Citations

OBJECTIVE The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I–II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%–93%) and 105/110 low-grade (95%, 95% CI 90%–98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%–18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%–28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%–9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 (ClinicalTrials.gov)

Prenatal tobacco use among Alaska Native (AN) women has decreased substantially over the past two decades. Previous research suggests that providing AN women with feedback regarding fetal exposure to tobacco may further promote cessation. Transporters in the placenta regulate fetal exposure to nutrients and xenobiotics, including compounds associated with tobacco use. We examined whether prenatal tobacco use impacts transporter expression in the placenta, and whether this is influenced by fetal sex, degree of tobacco exposure, or transporter genotype. At delivery, we obtained placental samples from AN research participants who smoked cigarettes, used commercial chew or iqmik (oral tobacco), or did not use tobacco during pregnancy. Transporter expression was evaluated using qRT‐PCR and Western blotting and tested for correlations between transcript levels and urinary biomarkers of tobacco use. The impact of BCRP/ABCG2 and OATP2B1/SLCO2B1 genotypes on protein expression was also examined. Oral tobacco use was associated with decreased P‐gp and increased MRP1, MRP3, LAT1, and PMAT mRNA expression. Transcript levels of multiple transporters significantly correlated with tobacco biomarkers in maternal and fetal urine. In women carrying male fetuses, both smoking and oral tobacco were associated with decreased P‐gp. Oral tobacco was also associated with decreased LAT1 in women carrying female fetuses. BCRP and OATP2B1 genotypes did not appear to impact protein expression. In conclusion, prenatal tobacco use is associated with altered expression of multiple placental transporters which differs by fetal sex. As transcript levels of multiple transporters were significantly correlated with tobacco use biomarkers, eliminating prenatal tobacco use should alleviate these changes.

Abstract Automated and accurate identification of refugees in healthcare databases is a critical first step to investigate healthcare needs of this vulnerable population and improve health disparities. In this study, we developed a machine‐learning method, named refugee identification system (RIS) to address this need. We curated a data set consisting of 103 refugees and 930 non‐refugees in Arizona. We compiled de‐identified individual‐level information including age, primary language, and noise‐masked home address, state‐level refugee resettlement statistics, and world language statistics. We then performed feature engineering to convert language and masked address into quantitative features. Finally, we built a random forest model to classify refugee and non‐refugees. RIS achieved high classification accuracy (overall accuracy=0.97, specificity=0.99, sensitivity=0.85, positive predictive value=0.88, negative predictive value=0.98, and area under receiver operating characteristic curve=0.98). RIS is customizable for refugee identification outside Arizona. Its application enables large‐scale investigation of refugee healthcare needs and improvement of health disparities.

Abstract Neuralgic amyotrophy (NA), also referred to as idiopathic brachial plexitis and Parsonage‐Turner syndrome, is a peripheral nerve disorder characterized by acute severe shoulder pain followed by progressive upper limb weakness and muscle atrophy. While NA is incompletely understood and often difficult to diagnose, early recognition may prevent unnecessary tests and interventions and, in some situations, allow for prompt treatment, which can potentially minimize adverse long‐term sequalae. High‐resolution ultrasound (HRUS) has become a valuable tool in the diagnosis and evaluation of NA. Pathologic HRUS findings can be grouped into four categories: nerve swelling, swelling with incomplete constriction, swelling with complete constriction, and fascicular entwinement, which may represent a continuum of pathologic processes. Certain ultrasound findings may help predict the likelihood of spontaneous recovery with conservative management versus the need for surgical intervention. We recommend relying heavily on history and physical examination to determine which nerves are clinically affected and should therefore be assessed by HRUS. The nerves most frequently affected by NA are the suprascapular, long thoracic, median and anterior interosseous nerve (AIN) branch, radial and posterior interosseous nerve (PIN) branch, axillary, spinal accessory, and musculocutaneous. When distal upper limb nerves are affected (AIN, PIN, superficial radial nerve), the lesion is almost always located in their respective fascicles within the parent nerve, proximal to its branching point. The purpose of this review is to describe a reproducible, standardized, ultrasonographic approach for evaluating suspected NA, and to share reliable techniques and clinical considerations when imaging commonly affected nerves.

AbstractObjectivesTo standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs).Material and methodsIn consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis.ResultsA total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively.ConclusionsThis analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Abstract Background Regorafenib is one of several FDA‐approved cancer therapies targeting multiple tyrosine kinases. However, there are few subtype‐specific data regarding kinase inhibitor activity in sarcomas. We report results of a single arm, phase II trial of regorafenib in advanced Ewing family sarcomas. Methods Patients with metastatic Ewing family sarcomas (age ≥ 18, ECOG 0–2, good organ function) who had received at least one line of therapy and experienced progression within 6 months of registration were eligible. Prior kinase inhibitors were not allowed. The initial dose of regorafenib was 160 mg oral days 1–21 of a 28‐day cycle. The primary endpoint was estimating progression‐free rate (PFR) at 8 weeks employing RECIST 1.1. Results Thirty patients (median age, 32 years; 33% women [10 patients]; bone primary, 40%; extraskeletal primary, 60%) enrolled at 14 sites. The most common grade 3 or higher toxicities were hypophosphatemia (5 grade 3, 1 grade 4), hypertension (2 grade 3), elevated ALT (2 grade 3). Sixteen patients required dose reductions, most often for hypophosphatemia ( n = 7 reductions in 6 patients); two stopped regorafenib for toxicity. There was one death unrelated to treatment in the 30‐day post‐study period. Median progression‐free survival (PFS) was 14.8 weeks (95% CI 7.3–15.9); PFR at 8 weeks by Kaplan–Meier analysis was 63% (95% CI 46–81%). The RECIST 1.1 response rate was 10%. Median OS was 53 weeks (95% CI 37–106 weeks). Conclusions Regorafenib has modest activity in the Ewing family sarcomas. Toxicity was similar to that seen in approval studies.

Abstract BACKGROUND The Food and Drug Administration recently issued guidance on conducting qualitative research to support patient-focused drug development. In prior FDA submissions, qualitative data has been critical to demonstrate the content validity of and meaningfulness of change in quantitative trial endpoints. Qualitative patient interviews embedded within neuro-oncology trials can supplement traditional quantitative measures by providing nuanced information on patients’ treatment priorities, benefit/risk assessments, and quality of life. METHODS We interviewed people with neurofibromatosis 2 (NF2) in stage one of the brigatinib arm of a multicenter, phase II, adaptive platform-basket trial for progressive NF2-related tumors (NCT04374305). Transcripts were coded by two analysts using a hybrid inductive/deductive framework; cross-cutting themes were generated using the Framework Method. RESULTS 16/20 trial enrollees participated in interviews May 2021-March 2022. The radiographic response rate (volume shrinkage ≥20% from baseline) at 6 months for target and non-target tumors was 5% and 22%, respectively. However, most participants rated their change in overall status as minimally (10/16) or much (3/16) improved. Several participants acknowledged their tumor size had not changed significantly but felt tumor stability was an improvement over previously accelerated growth rates; this importantly allowed them to avoid or postpone future surgery. Participants also valued prevention of symptomatic decline, minimal impact of side effects on social roles and activities, the convenience of oral medication, and the sense of hope and agency gained from participating in a trial. CONCLUSIONS Virtual, in-depth qualitative interviews were feasible across multiple sites and provided unique information on NF2 patients’ conceptualization of clinical benefit. Qualitative interviews embedded within neuro-oncology trials can reveal 1) whether trial design and choice of outcome measures align with patient priorities; 2) whether and how new treatments improve patients’ quality of life; and 3) what degree of change in quantitative measures such as radiographic progression are clinically meaningful.

Background: While the liability risks for obstetrics and gynecology (ob/gyn) physicians are widely recognized, little is known about how trainees have been involved in ob/gyn lawsuits. Objectives: To characterize involvement of trainees in malpractice lawsuits related to ob/gyn. Methods: The legal database Westlaw was utilized to collect ob/gyn-related malpractice lawsuits involving trainees reported from 1986 to 2020 in the USA. Outcome: Forty-six malpractice cases involving ob/gyn trainees were identified, including 34 cases related to obstetrics and 12 to gynecology. There were 11 cases alleging lack of informed consent, including 7 cases alleging lack of consent for trainee involvement. Of the 34 obstetrics cases, 27 related to procedural complications, 17 to treatment, 13 to diagnosis, and 4 to informed consent. Of these, 17 were decided in favor of the physician, 6 resulted in findings of negligence, 9 had unknown outcomes, and 3 ended in settlement. For the 6 cases ending in a finding of negligence, the mean award was $2,174,472 compared to $685,000 for those that were settled. Of the 12 gynecology cases, 8 related to procedural complications, 7 to informed consent, 3 to diagnosis, and 2 to treatment. Of these, 6 were decided in favor of the physician, 3 resulted in findings of negligence, and 3 had unknown outcomes. For the cases ending in a finding of negligence, the mean award was $465,000. Conclusions and Outlook: This review of malpractice cases highlights types of situations in which trainees are sued and reveals the importance of designing curriculum around faculty training and supervision regarding trainee involvement in patient care.

PURPOSE Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.