Citations

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease characterized by complement-mediated hemolysis. OPERA is the first US longitudinal real-world study on C3 inhibitor therapy, known as pegcetacoplan. Methods: OPERA enrolled US patients with PNH, age ≥18, who were prescribed pegcetacoplan, and data were collected from routine care. Hemoglobin was reported by patients during regular follow-up (censored from transfusions). The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (0–52 score) and Patient-Reported Outcomes Measurement Information System scale for Cognitive Function Abilities (PROMIS-CF; 23.27–67.09 t-score) were completed electronically (low score = negative outcome). Patients self-reported incidence of healthcare resource utilization (HCRU). Results: By January 2024, 70 patients (mean age 44.6 years; 57.1% female) reported up to 9 months of pegcetacoplan treatment, with a median [IQR] follow-up of 6.6 [3.8] months. The latest reported hemoglobin levels improved by a mean (SD) of 2.6 (1.9) g/dL from baseline. At 3, 6 and 9 months, patients reported clinically meaningful improvements (≥5 points) in FACIT-F (53.3–69.0%) and (≥2 points) PROMIS-CF (46.7–55.2%). Patients reported a <10% incidence rate per person month of all HCRU events. Conclusions: This first longitudinal real-world US study indicates a positive trend in Hb, fatigue, and cognition with limited HCRU during pegcetacoplan treatment in adults with PNH.

AbstractIntroductionAcute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.MethodsGiven the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next‐generation sequencing and mass spectrometry‐based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.ResultsWe identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein–RNA correlation.ConclusionTogether, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.

BACKGROUND AND OBJECTIVES: We aimed to develop and validate a prediction score for futile recanalization (FR) for large vessel occlusion (LVO) presenting low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) for patients who underwent endovascular thrombectomy (EVT). METHODS: Patients with anterior circulation LVO with low ASPECTS (<6) who underwent successful EVT (modified treatment in cerebral ischemia score ≥2b) from Stroke Thrombectomy and Aneurysm Registry were retrospectively analyzed. FR was defined as 90-day modified Rankin Scale (mRS) scores ≥4 despite successful EVT. Multivariable logistic regression was used to identify independent predictors of FR, and they were used to create a clinical score. The performance of the score was assessed by receiver operating characteristic curve analyses. RESULTS: Of 219 patients, 170 and 49 patients were randomly assigned to the training and validation cohort, respectively. Independent predictors of FR identified in the training cohort were used to construct the SNAP score: site of occlusion (middle cerebral artery = 0, internal carotid artery = 1), National Institutes of Health Stroke Scale score at admission (≤10 = 0, 10 to 19 = 1, ≥20 = 2), age (<75 = 0, ≥75 = 2), and prestroke mRS score (0-3). Receiver operating characteristic curve analyses of the SNAP score in the training and validation cohorts showed areas under the curve of 0.79 (95% CI 0.72-0.86) and 0.79 (95% CI 0.65-0.92) for predicting FR, respectively. A SNAP score ≥5 had a positive predictive value of 92.1% [95% CI 78.8%-97.3%] for FR. CONCLUSION: The SNAP score may be useful in predicting FR after EVT in low-ASPECTS patients with LVO. It can provide patients, family members, and physicians with reliable outcome expectations among patients with acute ischemic stroke with large infarcts.

AbstractINTRODUCTIONUnderstanding the relationship between amyloid beta (Aβ) positron emission tomography (PET) and Aβ cerebrospinal fluid (CSF) biomarkers will define their potential utility in Aβ treatment. Few population‐based or neuropathologic comparisons have been reported.METHODSParticipants 50+ years with Aβ PET and Aβ CSF biomarkers (phosphorylated tau [p‐tau]181/Aβ42, n = 505, and Aβ42/40, n = 54) were included from the Mayo Clinic Study on Aging. From these participants, an autopsy subgroup was identified (n = 47). The relationships of Aβ PET and Aβ CSF biomarkers were assessed cross‐sectionally in all participants and longitudinally in autopsy data.RESULTSCross‐sectionally, more participants were Aβ PET+ versus Aβ CSF− than Aβ PET− versus Aβ CSF+ with an incremental effect when using Aβ PET regions selected for early Aβ deposition. The sensitivity for the first detection of Thal phase ≥ 1 in longitudinal data was higher for Aβ PET (89%) than p‐tau181/Aβ42 (64%).DISCUSSIONAβ PET can detect earlier cortical Aβ deposition than Aβ CSF biomarkers. Aβ PET+ versus Aβ CSF− findings are several‐fold greater using regional Aβ PET analyses and in peri‐threshold‐standardized uptake value ratio participants.Highlights Amyloid beta (Aβ) positron emission tomography (PET) has greater sensitivity for Aβ deposition than Aβ cerebrospinal fluid (CSF) in early Aβ development. A population‐based sample of participants (n = 505) with PET and CSF tests was used. Cortical regions showing early Aβ on Aβ PET were also used in these analyses. Neuropathology was used to validate detection of Aβ by Aβ PET and Aβ CSF biomarkers.

Background A higher number of recanalization attempts reduces the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke secondary to large vessel occlusion (LVO). We assessed the impact of switching EVT techniques after a failed first pass on procedural and clinical outcomes. Methods This multicenter international study, conducted between January 2013 and December 2022, included patients undergoing EVT for anterior circulation LVO (internal carotid artery or M1 segments) with failed first pass recanalization. Propensity score matching identified a 1:1 matched cohort of patients in whom EVT technique was changed after a failed first pass and those with the same technique repeated. The primary outcome was successful recanalization at second attempt defined as Thrombolysis in Cerebral Ischemia (TICI) score of 2B or higher. Secondary outcomes were 90-day modified Rankin Score (mRS) and postprocedural hemorrhage. Results Among 2167 patients, converting to an alternative technique after a failed first pass was associated with higher odds of successful recanalization (adjusted OR (aOR)=1.5, p=0.041), and higher odds of mRS 0–2 at 90 days (aOR=1.6, p=0.005) without additional risk of symptomatic hemorrhage (p=0.379). Using a propensity score matched cohort of 490 patients, technique conversion at second attempt increased odds of successful recanalization at second attempt (aOR=1.32, p=0.006) and 90-day mRS 0–2 (aOR=1.38, p=0.008). Conclusions Early conversion to an alternative EVT technique after a failed first pass recanalization in patients with AIS is associated with better technical success and clinical outcomes.

Abstract Purpose To propose a clinically oriented quantitative metric, the HU coefficient, to evaluate contour quality, gauge the performance of auto contouring methods, and aid effective allocation of clinical resources. Materials and Methods Publicly available pelvic CT data from the Cancer Imaging Archive was used to demonstrate the clinical utility of the HU coefficient in contour evaluation. The bladder was selected as the organ of interest. It was contoured by a certified medical dosimetrist and reviewed by a certified medical physicist. This contour served as the ground truth contour. From this contour, we simulated two contour sets. The first set had the same Dice similarity coefficient (DSC) but different HU coefficients, whereas the second set kept a constant HU coefficient while exhibiting different DSCs. Four individuals were asked to adjust the simulated contours until they met clinical standards. The corresponding contour modification times were recorded and normalized by individual’s manual contouring times from scratch. The normalized contour modification time was correlated to the HU and DSC to evaluate their suitability as quantitative metrics assessing contour quality. Results The HU coefficient maintained a strong correlation with the normalized contour modification time when both sets of simulated contours were included in analysis. The correlation between the DSC and normalized contour modification time, however, was weak. Compared to DSC, HU is more suitable for evaluating contour quality. Conclusions We demonstrated that the HU coefficient correlated well with the average normalized contour modification time. Clinically, contour modification time is the most relevant factor in allocating clinical resources. Therefore, the HU coefficient is better suited than DSC to assess contour quality from a clinical perspective.