Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

National registry insights on genetic aortopathies and thoracic endovascular aortic interventions.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) in patients with genetic aortopathies (GA) is controversial, given concerns of durability. We describe characteristics and outcomes after TEVAR in patients with GA. METHODS: All patients undergoing TEVAR between 2010 and 2023 in the Vascular Quality Iniatitive were identified and categorized as having a GA or not. Demographics, baseline, and procedural characteristics were compared among groups. Multivariable logistic regression was used to evaluate the independent association of GA with postoperative outcomes. Kaplan-Meier methods and multivariable Cox regression analyses were used to evaluate 5-year survival and 2-year reinterventions. RESULTS: Of 19,340 patients, 304 (1.6%) had GA (87% Marfan syndrome, 9% Loeys-Dietz syndrome, and 4% vascular Ehlers-Danlos syndrome). Compared with patients without GA, patients with GA were younger (50 years [interquartile range, 37-72 years] vs 70 years [interquartile range, 61-77 years]), more often presented with acute dissection (28% vs 18%), postdissection aneurysm (48% vs 17%), had a symptomatic presentation (50% vs 39%), and were less likely to have degenerative aneurysms (18% vs 47%) or penetrating aortic ulcer (and intramural hematoma) (3% vs 13%) (all P < .001). Patients with GA were more likely to have prior repair of the ascending aorta/arch (open, 56% vs 11% [P < .001]; endovascular, 5.6% vs 2.1% [P = .017]) or the descending thoracic aorta (open, 12% vs 2% [P = .007]; endovascular, 8.2% vs 3.6% [P = .011]). No significant differences were found in prior abdominal suprarenal repairs; however, patients with GA had more prior open infrarenal repairs (5.3% vs 3.2%), but fewer prior endovascular infrarenal repairs (3.3% vs 5.5%) (all P < .05). After adjusting for demographics, comorbidities, and disease characteristics, patients with GA had similar odds of perioperative mortality (4.6% vs 7.0%; adjusted odds ratio [aOR], 1.1; 95% confidence interval [CI], 0.57-1.9; P = .75), any in-hospital complication (26% vs 23%; aOR, 1.24; 95% CI, 0.92-1.6; P = .14), or in-hospital reintervention (13% vs 8.3%; aOR, 1.25; 95% CI, 0.84-1.80; P = .25) compared with patients without GA. However, patients with GA had a higher likelihood of postoperative vasopressors (33% vs 27%; aOR, 1.44; 95% CI, 1.1-1.9; P = .006) and transfusion (25% vs 23%; aOR, 1.39; 95% CI, 1.03-1.9; P = .006). The 2-year reintervention rates were higher in patients with GA (25% vs 13%; adjusted hazard ratio, 1.99; 95% CI, 1.4-2.9; P < .001), but 5-year survival was similar (81% vs 74%; adjusted hazard ratio, 1.02; 95% CI, 0.70-1.50; P = .1). CONCLUSIONS: TEVAR for patients with GA seemed to be safe initially, with similar odds for in-hospital complications, in-hospital reinterventions, and perioperative mortality, as well as similar hazards for 5-year mortality compared with patients without GA. However, patients with GA had higher 2-year reintervention rates. Future studies should assess long-term durability after TEVAR compared with the recommended open repair to appropriately weigh the risks and benefits of endovascular treatment in patients with GA.

Surgeon volume and outcomes following thoracic endovascular aortic repair for blunt thoracic aortic injury.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injury (BTAI) at high-volume hospitals has previously been associated with lower perioperative mortality, but the impact of annual surgeon volume on outcomes following TEVAR for BTAI remains unknown. METHODS: We analyzed Vascular Quality Initiative (VQI) data from patients with BTAI that underwent TEVAR between 2013 and 2023. Annual surgeon volumes were computed as the number of TEVARs (for any pathology) performed over a 1-year period preceding each procedure and were further categorized into quintiles. Surgeons in the first volume quintile were categorized as low volume (LV), the highest quintile as high volume (HV), and the middle three quintiles as medium volume (MV). TEVAR procedures performed by surgeons with less than 1-year enrollment in the VQI were excluded. Using multilevel logistic regression models, we evaluated associations between surgeon volume and perioperative outcomes, accounting for annual center volumes and adjusting for potential confounders, including aortic injury grade and severity of coexisting injuries. Multilevel models accounted for the nested clustering of patients and surgeons within the same center. Sensitivity analysis excluding patients with grade IV BTAI was performed. RESULTS: We studied 1321 patients who underwent TEVAR for BTAI (28% by LV surgeons [0-1 procedures per year], 52% by MV surgeons [2-8 procedures per year], 20% by HV surgeons [≥9 procedures per year]). With higher surgeon volume, TEVAR was delayed more (in <4 hours: LV: 68%, MV: 54%, HV: 46%; P < .001; elective (>24 hours): LV: 5.1%; MV: 8.9%: HV: 14%), heparin administered more (LV: 80%, MV: 81%, HV: 87%; P = .007), perioperative mortality appears lower (LV: 11%, MV: 7.3%, HV: 6.5%; P = .095), and ischemic/hemorrhagic stroke was lower (LV: 6.5%, MV: 3.6%, HV: 1.5%; P = .006). After adjustment, compared with LV surgeons, higher volume surgeons had lower odds of perioperative mortality (MV: 0.49; 95% confidence interval [CI], 0.25-0.97; P = .039; HV: 0.45; 95% CI, 0.16-1.22; P = .12; MV/HV: 0.50; 95% CI, 0.26-0.96; P = .038) and ischemic/hemorrhagic stroke (MV: 0.38; 95% CI, 0.18-0.81; P = .011; HV: 0.16; 95% CI, 0.04-0.61; P = .008). Sensitivity analysis found lower adjusted odds for perioperative mortality (although not significant) and ischemic/hemorrhagic stroke for higher volume surgeons. CONCLUSIONS: In patients undergoing TEVAR for BTAI, higher surgeon volume is independently associated with lower perioperative mortality and postoperative stroke, regardless of hospital volume. Future studies could elucidate if TEVAR for non-ruptured BTAI might be delayed and allow stabilization, heparinization, and involvement of a higher TEVAR volume surgeon.

Likelihood-of-harm/help of microsurgery compared to radiosurgery in large vestibular schwannoma.

PURPOSE: It has been shown that in large vestibular schwannomas (VS), radiosurgery (SRS) is inferior with respect to tumor control compared to microsurgical resection (SURGERY). However, SURGERY poses a significantly higher risk of facial-function deterioration (FFD). The aim of this study was to illustrate the effectiveness in terms of number-needed-to-treat/operate (NNO), number-needed-to-harm (NNH), and likelihood-of-harm/help (LHH) by comparing both treatment modalities in large VS. METHODS: This was a retrospective, dual-center cohort study. Tumor size was classified by Hannover Classification. Absolute risk reduction and risk increase were used to derive additional estimates of treatment effectiveness, namely NNO and NNH. LHH was then calculated by a quotient of NNH/NNO to illustrate the risk-benefit-ratio of SURGERY. RESULTS: Four hundred and forty-nine patients treated met the inclusion criteria. The incidence of tumor recurrence was significantly higher in SRS (14%), compared to SURGERY (3%) resulting in ARR of 11% and NNO of 10. At the same time, SURGERY was related to a significant risk of FFD resulting in an NNH of 12. Overall, the LHH calculated at 1.20 was favored SURGERY, especially in patients under the age of 40 years (LHH = 2.40), cystic VS (LHH = 4.33), and Hannover T3a (LHH = 1.83) and T3b (LHH = 1.80). CONCLUSIONS: Due to a poorer response of large VS to SRS, SURGERY is superior with respect to tumor control. One tumor recurrence can be prevented, when 10 patients are treated by SURGERY instead of SRS. Thus, LHH portrays the benefit of SURGERY in large VS even when taking raised FFD into account.

Cystic vestibular schwannoma - a subgroup analysis from a comparative study between radiosurgery and microsurgery.

Some vestibular schwannoma (VS) show cystic morphology. It is known that these cystic VS bear different risk profiles compared to solid VS in surgical treatment. Still, there has not been a direct comparative study comparing both SRS and SURGERY effectiveness in cystic VS. This retrospective bi-center cohort study aims to analyze the management of cystic VS compared to solid VS in a dual center study with both microsurgery (SURGERY) and stereotactic radiosurgery (SRS). Cystic morphology was defined as presence of any T2-hyperintense and Gadolinium-contrast-negative cyst of any size in the pre-interventional MRI. A matched subgroup analysis was carried out by determining a subgroup of matched SURGERY-treated solid VS and SRS-treated solid VS. Functional status, and post-interventional tumor volume size was then compared. From 2005 to 2011, N = 901 patients with primary and solitary VS were treated in both study sites. Of these, 6% showed cystic morphology. The incidence of cystic VS increased with tumor size: 1.75% in Koos I, 4.07% in Koos II, 4.84% in Koos III, and the highest incidence with 15.43% in Koos IV. Shunt-Dependency was significantly more often in cystic VS compared to solid VS (p = 0.024) and patients with cystic VS presented with significantly worse Charlson Comorbidity Index (CCI) compared to solid VS (p < 0.001). The rate of GTR was 87% in cystic VS and therefore significantly lower, compared to 96% in solid VS (p = 0.037). The incidence of dynamic volume change (decrease and increase) after SRS was significantly more common in cystic VS compared to the matched solid VS (p = 0.042). The incidence of tumor progression with SRS in cystic VS was 25%. When comparing EOR in the SURGERY-treated cystic to solid VS, the rate for tumor recurrence was significantly lower in GTR with 4% compared to STR with 50% (p = 0.042). Tumor control in cystic VS is superior in SURGERY, when treated with a high extent of resection grade, compared to SRS. Therapeutic response of SRS was worse in cystic compared to solid VS. However, when cystic VS was treated surgically, the rate of GTR is lower compared to the overall, and solid VS cohort. The significantly higher number of patients with relevant post-operative facial palsy in cystic VS is accredited to the increased tumor size not its sole cystic morphology. Cystic VS should be surgically treated in specialized centers.

Predictive value of facial motor-evoked potential and electromyography for facial motor function in vestibular schwannoma surgery.

PURPOSE: Intraoperative neuromonitoring (IONM) aims to preserve facial nerve (FN) function during vestibular schwannoma (VS) surgery. However, current techniques such as facial nerve motor evoked potentials (FNMEP) or electromyography (fEMG) alone are limited in predicting postoperative facial palsy (FP). The objective of this study was to analyze a compound fEMG/FNMEP approach. METHODS: Intraoperative FNMEP amplitude and the occurrence of fEMG-based A-trains were prospectively determined for the orbicularis oris (ORI) and oculi (OCU) muscle in 322 VS patients. Sensitivity and specificity of techniques to predict postoperative FN function were calculated. Confounding factors as tumor size, volume of intracranial air, or IONM duration were analyzed. RESULTS: A relevant immediate postoperative FP was captured in 105/322 patients with a significant higher risk in large VS. While fEMG demonstrated a high sensitivity (77% and 86% immediately and 15 month postoperative, respectively) for identifying relevant FP, specificity was low. In contrast, FNMEP have a significantly higher specificity of 80.8% for predicting postoperative FP, whereas the sensitivity is low. A retrospective combination of techniques demonstrated still an incorrect prediction of FP in ~ 1/3 of patients. CONCLUSIONS: FNMEP and fEMG differ in sensitivity and specificity to predict postoperative FP. Although a combination of IONM techniques during VS surgery may improve prediction of FN function, current techniques are still inaccurate. Further development is necessary to improve IONM approaches for FP prediction.

Health-Related Quality of Life and Neuropsychological Outcome After EC-IC Bypass Revascularization in Adult Patients With Moyamoya Disease.

BACKGROUND AND OBJECTIVES: Patients with Moyamoya disease (MMD) have an above-average incidence of neuropsychological impairment and psychiatric comorbidities such as depression. Prevalence and correlation with preoperative imaging findings were identified in previous studies, and a reduced health-related quality of life (HRQOL) has been shown. This study investigates changes in neuropsychological performance and HRQOL after revascularization. METHODS: Thirty-two adult patients with MMD (23 female, 9 male; mean age 39.1 year ±14.7) with revascularization were included in this retrospective cohort study, and their results of structured neuropsychological testing were analyzed preoperatively and 1 year postoperatively. Sensorimotor deficits assessed with the National Institutes of Health Stroke Scale were considered to be possible confounders. RESULTS: Patients with preoperatively poor test results showed improvement in various items such as psychological well-being (95% CI [0.55-2.25], P = .002), vitality (95% CI [0.23-1.68], P = .007), general health perception (95% CI [0.09-1.44], P = .014), psychoticism (95% CI [-12.24 to -4.85], P < .001), and psychomotor processing speed (95% CI [0.10-1.14], P = .010), whereas the intensity of depression fell by a mean of 6.9 points (95% CI [-10.14 to -3.61], P < .001). For patients without preoperative neuropsychological or HRQOL deterioration, preservation of these functions without relevant worsening after revascularization was observed. Significant improvement in vitality, psychological well-being, psychoticism, psychomotor processing speed, and depression were also seen in patients with unchanged National Institutes of Health Stroke Scale. CONCLUSION: Chronic steno-occlusive cerebral hypoperfusion in patients with MMD not only may lead to neurological deficits but is also associated with neuropsychological impairment, reduced HRQOL, and increased depression. The results of this study show that patients with preoperative neuropsychological deterioration might benefit from revascularization surgery, whereas patients without preoperative impairment continue to remain stable postoperatively. Neuropsychological assessment should be routinely evaluated and considered a relevant variable when determining treatment for patients with MMD.

Intensity Score of Vessel Wall Contrast Enhancement in MRI Allows Prediction of Disease Progression in Moyamoya Angiopathy.

BACKGROUND AND OBJECTIVES: The underlying pathophysiological cause of moyamoya angiopathy (MMA) is still unclear. High-resolution vessel wall imaging has become a useful tool. The aim was to study vessel wall contrast-enhancement (VW-CE) as an imaging marker to predict disease progression in MMA. METHODS: Patients with MMA, who had undergone serial contrast-enhanced high-resolution MRI with concomitant and follow-up digital subtraction angiography, were analyzed retrospectively. VW-CE was semiquantified by measurement of the signal intensity of the vessel wall in in contrast-enhanced high-resolution MRI. A comparative quotient with the contrast-intensity of the pituitary stalk was calculated and graded accordingly from grade 1 to 5. VW-CE status was correlated with disease status, stroke, cerebrovascular reactivity in CO2-triggered blood-oxygen level-dependent MRI, angiographic disease progression, revascularization surgery, and follow-up imaging. RESULTS: Forty eight patients met the inclusion criteria. N = 56 MRI and digital subtraction angiography time-intervals were evaluated for 12 vessel sections per hemisphere each (N = 1344). N = 38 (79%) patients showed VW-CE and N = 10 (21%) did not. VW-CE was only observed in the terminal internal carotid artery and the proximal circle of Willis (N = 96/1344). Notably, patients with VW-CE significantly more often presented with acute infarction in the concomitant MRI. The incidence of angiographically proven disease progression was significantly associated with the incidence of VW-CE, and time to disease progression was earlier in higher grades of VW-CE compared with lower grades. CONCLUSION: VW-CE is a semiquantifiable marker for disease activity in patients with MMA and associated with disease progression and increased risk of stroke. VW-CE analysis can be routinely performed in patients with MMA to estimate the risk for disease progression and stroke.

Soft robotic platform for progressive and reversible aortic constriction in a small-animal model.

Our understanding of cardiac remodeling processes due to left ventricular pressure overload derives largely from animal models of aortic banding. However, these studies fail to enable control over both disease progression and reversal, hindering their clinical relevance. Here, we describe a method for progressive and reversible aortic banding based on an implantable expandable actuator that can be finely tuned to modulate aortic banding and debanding in a rat model. Through catheterization, imaging, and histologic studies, we demonstrate that our platform can recapitulate the hemodynamic and structural changes associated with pressure overload in a controllable manner. We leveraged soft robotics to enable noninvasive aortic debanding, demonstrating that these changes can be partly reversed because of cessation of the biomechanical stimulus. By recapitulating longitudinal disease progression and reversibility, this animal model could elucidate fundamental mechanisms of cardiac remodeling and optimize timing of intervention for pressure overload.

Outpatient care for facial palsy-a survey on patient satisfaction in uni- and interdisciplinary approaches.

Objective: The various causes of facial palsy, diagnostic methods and treatment approaches frequently involve different medical specialities. Nevertheless, there exist only few specialized consultation and therapy services for patients with facial palsy (FP) in Germany. The aim of the present study was to evaluate factors affecting quality of life (QoL) and treatment satisfaction of patients presenting to an interdisciplinary facial nerve outpatient clinic. Methods: The study analyzed patients presenting to the interdisciplinary facial palsy outpatient clinic in Tuebingen between February 2019 and December 2022. General satisfaction and QoL was estimated by numerous self-rating questionnaires: ZUF-8, SF-36, FDI, FaCE, PHQ-9. An ANOVA was performed to analyze determinants affecting the ZUF-8. Correlation analyses between cause and regeneration of FP as well as questionnaire scores were performed. Results were compared with a group of patients who were managed in an unidisciplinary setting. Results: In total, 66 patients with FP were enrolled. FP patients showed increased levels of depression (PHQ-9: 14.52 ± 3.8) correlating with recovery of the palsy (p = 0.008), FaCE (p < 0.001) and FDI ratings (p < 0.001). There was a high level of satisfaction with the services provided during the uni-and interdisciplinary consultation (ZUF-8: 24.59 ± 6.2), especially among the 12/66 patients who received reconstructive, surgical treatment. However, some patients requested more psychological and ophthalmological support. Conclusion: High levels of treatment satisfaction can be achieved in both an uni-and interdisciplinary setting. However, multimodal therapy approaches should be applied, considering physical and psychological aspects. In the absence of recovery, surgical interventions must be considered as treatment options. Further studies should continue to investigate potential differences between uni-and interdisciplinary treatment.

Hemodynamic evaluation of biomaterial-based surgery for Tetralogy of Fallot using a biorobotic heart, in silico, and ovine models.

Tetralogy of Fallot is a congenital heart disease affecting newborns and involves stenosis of the right ventricular outflow tract (RVOT). Surgical correction often widens the RVOT with a transannular enlargement patch, but this causes issues including pulmonary valve insufficiency and progressive right ventricle failure. A monocusp valve can prevent pulmonary regurgitation; however, valve failure resulting from factors including leaflet design, morphology, and immune response can occur, ultimately resulting in pulmonary insufficiency. A multimodal platform to quantitatively evaluate the effect of shape, size, and material on clinical outcomes could optimize monocusp design. This study introduces a benchtop soft biorobotic heart model, a computational fluid model of the RVOT, and a monocusp valve made from an entirely biological cell-assembled extracellular matrix (CAM) to tackle the multifaceted issue of monocusp failure. The hydrodynamic and mechanical performance of RVOT repair strategies was assessed in biorobotic and computational platforms. The monocusp valve design was validated in vivo in ovine models through echocardiography, cardiac magnetic resonance, and catheterization. These models supported assessment of surgical feasibility, handling, suturability, and hemodynamic and mechanical monocusp capabilities. The CAM-based monocusp offered a competent pulmonary valve with regurgitation of 4.6 ± 0.9% and a transvalvular pressure gradient of 4.3 ± 1.4 millimeters of mercury after 7 days of implantation in sheep. The biorobotic heart model, in silico analysis, and in vivo RVOT modeling allowed iteration in monocusp design not now feasible in a clinical environment and will support future surgical testing of biomaterials for complex congenital heart malformations.

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice.

GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given that Cln2 R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on the Cln2 R207X/R207X genetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice with Vgat-Cre mice to introduce interneuron-specific TPP1 deficiency. Vgat-Cre ; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells in Cln2 R207X/R207X mice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) in in Vgat-Cre : Cln2 R207X/R207X mice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death in Vgat-Cre : Cln2 R207X/R207X mice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.

Automatically Detecting Pancreatic Cysts in Autosomal Dominant Polycystic Kidney Disease on MRI Using Deep Learning.

BACKGROUND: Pancreatic cysts in autosomal dominant polycystic kidney disease (ADPKD) correlate with PKD2 mutations, which have a different phenotype than PKD1 mutations. However, pancreatic cysts are commonly overlooked by radiologists. Here, we automate the detection of pancreatic cysts on abdominal MRI in ADPKD. METHODS: Eight nnU-Net-based segmentation models with 2D or 3D configuration and various loss functions were trained on positive-only or positive-and-negative datasets, comprising axial and coronal T2-weighted MR images from 254 scans on 146 ADPKD patients with pancreatic cysts labeled independently by two radiologists. Model performance was evaluated on test subjects unseen in training, comprising 40 internal, 40 external, and 23 test-retest reproducibility ADPKD patients. RESULTS: Two radiologists agreed on 52% of cysts labeled on training data, and 33%/25% on internal/external test datasets. The 2D model with a loss of combined dice similarity coefficient and cross-entropy trained with the dataset with both positive and negative cases produced an optimal dice score of 0.7 ± 0.5/0.8 ± 0.4 at the voxel level on internal/external validation and was thus used as the best-performing model. In the test-retest, the optimal model showed superior reproducibility (83% agreement between scan A and B) in segmenting pancreatic cysts compared to six expert observers (77% agreement). In the internal/external validation, the optimal model showed high specificity of 94%/100% but limited sensitivity of 20%/24%. CONCLUSIONS: Labeling pancreatic cysts on T2 images of the abdomen in patients with ADPKD is challenging, deep learning can help the automated detection of pancreatic cysts, and further image quality improvement is warranted.

Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma.

BACKGROUND: Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti-PD1/PD-L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4), with and without an interventional radiology (IR) procedure in advanced BTC. METHODS: Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Twenty-three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3-3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9-4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5-6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9-40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1-2. CONCLUSION: Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC.

Severe central nervous system demyelination in Sanfilippo disease.

Introduction: Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients. Methods: Brain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms. Results: Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice. Discussion: Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

A novel percutaneous double-lumen stent graft technique for treatment of chronic type B aortic dissection under local anesthesia.

We present a novel endovascular technique for treatment of chronic dissection with abdominal aortic aneurysm whereby multiple overlapping stent grafts are placed in parallel in the true and false lumens in a 65-year-old woman. The use of multiple stent grafts within each lumen allowed total aneurysm exclusion and prevention of false lumen reperfusion while the parallel placement preserved flow in both lower extremities. Postoperative imaging showed complete exclusion of the aneurysm with patency of all aortic branches and no evidence of endoleak. The success of this novel procedure demonstrates feasibility of parallel stent graft implantation in both true and false lumens.