Citations

Introduction: "Mild" stroke is not well defined, but is a relative contraindication for the administration of IV rtPA. Advances in telemedicine have allowed for specialized practitioners to observe the examination, rather than rely on the on-scene examiner. We investigated whether there were differences in rates of identification, treatment, and outcomes of mild stroke patients in the phone compared to the video arms of a telestroke network. Methods: The STRokE DOC trials were prospective, randomized, outcome-blinded trials comparing video telemedicine to phone-only evaluations, which assessed eligibility for IV rtPA and correctness of decision-making for 2 hubs and 6 spokes. This analysis included all adult acute ischemic stroke patients from the STRokE DOC trials who were defined as “mild” using a recent definition from the TREAT Task Force. Rates of ICH, mortality, and dichotomized 90-day mRS scores were compared between the video and phone arms. Results: Mild stroke accounted for 32% and 29% of the video and phone arms, respectively. The two groups had similar baseline characteristics except hypertension (higher rate in video arm). Of the video mild stroke patients, 13% had poor outcome (mRS>1) compared to 24% of the phone arm (p=0.45). There were no symptomatic ICH or deaths. Among IV rtPA treated mild stroke patients, all of the video arm had good outcome, versus 25% of the phone arm. Of 100 non-treated patients, 34 were excluded because of "too mild" a deficit (TMT). In the phone arm, 7 of these did not meet the TREAT-derived criteria for mild stroke (p=0.03). One TMT patient in the phone arm had poor outcome. Conclusions: Mild stroke made up a third of the patients in each group. Some TMT patients in the phone arm did not meet the criteria for mild stroke; their subtle findings may not have been conveyed adequately over the phone. Among IV rtPA treated patients, the phone arm had worse outcomes. The results raise concern regarding accuracy of predicting outcomes for mild stroke patients, especially when based on a phone description. The study numbers were small, so conclusions cannot be definitively made. Future studies are necessary to determine decision making factors within the telemedicine process that influence treatment outcomes among mild stroke patients.

Introduction: Cross-sectional studies in patient with hypertensive heart disease (HHD) and heart failure with normal ejection fraction (HFnlEF) suggested impairment of longitudinal myocardial mechanics as assessed by tissue Doppler imaging. It has been suggested that enhanced circumferential, and/or radial LV mechanics or LV remodeling compensates for depression in longitudinal function and thus, preserves EF in HHD or HFnlEF. Hypothesis : We hypothesized that if longitudinal performance is depressed, whether due to increased afterload or to intrinsic myocardial dysfunction, circumferential and radial LV mechanics would also be effected. To test this hypothesis, we used an aged canine model of hypertension. Methods: Elderly dogs (n=22) underwent bilateral renal wrapping to induce hypertension. 2D echocardiography (mid-short axis views) was performed before and 8 weeks after renal wrapping; peak radial (PR) and peak circumferential (PC) regional strains were measured by speckle tracking averaging data from 6 segments. Ejection fraction (EF), LV mass index (LVMI), systolic blood pressure (SBP), and circumferential wall stress (CWS) were assessed as well. Results : See table . PR correlated with PC (r=0.65), EF (r=0.67), LWMI (r=0.71) and CWS (r=0.58) (p<0.005 for all). PC correlated also with EF (r=0.60), LWMI (r=0.49) and CWS (r=0.48) (p<0.01 for all). The relationship between EF and CWS (r 2 =0.64, p<0.001) was modified by the addition of either PC (r 2 =0.74, p for PC =0.005) or PR strain(r 2 =0.69, p for PR =0.04). Conclusions : These data show that development of hypertension with LV hypertrophy does not enhance but impairs circumferential and radial LV mechanics as assessed with strain imaging, and that like EF, circumferential and radial strain are related to afterload (wall stress). However, both confer additional information regarding contractility. Conclusions regarding myocardial function based on strain imaging must account for its load dependence.

Coronary microvascular dysfunction (CMD) is an important primary feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and ventricular remodelling, and is predictive of adverse outcome. Whether there is any association between presence/severity of CMD and HCM’s pathogenic substrate remains to be determined. To address this issue, we used positron emission tomography (PET) to assess CMD in an HCM cohort that received comprehensive genetic testing for sarcomeric/myofilament-HCM. We measured maximum (intravenous dipyridamole, 0.56 mg/kg) myocardial blood flow (Dip-MBF), using 13 N-labeled ammonia and PET in 46 HCM patients (age 38±14 years, 32 male). Genetic testing was performed by denaturing high performance liquid chromatography and automatic DNA sequencing of nine myofilament-encoding genes including both thick filament proteins (myosin binding protein C, beta-myosin heavy chain, regulatory and essential light chains); and thin filament proteins (troponin-T, troponin-I, troponin-C, alpha-tropomyosin and alpha-actin). Results . Thirty-four mutations were identified in 30/46 patients (myofilament-HCM; 65%), including 29 with thick filament and 6 with thin filament mutations, as well as 4 with complex genotype. Despite similar age and clinical features, patients with myofilament-HCM showed lower Dip-MBF values than the patients with a negative genetic test (1.6±0.7 versus 2.2±0.9 ml/min/g, respectively; p=0.03). Specifically, 13/30 (43%) patients with myofilament-HCM had a Dip-MBF below the lower tertile for the study group (≤1.38 ml/min/g), compared to 2/16 (12%) patients with a negative genetic test (p=0.034). No difference in Dip-MBF was evident with respect to the particular sarcomeric gene involved (ANOVA p=0.63). HCM due to sarcomere gene mutations is characterized by more severe impairment in microvascular function compared to myofilament negative disease, irrespective of the involved contractile protein. These findings suggest that sarcomeric mutations might be implicated in adverse remodelling of the microcirculation in patients with HCM, and account for the greater prevalence of ventricular dysfunction and failure in this subset.

Introduction: Small vessel disease is associated with decreased cognitive function, possibly differential by race. Age-related central arterial stiffening increases pulsatility resulting in hypoperfusion, microvascular damage and remodeling in the brain, potentially impairing cognition. We examined if arterial stiffness and pressure amplification are associated with lacunar infarcts and greater volumes of white matter hyperintensities (WMH) in a sample of Caucasian and African American (AA) older adults. Methods: We analyzed a cross-sectional sample of ARIC participants aged 67-90 years (n=1486) from visit 5 (2011-2013), with brain magnetic resonance imaging (MRI). The Omron VP-1000 Plus was used to measure aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]) and pressure amplification measures (pulse pressure amplification [PPA], central pulse pressure [cPP], and estimated central systolic blood pressure [cSBP]). Aortic stiffness and pressure amplification were dichotomized at race-specific 25th percentile cut points. Brain MRI using 3D-1.5T equipment quantified the presence of lacunar infarcts and volumes of WMH following a standardized protocol. Logistic regression, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index, was used to quantify the odds of lacunar infarcts in participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Linear regression models, additionally adjusted for intracranial volume, estimated the difference in log-transformed volumes of WMH among participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Probability sampling weights for an MRI were included to allow for generalizability to the full visit 5 cohort. Results: Among the 1486 participants with a brain MRI (mean age: 76, 41% male, 26% AA), measures of aortic stiffness and pressure amplification were associated with lacunar infarcts in Caucasians, but not in AAs. Caucasian participants with a high cfPWV had greater odds of lacunar infarcts (Odds Ratio [OR] =2.02, 95% confidence interval [CI]: 1.23, 2.20). Caucasians with high cSBP had higher odds of lacunar infarcts (OR=1.72, 95% CI: 1.10, 2.69). In Caucasians, high cfPWV was associated with a 21% (95% CI: 6, 38) greater volume of WMH as compared to a low cfPWV; high cSBP was associated with a 28% (95% CI: 14, 45) greater volume of WMH compared to a low cSBP. In AAs, high cfPWV was associated with a 32% (95% CI: 7, 62) greater volume of WMH as compared to low cfPWV. Cerebral microvascular imaging markers did not differ quantitatively with measures of PPA and cPP. Conclusions: Central arterial stiffening and pressure amplification are plausible microvascular contributors to cognitive aging, providing new information on modifiable pathways for previously observed associations between cardiovascular disease risk factors and the rates of cognitive decline and dementia among older adults.

Introduction: Granulomatosis with polyangiitis (GPA) is a vasculitic process that can cause neurological dysfunction in addition to characteristic sinus and pulmonary manifestations. This case report highlights the spectrum of nervous system manifestations and includes rarely reported autonomic and pituitary involvement. Case Report: A 62-year-old woman presented with orthostatic intolerance, tachycardia, dry mouth, and temperature sensitivity; subsequent autonomic reflex study demonstrated widespread postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic impairment reflective of autonomic neuropathy and overall autonomic failure. Additional progressive symptoms included dysarthria, dysphagia, bilateral hearing loss, voice hoarseness, and right-sided facial numbness with multiple cranial neuropathies identified on neurological examination. The diagnosis of central diabetes insipidus was also confirmed. Pachymeningitis was present on brain magnetic resonance imaging. Pathologic review of the dural biopsy specimen revealed necrotizing granulomatous vasculitis consistent with GPA. She was treated with intravenous methylprednisolone and rituximab. Over the next 2 months, she had near-complete resolution of her symptoms with normalization on repeat autonomic testing. Conclusions: This is a unique GPA case presenting with autonomic failure and pituitary dysfunction with conclusive objective findings of autonomic dysfunction. Autonomic dysfunction and other disease manifestations were responsive to immunosuppressive therapy.

AbstractPlasma cell neoplasms (PCN) and mantle cell lymphoma (MCL) can both harbor t(11;14)(q13;q32) (CCND1/IGH), usually resulting in cyclin D1 overexpression. In some cases, particularly at low levels of disease, it can be morphologically challenging to distinguish between these entities in the bone marrow (BM) since PCN with t(11;14) are often CD20‐positive with lymphoplasmacytic cytology, while MCL can rarely have plasmacytic differentiation. We compared the difference in CCND1/IGH by fluorescence in situ hybridization (FISH) in PCN and MCL to evaluate for possible differentiating characteristics. We identified 326 cases of MCL with t(11;14) and 279 cases of PCN with t(11;14) from either formalin‐fixed, paraffin‐embedded tissue or fresh BM specimens. The “typical,” balanced CCND1/IGH FISH signal pattern was defined as three total CCND1 signals, three total IGH signals, and two total fusion signals. Any deviation from the “typical” pattern was defined as an “atypical” pattern, which was further stratified into “gain of fusion” vs “complex” patterns. There was a significantly higher proportion of cases that showed an atypical FISH pattern in PCN compared with MCL (53% vs 27%, P < .0001). There was also a significantly higher proportion of cases that showed a complex FISH pattern in PCN compared with MCL (47% vs 17%, P < .0001). We confirmed these findings using mate‐pair sequencing of 25 PCN and MCL samples. PCN more often have a complex CCND1/IGH FISH pattern compared with MCL, suggesting possible differences in the genomic mechanisms underlying these rearrangements in plasma cells compared with B cells.

OBJECTIVE The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR). METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed. RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234). CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

OBJECTIVES: Investigate the challenges experienced by survivors of critical illness and their caregivers across the transitions of care from intensive care to community, and the potential problem-solving strategies used to navigate these challenges. DESIGN: Qualitative design—data generation via interviews and data analysis via the framework analysis method. SETTING: Patients and caregivers from three continents, identified through the Society of Critical Care Medicine’s THRIVE international collaborative sites (follow-up clinics and peer support groups). SUBJECTS: Patients and caregivers following critical illness. INTERVENTIONS: Nil MEASUREMENTS AND MAIN RESULTS: From 86 interviews (66 patients, 20 caregivers), we identified the following major themes: 1) Challenges for patients—interacting with the health system and gaps in care; managing others’ expectations of illness and recovery. 2) Challenges for caregivers—health system shortfalls and inadequate communication; lack of support for caregivers. 3) Patient and caregiver-driven problem solving across the transitions of care—personal attributes, resources, and initiative; receiving support and helping others; and acceptance. CONCLUSIONS: Survivors and caregivers experienced a range of challenges across the transitions of care. There were distinct and contrasting themes related to the caregiver experience. Survivors and caregivers used comparable problem-solving strategies to navigate the challenges encountered across the transitions of care.

8023 Background: MGTA-145 (GroβT), a CXCR2 agonist, has shown promising activity for HSC mobilization with plerixafor in pre-clinical models and healthy volunteers. Methods: This phase 2 single center study evaluates HSC mobilization with MGTA-145 + plerixafor and same day apheresis in patients with multiple myeloma. Patients received plerixafor 0.24 mg/kg (0.16 mg/kg if renal dysfunction) SQ, followed 2 hours later by MGTA-145 (0.03 mg/kg) IV over 3-10 minutes and apheresis within 30 minutes. Mobilization was repeated for a second day if day 1 yield was < 6 x 106 CD34+ cells/kg. This interim analysis reports on mobilization in 10 patients (of 25 planned), including safety cohort of first 6 patients completing transplant. Primary endpoint is collection of 2 x 106 CD34+ cells/kg. Results: Median age was 63 years (range: 46-68), 50% were female, 22% had ISS stage 3 & 50% had high-risk FISH. Induction therapy was VRD in 7 and daratumumab + VRD in 3 patients; median induction duration: 4 months (3-6) & median lenalidomide exposure: 6 cycles (4-6), with > VGPR in 70%. Median total stem cell yield (CD34+ cells/kg x 106) was 7.1 (3-16.2), day 1 yield was 5.4 (1.1-16.2) & yield per apheresis session was 4 (1.1-16.2). 100% of patients met the primary endpoint of collecting sufficient HSCs in < 2 days of mobilization + apheresis to proceed to transplant (2 x 106 CD34+ cells/kg). Secondary endpoints of 4 and 6 x 106 CD34+ cells/kg in < 2 days were met in 90% & 80% patients. 30% patients underwent 1 apheresis, while 70% underwent 2 sessions. MGTA-145 was well tolerated. At least 1 adverse event (AE) was seen in 90% of patients, 20% had grade 2 AEs (anemia, hypokalemia) and 20% had grade 3 AEs (worsening of baseline grade 3 anemia; hypocalcemia); all resolved. Acute & transient bone pain was seen in 40% of patients (back-2, hip-1, sternum-1), all grade 1, all on day 1, & resolved without intervention after 6 minutes (3-10). All 6 patients in the safety cohort have completed transplant with melphalan 200 mg/m2. Median of 4.1 (3.4-5.6) x 106 CD34+ cells/kg were infused. All patients have engrafted timely (DiPersio Blood 2009); median time to neutrophil engraftment: 12 days (11-13) & platelet engraftment: 17 days (16-19). Apheresis graft analysis is available in these 6 patients. Grafts with MGTA-145+plerixafor showed high enrichment for CD90+CD45RA- among CD34+ cells, a CD34 subset of long term engrafting HSCs (median: 31% of CD34+ cells, 27-52), higher than seen with G-CSF (6%, Goncalves TCT 2021). 67% of grafts were minimal residual disease negative with next generation flow cytometry. Conclusions: This is the first study to evaluate the novel regimen of MGTA-145 + plerixafor for same day stem cell mobilization & collection in myeloma/hematologic malignancies, with 100% efficacy in interim analysis and the first to demonstrate successful engraftment in patients with cells collected with this GCSF free regimen. Clinical trial information: NCT04552743.