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AbstractBackground and purposeSeveral clinical and demographic factors relate to anatomic spread of adult‐onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult‐onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.MethodsAdult‐onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation (“dystonia‐only”) and one accepting dystonia OR tremor in any body part as disease manifestations (“dystonia OR tremor”). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.ResultsBoth predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62–0.70 and 0.62–0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.ConclusionsThis predictive modeling of spread in adult‐onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals’ risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

Abstract Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

Background While venous congestion in the peripheral vasculature has been described and accepted, intracranial venous congestion remains poorly understood. The characteristics, pathophysiology, and management of cerebral venous stasis, venous hypertension and venous congestion remain controversial, and a unifying conceptual schema is absent. The cerebral venous and lymphatic systems are part of a complex and dynamic interaction between the intracranial compartments, with interplay between the parenchyma, veins, arteries, cerebrospinal fluid, and recently characterized lymphatic-like systems in the brain. Each component contributes towards intracranial pressure, occupying space within the fixed calvarial volume. This article proposes a framework to consider conditions resulting in brain and neck venous congestion, and seeks to expedite further study of cerebral venous diagnoses, mechanisms, symptomatology, and treatments. Methods A multi-institution retrospective review was performed to identify unique patient cases, complemented with a published case series to assess a spectrum of disease states with components of venous congestion affecting the brain. These diseases were organized according to anatomical location and purported mechanisms. Outcomes of treatments were also analyzed. Illustrative cases were identified in the venous treatment databases of the authors. Conclusion This framework is the first clinically structured description of venous pathologies resulting in intracranial venous and cerebrospinal fluid hypertension. Our proposed system highlights unique clinical symptoms and features critical for appropriate diagnostic work-up and potential treatment. This novel schema allows clinicians effectively to approach cases of intracranial hypertension secondary to venous etiologies, and furthermore provides a framework by which researchers can better understand this developing area of cerebrovascular disease.

Introduction: Axial and centrifugal-flow left ventricular assist devices (LVAD) have varied response to changes in loading conditions. Whether ventricular size modulates the response to LVAD therapy between the axial flow Heartmate II (HMII) and centrifugal flow Heartware (HVAD) is unknown. Hypothesis: Adverse event and survival rates between devices are affected by recipient pre-op left ventricular end-diastolic diameter (LVEDD). Methods: Data on 1,149 continuous-flow LVAD recipients from May 2004 to May 2015 was pooled from the Mechanical Circulatory Support Research Network (MCSRN). The effect of pre-op LVEDD on the instantaneous hazard of death and adverse events was evaluated between HMII (n=864) and HVAD (n=283). Results: The average LVEDD was 7.0cm and did not differ between the device recipients. Patients with a smaller LVEDD (≤ 6.3cm) were more likely female 39% v. 24% (p < 0.0001) and to have an ischemic cardiomyopathy (30% v. 24%, p = 0.045). For every 1cm increase in pre-op LVEDD, the adjusted hazard ratio (HR) for mortality increased with HVAD (HR 1.31, 95% CI 0.94-1.82, p = 0.005) and decreased with HMII (HR 0.78, 95% CI 0.67-0.92, p = 0.005), Figure 1a. Other predictors of mortality included age (HR 1.31, 95% CI 1.12 - 1.53 per 10y, p < 0.001) and bilirubin (HR 1.15, 95% CI 0.94-1.42 per mg/dL, p = 0.027). LVEDD by device type interaction was not a significant predictor of gastrointestinal bleeding or pump thrombosis. The risk of stroke increased with LVEDD for HVAD and decreased for HMII, but this did not reach statistical significance, Figure 1b. Ischemic etiology of heart failure (HR 1.7 95% CI 1.14 - 2.55, p = 0.01) and HVAD device use (HR 1.47 95% CI 1.00 - 2.17, p = 0.03) were significant predictors of stroke. Conclusions: Our data suggest important differences exist in patient outcomes between HMII and HVAD based on pre-op ventricular size. Studies are needed to determine if these differences in outcome are due to device or flow-specific differences in patient support.

Background: Strain and strain rate has been shown to identify subtle contraction abnormalities of left ventricle. Objectives: We hypothesized that S and SR derived from velocity vector imaging (VVI) will allow early identification of global and regional RV systolic function in patients with pulmonary hypertension (PHT) compared to conventional echo parameters. Methods: 96 patients, 35 normal RV Systolic Pressure (RVSP < 30 mmHg) and 61 with PHT, {24 mild-moderate (RVSP > 60 mmHg) and 37 severe (RVSP < 60 mmHg)} underwent echo-Doppler assessment of RV. Apical 4 chamber images at end expiration were used for RV lateral wall (LW) and ventricular septal (VS) segment analysis for systolic tangential velocity (Ta V), S and SR. In addition RV end systolic and diastolic area, RV fractional area change (RV FAC), RV performance index (RIMP) and tricuspid annulus systolic excursion were measured. Results: Peak S, systolic SR and Ta V at the basal, mid and apical segments of the RV LW and VS were depressed in patients with PHT compared with controls, Table 1 , P 0.001. Similarly, significant decrease in RIMP was seen in patients with PHT compared to controls, p <0.001. Significant correlation (p<0.001, r >0.6) was noted between the 2D FAC and S, SR. The time to peak systolic S indexed to end diastolic area (EDA) is significantly prolonged, p<0.01 in all segments in patients with PHT indicating dyssynchrony. Conclusion: S and SR allows assesment of Regional RV systolic function otherwise difficult to assess from conventional echo-Doppler technique. PHTN is associated with not only regional RV systolic dysfunction but also with dyssynchrony. Thus, this new tool can offer new insights in the functioning of right ventricular global and regional function. mean±SD of strain

(1) Purpose: To determine the association between visceral adipose tissue (VAT) and proton density fat fraction (PDFF) with magnetic resonance imaging (MRI), and hepatic steatosis (HS), non-alcoholic steatohepatitis (NASH) and hepatic fibrosis (HF) in patients with known or suspected non-alcoholic fatty liver disease (NAFLD). (2) Methods: 135 subjects that had a liver biopsy performed within 3 months (bariatric cohort) or 1 month (NAFLD cohort) of an MRI exam formed the study group. VAT volume was quantified at L2-L3 level on opposed-phase images with signal intensity-based painting using a semi-quantitative software. Liver PDFF and pancreas PDFF were calculated on fat fraction maps. Liver volume (Lvol) and spleen volume (Svol) were also calculated using a semi-automated 3D volume tool available on PACS. A histological analysis was performed by an expert hepatopathologist blinded to imaging findings. (3) Results: The mean Lvol, Svol, liver PDFF, pancreas PDFF and VAT of the study population were 2492.2 mL, 381.6 mL, 13.2%, 12.7% and 120.6 mL, respectively. VAT showed moderate correlation with liver PDFF (r = 0.41, p < 0.001) and weak correlation with Lvol (r = 0.38, p < 0.001), Svol (r = 0.20, p = 0.025) and pancreas PDFF (rs = 0.29, p = 0.001). VAT, Lvol and liver PDFF were significantly higher in patients with HS (p < 0.001), NASH (p < 0.05) and HF (p < 0.05). VAT was also significantly higher in the presence of lobular inflammation (p = 0.019) and hepatocyte ballooning (p = 0.001). The cut-off VAT volumes for predicting HS, NASH and HF were 101.8 mL (AUC, 0.7), 111.8 mL (AUC, 0.64) and 111.6 mL (AUC, 0.66), respectively. (4) Conclusion: The MRI determined VAT can be used for predicting the presence of HS, NASH and HF in patients with known or suspected NAFLD.

Getting around the blood–brain barrier The meninges comprise three membranes that surround and protect the central nervous system (CNS). Recent studies have noted the existence of myeloid cells resident there, but little is known about their ontogeny and function, and whether other meningeal immune cell populations have important roles remains unclear (see the Perspective by Nguyen and Kubes). Cugurra et al. found in mice that a large proportion of continuously replenished myeloid cells in the dura mater are not blood derived, but rather transit from cranial bone marrow through specialized channels. In models of CNS injury and neuroinflammation, the authors demonstrated that these myeloid cells have an immunoregulatory phenotype compared with their more inflammatory blood-derived counterparts. Similarly, Brioschi et al. show that the meninges host B cells that are also derived from skull bone marrow, mature locally, and likely acquire a tolerogenic phenotype. They further found that the brains of aging mice are infiltrated by a second population of age-associated B cells, which come from the periphery and may differentiate into autoantibody-secreting plasma cells after encountering CNS antigens. Together, these two studies may inform future treatment of neurological diseases. Science , abf7844, abf9277, this issue p. eabf7844 , p. eabf9277 ; see also abj8183, p. 396

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]

Abstract Background MR elastography can determine organ‐related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post‐prandially due to increased portal blood in‐flow. Non‐selective beta‐blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. Aims To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. Methods Fifty‐two patients with cirrhosis underwent liver vein catheterization and two‐dimensional (2D) MR elastography on separate days. Thirty‐six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. Results HVPG showed a strong, positive, linear relationship with liver stiffness ( r 2 = 0.92; P < .001) and spleen stiffness ( r 2 = 0.94; P < .001). The cut‐off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5‐10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response ( P = .75). Conclusions Two‐dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.

Background: In a study from our institution, ultrasonic percutaneous tenotomy of the brevis and the common extensor tendon for recalcitrant lateral elbow tendinopathy showed excellent safety profiles, high tolerability, efficiency, sustained pain relief, functional improvement, and sonographic evidence of tissue healing in 20 patients at 3 years’ follow-up. Purpose: To explore the long-term clinical and sonographic results of ultrasonic percutaneous tenotomy of the brevis and the common extensor tendon. Study Design: Case series; Level of evidence, 4. Methods: The same cohort of 20 patients was recalled after 7 years, and visual analog scale (VAS) for pain and Disabilities of the Arm, Shoulder and Hand (DASH) scores, need for secondary intervention, and overall satisfaction were assessed. They were also reassessed using ultrasound imaging of the brevis and the common extensor tendon to evaluate tendon hypervascularity, tendon thickness, and the progress or the recurrence of the hypoechoic scar tissue. Results: We successfully scored 19 patients and performed ultrasound on 16 patients with a median follow-up of 90 months (range, 86-102 months). There were no adverse outcomes and satisfaction remained at 100% (6 patients, satisfied; 13 patients, very satisfied). No patient developed a recurrence of symptoms and signs of lateral elbow tendinopathy, and therefore no secondary intervention was required. The improvement from baseline and early term scores was sustained ( P < .001 for all). At 90 months, there was a significant improvement in VAS scores and DASH–Compulsory scores compared with preprocedure scores and all follow-up times until 3 months. There was no difference in VAS scores and DASH–Compulsory scores at 90 months compared with 6 and 36 months. For DASH–Work scores, there was a significant improvement at 90 months compared with preprocedure scores, but there was no difference between DASH–Work scores at 90 months and scores at all other points of follow-up. At 90 months, hypervascularity remained resolved in 79% of patients, while all patients had reduced tendon swelling and sustained resolution or reduction of the hypoechoic lesion. Conclusion: At the long-term follow-up of 90 months, ultrasonic percutaneous tenotomy of the brevis and the common extensor tendon, previously shown to enhance recovery of lateral elbow tendinopathy, demonstrated good durability of pain relief and functional recovery that was previously achieved. This was accompanied by sustained sonographic tissue healing with no significant deterioration.