Citations

Abstract BACKGROUND Appropriate thrombus-device interaction is critical for recanalization. Histology can serve as a proxy for mechanical properties, and thus inform technique selection. OBJECTIVE To investigate the value of histologic characterization, we conducted a systematic review and meta-analysis on the relationship between thrombus histology and recanalization, technique, etiology, procedural efficiency, and imaging findings. METHODS In this meta-analysis, we identified studies published between March 2010 and March 2020 reporting findings related to the histologic composition of thrombi in large vessel occlusion stroke. Studies with at least 10 patients who underwent mechanical thrombectomy using stent retriever or aspiration were considered. Only studies in which retrieved thrombi were histologically processed were included. Patient-level data were requested when data could not be directly extracted. The primary outcome assessed was the relationship between thrombus histology and angiographic outcome. RESULTS A total of 22 studies encompassing 1623 patients met inclusion criteria. Clots associated with good angiographic outcome had higher red blood cell (RBC) content (mean difference [MD] 9.60%, 95% CI 3.85-15.34, P = .008). Thrombi retrieved by aspiration had less fibrin (MD −11.39, 95% CI −22.50 to −0.27, P = .046) than stent-retrieved thrombi. Fibrin/platelet-rich clots were associated with longer procedure times (MD 13.20, 95% CI 1.30-25.10, P = .037). Hyperdense artery sign was associated with higher RBC content (MD 14.17%, 95% CI 3.07-25.27, P = .027). No relationship was found between composition and etiology. CONCLUSION RBC-rich thrombi were associated with better recanalization outcomes and shorter procedure times, suggesting that preinterventional compositional characterization may yield important prognostic and therapeutic guidance.

Abstract Primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved‐site radiation therapy (ISRT) is considered standard front‐line therapy. Over‐expression of PD‐L1/PD‐L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan–Meier method, we calculated progression‐free survival, duration of response, and overall survival in patients who received front‐line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R‐CHOP plus ISRT was 58 months (95% CI: 18–112) compared to 14 months (95% CI: 5–not reached; p = 0.04) in those treated with R‐CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4–not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4–26]. R‐CHOP with ISRT had a significantly longer median PFS compared to R‐CHOP without ISRT as front‐line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre‐treated patients was observed in this study.

With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2-SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4-SE post-chest radiotherapy and chemotherapy (SERA); 5-Artificial intelligence SE evaluation (AI-SEE); 6-Environmental stress echocardiography and air pollution (ESTER); 7-SE in repaired Tetralogy of Fallot (SETOF); 8-SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10-SE for mitral ischemic regurgitation (SEMIR); 11-SE in valvular heart disease (SEVA); 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.

Background Using computed tomography angiography to differentiate between components of carotid atherosclerotic lesions remains largely elusive. This study sought to validate a semi-automated software for computed tomography angiography plaque analysis using histologic comparisons. Materials and Methods A retrospective review was performed of consecutive patients that underwent a carotid endarterectomy, with pre-procedural computed tomography angiography imaging of the cervical arterial vasculature available for review. Images were evaluated using a commercially-available software package, which produced segmented analyses of intraplaque components (e.g. intraplaque hemorrhage, lipid-rich necrotic core, and calcifications). On imaging, each component was assessed in terms of its (1) presence or absence, and (2) both volume and proportion of the total plaque volume (if present). On histological evaluation of carotid endarterectomy specimens, each component was evaluated as an estimated proportion of total plaque volume. Results Of 80 included patients, 30 (37.5%) were female. The average age was 69.7 years (SD = 9.1). Based on imaging, intraplaque hemorrhage was the smallest contributor to plaque composition (1.2% of volumes on average). Statistically significant linear associations were noted between the proportion of intraplaque hemorrhage, lipid-rich necrotic core, and calcifications on histology and the volume of each component on imaging ( p values ranged from 0.0008 to 0.01). Area under curve were poor for intraplaque hemorrhage and lipid-rich necrotic core (0.59 and 0.61, respectively) and acceptable for calcifications (0.73). Conclusion Semi-automated analyses of computed tomography angiography have limited diagnostic accuracy in the detection of intraplaque hemorrhage and lipid-rich necrotic core in carotid artery plaques. However, volumetric imaging measurements of different components corresponded with histologic analysis.

Abstract Aims The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis. Methods Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia. Conclusions These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Abstract Study question Does the selection of blastocysts for single embryo transfer, through the diagnosis of aneuploidy, improves the live birth rate in patients undergoing in vitro fertilization? Summary answer There seems to be no statistical difference in live birth rates between embryos with preimplantational genetic diagnosis (PGD) and those without. What is known already: Initial reports indicate that reproductive results improve after the selection of embryos to be transfer after performing a biopsy of the blastomeres, or trophectoderm cells, with the subsequent comprehensive analysis of the chromosomes. However, these results are now questioned. Reports in the literature are contrasting, so the real utility of selecting all embryos through comprehensive chromosome analysis calls for a more careful analysis that compares the risks, costs, and benefits of these techniques and their actual utility in reproductive results of patients treated with in vitro fertilization. Specifically results related to live birth rate. Study design, size, duration A systematic review of prospective studies evaluating live birth rate after embryo transfer of embryos selected by blastocyst biopsy for aneuploidy analysis compared with reproductive outcomes in embryo transfers of embryos selected morphologically, without biopsy nor screening for aneuploidies. Participants/materials, setting, methods A literature search was performed in PubMed, EmBase, and the Cochrane library (from January 2000 to december 2019). A cumulative meta-analysis and evaluation of heterogeneity was performed for the clinical pregnancy rate. The quality of the included studies was assessed using Cochrane’s Risk of Bias tool and ROBINS I for observational studies Main results and the role of chance Seven studies were included, three were randomized controlled trials and four were non-randomized studies of intervention (NRSI). The included studies were published between 2013 and 2019. For the preimplantational genetic diagnosis, three studies used array comparative genomic hybridization, three studies used next generation sequencing and only one study used qPCR. A total of 1638 patients were included, only two studies excluded patients with advanced maternal age (>35 years), two studies studied patients with recurrent implantation failure and three studies patients with recurrent pregnancy loss. Regarding the assisted reproduction techniques (ART), only studies where embryos where biopsied after day five for the genetic diagnosis where considered, most used ICSI and performed frozen-thawed transfer of up to two embryos, only one study allowed patients to be transferred with more than two embryos per cycle. Reproductive outcomes (live birth rate, miscarriage rate, clinical pregnancy) were extracted considering the events per embryo transfer and calculating the pooled odds ratios (OR) with 95% confidence intervals (95%CI) as our main outcome, sensitivity analyses will be performed using the events per cycles to assess the robustness of the effect estimate. Preliminary meta-analyses resulted in a pooled OR of 1.45 (95%CI 0.24–8.78) for NRSI and 1.34 (95%CI 0.85–2.11) for RCT. Limitations, reasons for caution The main limitation was the quantity of studies with acceptable methodology. This generated heterogeneity, hindering the evaluation of the true impact of PGD in ART outcomes. The use of events per embryo transfer as a main outcome could bias the results favoring PGD as less embryos are usually transferred. Wider implications of the findings: Our results show that there are too few studies with adequate methodology to generate a conclusion about the true benefit of PGD. However, a slight tendency favoring the reproductive outcomes of PGD was found. Trial registration number PROSPERO CRD42020198866

Study Design: Retrospective cohort study. Objective: The influence that race has on mortality rates in patients with spinal cord tumors is relatively unknown. The aim of this study was to investigate the influence of race on the outcomes of patients with primary malignant or nonmalignant tumors of the spinal cord or spinal meninges. Methods: The Surveillance, Epidemiology, and End Results (SEER) Registry was used to identify all patients with a code for primary malignant or nonmalignant tumor of the spinal cord (C72.0) or spinal meninges (C70.1) from 1973 through 2016. Racial groups (African-American/Black vs. White) were balanced using propensity-score (PS) matching using a non-parsimonious 1:1 nearest neighbor matching algorithm. Overall survival (OS) estimates were obtained using the Kaplan-Meier method and compared across non-PS-matched and PS-matched groups using log-rank tests. Associations of survival with clinical variables was assessed using doubly robust Cox proportional-hazards (CPH) regression analysis. Results: There were a total of 7,498 patients identified with 648 (6.8%) being African American. African-American patients with primary intradural spine tumors were more likely to die of all causes than were White patients in both the non-PS-matched [HR: 1.26, 95% CI: (1.04, 1.51), P = 0.01] and PS-matched cohorts [HR: 1.64, 95% CI: (1.28, 2.11), P < 0.0001]. On multivariate CPH regression analysis age at diagnosis [HR: 1.03, 95% CI: (1.02, 1.05), P < 0.0001], race [HR: 1.82, 95% CI: (1.22, 2.74), P = 0.004), and receipt of RT [HR: 2.62, 95% CI: (1.56, 4.37), P = 0.0002) were all significantly associated with all-cause mortality, when controlling for other demographic, tumor, and treatment variables. Conclusions: Our study provides population-based estimates of the prognosis for patients with primary malignant or nonmalignant tumors of the spinal cord or spinal meninges and suggests that race may impact all-cause mortality.

Abstract Background: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer (NSCLC). Methods: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial NGS panel in liquid biopsy.Results: There were ten males (66.7%), and the median patient’s age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival (OS) of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate (ORR) was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.Conclusions: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

There has been growing interest and insight into the histological composition of retrieved stroke emboli. One of the main focuses of the stroke clot analysis literature has been the implications of clot composition on mechanical thrombectomy procedures. However, the holy grail of clot analysis may not be in the field of clot–device interaction, but rather, in understanding mechanisms of fibrinolysis resistance. The mechanisms underlying the low response to fibrinolytic therapy, even with the newer, more powerful agents, remain poorly understood. While factors such as embolus size, location and collateral status influence alteplase delivery and recanalisation rates; compositional analyses focused on histological and ultrastructural characteristics offer unique insights into mechanisms of alteplase resistance. In this review, we strive to provide comprehensive review of current knowledge on clot composition and ultrastructural analyses that help explain resistance to fibrinolysis.