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Abstract Background: ABO blood group is associated with pancreatic cancer risk. Whether ABO blood group alone or when combined with inherited mutation status of index pancreatic cancer cases (probands) can enhance pancreatic cancer risk estimation in first-degree relatives (FDR) is unclear. We examined FDRs' risk for pancreatic cancer based on probands' ABO blood group and probands' cancer susceptibility gene mutation status. Methods: Data on 23,739 FDRs, identified through 3,268 pancreatic cancer probands, were analyzed. Probands' ABO blood groups were determined serologically or genetically, and 20 cancer susceptibility genes were used to classify probands as “mutation-positive” or “mutation-negative.” SIRs and 95% confidence intervals (CI) were calculated, comparing observed pancreatic cancer cases in the FDRs with the number expected in SEER-21 (reference population). Results: Overall, FDRs had 2-fold risk of pancreatic cancer (SIR = 2.00; 95% CI = 1.79–2.22). Pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.80; 95% CI = 2.81–5.02) than mutation-negative (SIR = 1.79; 95% CI = 1.57–2.04) probands (P < 0.001). The magnitude of risk did not differ by ABO blood group alone (SIRblood-group-O = 1.57; 95% CI = 1.20–2.03, SIRnon-O = 1.83; 95% CI = 1.53–2.17; P = 0.33). Among FDRs of probands with non-O blood group, pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.98; 95% CI = 2.62–5.80) than mutation-negative (SIR = 1.66; 95% CI = 1.35–2.03) probands (P < 0.001), but risk magnitudes were statistically similar when probands had blood group O (SIRmutation-positive = 2.65; 95% CI = 1.09–5.47, SIRmutation-negative = 1.48; 95% CI = 1.06–5.47; P = 0.16). Conclusions: There is a range of pancreatic cancer risk to FDRs according to probands' germline mutation status and ABO blood group, ranging from 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive. Impact: Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3) 2/3 × (6.106/[V T2 1/1 − V T1 1/1 ]) 2 , where V T2 and V T1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

Abstract IntroductionRadiotherapy is considered standard of care for adjuvant peri-operative treatment of many spinal tumors, including those with instrumented fusion. Unfortunately, radiation treatment has been linked to increased risk of pseudoarthrosis. Newerfocused radiotherapy strategies with enhanced conformalitycould offer improved fusion rates for these patients, but this has not been confirmed.MethodsWe performed a retrospective analysis of patients at three tertiary care academic institutions withprimary and secondary spinal malignancies that underwent resection, instrumented fusion, and peri-operative radiotherapy. Two board certified neuro-radiologists used theLenke fusion score to grade fusion status at6 and 12-months after surgery. Secondary outcomes includedclinical pseudoarthrosis, wound complications, and the effect of radiation timing, radiobiological dose delivered, the use of photons versus protons, tumor type, tumor location,and use of autograft on fusion outcomes.ResultsAfter reviewof 1252 spinal tumor patients, there were 60 patients with at least 6 months follow-up that were included in our analyses. Twenty-five of these patients received focused radiotherapy,20 patients received conventional radiotherapy, and 15 patients were treated with protons. There was no significant difference between the groups for covariates such assmoking status,obesity, diabetes, intraoperative use of autograft, and use of peri-operative chemotherapy. There was a significantly higher rate of fusion for patients treated with focused radiotherapy compared to those treated with conventional radiotherapy at 6-months (64.0% versus 30.0%, Odds ratio: 4.15, p=0.036) and 12-months (80.0% versus 42.1%, OR: 5.50, p=0.022). There was a significantly higher rate of clinical pseudoarthrosis in the conventional radiotherapy cohortcompared to patients in the focused radiotherapy cohort (19.1% versus 0%,p=0.037). There was no difference in fusion outcomes for any of the secondary outcomes except for use of autograft. The use ofintra-operative autograft was associated with an improved fusion at 12-months (66.7% versus 37.5%, OR: 3.33, p=0.043). ConclusionFocused radiotherapy may be associated withan improved rate of fusion and clinical pseudoarthrosis when compared to conventional radiation delivery strategiesin patients with spinal tumors.Use of autograft at the time of surgery may be associated with improved 12-month fusion rates.Further large-scale prospective and randomized controlled studies are needed to better stratify the effects of radiation delivery modality in these patients.

Small-molecule recruitment of an endogenous nuclease rescues pathologies associated with c9ALS/FTD in vivo by targeting an RNA repeat expansion.

Abstract Background The aim of the Subcutaneous ICD Combined with Ventricular Tachycardia Ablation (SICD-VTAbl) Study is to provide preliminary data on the safety and efficacy of a management strategy that incorporates S-ICD implantation and VT ablation among patients with a secondary prevention indication for an ICD. We hypothesize that VT ablation for the prevention of monomorphic VT recurrence combined with S-ICD implantation for termination of life-threatening VT/VF is safe, while reducing the need for device interventions and systemic complications associated with conventional transvenous ICD implantation for secondary prevention. Methods SICD-VTAbl is an uncontrolled, prospective, multinational observational study, conducted in France, Germany, US (Rochester NY, and Rochester MN) and coordinated in Israel. We aim to prospectively enroll 30 patients presenting with scar-related VT/VF who will undergo VT ablation/substrate modification followed by S-ICD implantation. The primary endpoint is the first occurrence of S-ICD therapy (appropriate and inappropriate). Secondary endpoints include separate occurrence of appropriate and inappropriate ICD therapies, peri-procedural complications, and adverse clinical outcomes. Results We provide clinical, arrhythmia, and outcome data on the first 15 patients enrolled in the SICD-VTAbl Study through February 2021. Mean age was 59±12 years, 78% were males, 60% had New York Heart Association (NYHA) Class ≥II symptoms, 20% had renal insufficiency, and 33% were treated with an antiarrhythmic medication (all amiodarone). Periprocedural, arrhythmia, and long-term outcome data are provided in Table 1. There were no major complications associated with the VT ablation and the S-ICD implantation procedures. During a median follow-up of 6 months (interquartile range: 2–12 months), 2 patients (13%) received S-ICD therapy: one patient (7%) experienced VF terminated by the S-ICD and one patient experienced a single episode of inappropriate S-ICD therapy. Adverse events during follow-up, unrelated to study procedures, occurred in 3 patients (20%): hospitalization for heart failure exacerbation (N=1) and non-cardiovascular hospitalizations (N=2). None of the patients died during follow-up (Table 1). Conclusions Our preliminary data from the SICD-VTAbl Study suggest that a management approach that incorporates VT ablation followed by S-ICD implantation is safe and may lead to improved arrhythmia and clinical outcomes in patients presenting with a secondary prevention indication for an ICD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Research grant to Sheba Medical Center from Boston Scientific

Abstract The detection of recurrent genetic abnormalities in acute myeloid leukemia (AML), including RUNX1T1/RUNX1 gene fusion, is critical for optimal medical management. Herein, we report a 45 year old woman with newly diagnosed AML and conventional chromosome studies that revealed an apparently balanced t(8;20)(q22;p13) in all 20 metaphases analyzed. A RUNX1T1/RUNX1 dual-color dual-fusion fluorescence in situ hybridization (FISH) probe set was subsequently performed and revealed a RUNX1T1/RUNX1 gene fusion. Metaphase FISH studies performed on abnormal metaphases revealed a cryptic, complex translocation resulting in RUNX1T1/RUNX1 fusion, t(8;20;21)(q22;p13;q22). This case study shows the importance of performing FISH studies or other high-resolution genetic testing concurrently with conventional chromosome studies for the detection of cryptic recurrent gene fusions in AML, particularly a focused genetic evaluation such as RUNX1T1/RUNX1 gene fusion, when specific abnormalities involving 8q22 are identified.

OBJECTIVE The authors’ objective was to reevaluate the role of microsurgery for epidermoid tumors by examining the associations between extent of resection (EOR), tumor control, and clinical outcomes. METHODS This was a retrospective study of patients with microsurgically treated intracranial epidermoid tumors. The recurrence-free and intervention-free rates were calculated using the Kaplan-Meier method. EOR was graded as gross-total resection (GTR) (total resection without residual on MRI), near-total resection (NTR) (a cyst lining was left in place), subtotal resection (STR) (> 90% resection), and partial resection (PR) (any other suboptimal resection) and used to stratify outcomes. RESULTS Sixty-three patients with mean clinical and radiological follow-up periods of 87.3 and 81.8 months, respectively, were included. Sixteen patients underwent second resections, and 5 underwent third resections. The rates of GTR/NTR, STR, and PR were 43%, 35%, and 22%, respectively, for the initial resections; 44%, 13%, and 44% for the second resections; and 40%, 0%, and 60% for the third resections (p < 0.001). The 5- and 10-year cumulative recurrence-free rates after initial resection were 64% and 32%, respectively. When stratified according to EOR, the 10-year recurrence-free rate after GTR/NTR was marginally better than that after STR (61% vs 35%, p = 0.130) and significantly better than that after PR (61% vs 0%, p < 0.001). The recurrence-free rates after initial microsurgery were marginally better than those after second surgery (p = 0.102) and third surgery (p = 0.065). The 5- and 10-year cumulative intervention-free rates after initial resection were 91% and 58%, respectively. When stratified according to EOR, the 10-year intervention-free rate after GTR/NTR was significantly better than that after STR (100% vs 51%, p = 0.022) and PR (100% vs 27%, p < 0.001). The 5-year intervention-free rate after initial surgery was marginally better than that after second surgery (52%, p = 0.088) and significantly better than that after third surgery (0%, p = 0.004). After initial, second, and third resections, permanent neurological complications were observed in 6 (10%), 1 (6%), and 1 (20%) patients, respectively. At the last follow-up visit, 82%, 23%, and 7% of patients were free from radiological recurrence after GTR/NTR, STR, and PR as the initial surgical procedure, respectively. CONCLUSIONS GTR/NTR seems to contribute to better disease control without significantly impairing functional status. Initial resection offers the best chance to achieve better EOR, leading to better disease control.

Background Relationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes. Methods Prospective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation. Results Up to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality. Conclusions The EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings. Trial registration number NCT03685578 .

The composition of ischemic stroke thrombi has gained an increasing amount of interest in recent years. The implementation of endovascular procedures in standard stroke care has granted researchers the unique opportunity to examine patient thrombus material. Increasing evidence indicates that stroke thrombi are complex and heterogenous, consisting of various biochemical (eg, fibrin, von Willebrand Factor, and neutrophil extracellular traps) and cellular (eg, red blood cells, platelets, leukocytes, and bacteria) components. This complex composition may explain therapeutic limitations and also offer novel insights in several aspects of stroke management. Better understanding of thrombus characteristics could, therefore, potentially lead to improvements in the management of patients with stroke. In this review, we provide a comprehensive overview of the lessons learned by examining stroke thrombus composition after endovascular thrombectomy and its potential relevance for thrombectomy success rates, thrombolysis, clinical outcomes, stroke etiology, and radiological imaging.