poor CTA resolution in 4/11. Fractional flow (ΔP) across stenosis was mean 0.64 ± SD 0.33, with maximal stenosis velocity of mean 192 ± SD 101 cm/s and maximal WSS 0.36 ± SD 0.25 mm Hg. SAMMPRIS angiography percent stenosis was unrelated to ΔP -0.163 (p=0.399), velocity 0.126 (p=0.514) or WSS 0.078 (p=0.689). Worse collateral blood flow grades were associated with larger ΔP (p=0.137), higher velocity (p=0.059), higher WSS (p=0.112). Asymmetric WSS with high and low regions on opposing arterial walls was measured in the post-stenotic segment in 25/30 (83%). TKE maps revealed focal increases in the post-stenotic region, yet not above abnormal thresholds based on arterial diameter. Conclusions: CTA CFD of intracranial atherosclerosis provides detailed noninvasive measures of hemodynamics.

Background: Tissue reperfusion is a critical determinant of outcomes after intra-arterial therapy (IAT). However, there is no standardized method for grading angiographic reperfusion. We sought to compare the two most commonly used reperfusion scales, TIMI and modified TICI (m-TICI), for predicting good long-term outcome following IAT. Methods: From a multicenter database, we evaluated acute stroke patients presenting with middle cerebral artery (MCA) M1 occlusions who underwent IAT. Clinical and angiographic data were collected. Reperfusion for each case was graded using the TIMI and m-TICI scales. The primary distinction between these scales is that partial reperfusion (TIMI 2) is sub-divided into minor (m-TICI 2A: <50%) and major (m-TICI 2B: 50-99%) grades in the m-TICI system. The performance of these scales for predicting a good 90-day outcome (mRS 0-2) was evaluated using the c-statistic. Results: There were 313 acute stroke patients with MCA M1 segment occlusions who underwent IAT at 6 academic centers; 171 (54.6%) were female. Mean age was 65.3±16.5 years. There were 157 (50.2%) right-sided strokes. Median baseline NIHSS score was 17 (IQR 15-20). Good outcome at 90 days was achieved in 32.5%. For predicting good outcome, the c-statistic was significantly higher for m-TICI (0.74 vs. 0.68; p<0.0001). The threshold that maximized predictive accuracy was m-TICI ≥2B (sensitivity 78%, specificity 65%; figure). Conclusions: The modified TICI scale is superior to the TIMI scale for predicting clinical outcome after IAT, and should be the standard tool for grading angiographic reperfusion. An m-TICI score ≥2B (≥50% reperfusion) is the optimal biomarker for successful reperfusion.