Nonaneurysmal perimesencephalic subarachnoid hemorrhage on noncontrast head CT: An accuracy, inter-rater, and intra-rater reliability study.

BACKGROUND AND PURPOSE: To evaluate the reliability and accuracy of nonaneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH) on Noncontrast Head CT (NCCT) between numerous raters. MATERIALS AND METHODS: 45 NCCT of adult patients with SAH who also had a catheter angiography (CA) were independently evaluated by 48 diverse raters; 45 raters performed a second assessment one month later. For each case, raters were asked: 1) whether they judged the bleeding pattern to be perimesencephalic; 2) whether there was blood anterior to brainstem; 3) complete filling of the anterior interhemispheric fissure (AIF); 4) extension to the lateral part of the sylvian fissure (LSF); 5) frank intraventricular hemorrhage; 6) whether in the hypothetical presence of a negative CT angiogram they would still recommend CA. An automatic NAPSAH diagnosis was also generated by combining responses to questions 2-5. Reliability was estimated using Gwet's AC1 (κG), and the relationship between the NCCT diagnosis of NAPSAH and the recommendation to perform CA using Cramer's V test. Multi-rater accuracy of NCCT in predicting negative CA was explored. RESULTS: Inter-rater reliability for the presence of NAPSAH was moderate (κG = 0.58; 95%CI: 0.47, 0.69), but improved to substantial when automatically generated (κG = 0.70; 95%CI: 0.59, 0.81). The most reliable criteria were the absence of AIF filling (κG = 0.79) and extension to LSF (κG = 0.79). Mean intra-rater reliability was substantial (κG = 0.65). NAPSAH weakly correlated with CA decision (V = 0.50). Mean sensitivity and specificity were 58% (95%CI: 44%, 71%) and 83 % (95%CI: 72 %, 94%), respectively. CONCLUSION: NAPSAH remains a diagnosis of exclusion. The NCCT diagnosis was moderately reliable and its impact on clinical decisions modest.

Predictors of prolonged treatment time intervals in oral cavity cancer.

OBJECTIVES: Delays in treatment time intervals have been associated with overall survival in oral cavity squamous cell carcinoma (OCSCC). The aim of this study was to identify bottlenecks leading to prolonged treatment intervals. MATERIAL AND METHODS: A retrospective analysis was conducted using a cohort of OCSCC patients who underwent surgery and adjuvant radiation therapy. The endpoints of interest were prolonged treatment intervals. Multivariable logistic regression was used to adjust for patient and tumour characteristics. RESULTS: Median diagnosis-to-treatment interval (DTI) and surgery to initiation of postoperative radiation therapy interval (S-PORT) were 39 days (IQR 30-54) and 64 days (IQR 54-66), respectively. Prolonged DTI was associated with older age, worse Charlson Comorbidity index scores and worse T stages. Patients with prolonged DTI had longer times to preoperative imaging reports (25 vs 9 days; P < 0.01). Time to preoperative pathology did not differ. Prolonged S-PORT was associated with longer times to pathology report (28 vs 18 days; P < 0.01), to maxillofacial consult (38 vs 15 days; P < 0.01) and to maxillofacial approval of radiation (50 vs 28 days; P < 0.01). In patients requiring medical oncology consults, those with prolonged S-PORT had longer waiting times until consultation (58 vs 38 days; P = 0.02). Multivariate analysis showed independent predictors of prolonged DTI: time to preoperative imaging; and prolonged S-PORT: time to pathology report, time to maxillofacial consult, and time to medical oncology consult. CONCLUSIONS: Strategies targeting these organizational bottlenecks may be effective for shortening treatment time intervals, hence representing potential opportunities for improving oncological outcomes in OCSCC patients.

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Preoperative evaluation of depth of invasion in oral tongue squamous cell carcinoma: A systematic review and meta-analysis.

The inclusion of depth of invasion (DOI) in the American Joint Committee on Cancer's staging system for oral cavity squamous cell carcinoma (SCC) has major clinical impacts. Recent studies have evaluated the reliability of imaging modalities and biopsy techniques to measure DOI preoperatively. The objective of this systematic review and meta-analysis was to comprehensively include all previously described methods to measure preoperative DOI in oral tongue SCC (OTSCC) and to compare their reliability. A systematic review was conducted on PubMed, Embase and Cochrane according to the PRISMA guidelines. Studies that evaluated the reliability of DOI measured on biopsy or imaging (rDOI) by comparing it to DOI on histopathology (pDOI) were included for extraction. A meta-analysis was conducted to obtain pooled correlation coefficients for each imaging modality. The pooled correlation coefficients between rDOI and pDOI were 0.86 (CI95% = [0.82-0.88]) and 0.80 (CI95% = [0.70-0.87]) for magnetic resonance imaging (MRI) studies and computed tomography (CT) studies, respectively. For ultrasound (US), the correlation coefficient could only be measured by including studies which measured not only DOI but also tumor thickness. It was 0.89 (CI95%= [0.82-0.94]). Overall, MRI is the better studied modality. It has a good reliability to measure preoperative rDOI in OTSCC. CT is less studied but appears to be less reliable. US cannot be compared to these imaging modality as it has been used more often to measure TT than DOI.

Should Magnetic Resonance Angiography Be Used for Screening of Intracranial Aneurysm in Adults with Sickle Cell Disease?

Magnetic resonance imaging (MRI) is used in patients with sickle cell disease (SCD) to detect silent cerebral infarcts. MR angiography (MRA) can identify arterial stenoses and intracranial aneurysms (ICANs) associated with SCD. In this study, we aimed to estimate the prevalence of ICANs in asymptomatic adult patients with SCD referred from the SCD clinic for routine screening by MRI/MRA using a 3T-MRI scanner. Findings were independently reviewed by two neuroradiologists. Between 2016 and 2020, 245 asymptomatic adults with SCD were stratified according to genotype (SS/S-ß0thalassemia and SC/Sß+). ICANs were found in 27 patients (11%; 0.95 CI: 8-16%). ICANs were more frequent in SS/S-ß0thalassemia patients (20/118 or 17%; 0.95 CI: 11-25%) than in SC/ßb+ patients (7/127 or 6%; 0.95 CI: 2-11%; p = 0.007). Individuals with SCD (particularly SS/S-ß0thalassemia) have a higher prevalence of ICANs than the general population. We believe that MRA should be considered in the current American Society of Hematology guidelines, which already contain a recommendation for MRI at least once in adult SCD patients. However, the clinical significance of preventive treatment of unruptured aneurysms remains controversial.

Non-contrast CT markers of intracerebral hematoma expansion: a reliability study.

OBJECTIVES: We evaluated whether clinicians agree in the detection of non-contrast CT markers of intracerebral hemorrhage (ICH) expansion. METHODS: From our local dataset, we randomly sampled 60 patients diagnosed with spontaneous ICH. Fifteen physicians and trainees (Stroke Neurology, Interventional and Diagnostic Neuroradiology) were trained to identify six density (Barras density, black hole, blend, hypodensity, fluid level, swirl) and three shape (Barras shape, island, satellite) expansion markers, using standardized definitions. Thirteen raters performed a second assessment. Inter- and intra-rater agreement were measured using Gwet's AC1, with a coefficient > 0.60 indicating substantial to almost perfect agreement. RESULTS: Almost perfect inter-rater agreement was observed for the swirl (0.85, 95% CI: 0.78-0.90) and fluid level (0.84, 95% CI: 0.76-0.90) markers, while the hypodensity (0.67, 95% CI: 0.56-0.76) and blend (0.62, 95% CI: 0.51-0.71) markers showed substantial agreement. Inter-rater agreement was otherwise moderate, and comparable between density and shape markers. Inter-rater agreement was lower for the three markers that require the rater to identify one specific axial slice (Barras density, Barras shape, island: 0.46, 95% CI: 0.40-0.52 versus others: 0.60, 95% CI: 0.56-0.63). Inter-observer agreement did not differ when stratified for raters' experience, hematoma location, volume, or anticoagulation status. Intra-rater agreement was substantial to almost perfect for all but the black hole marker. CONCLUSION: In a large sample of raters with different backgrounds and expertise levels, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement. KEY POINTS: • In a sample of 15 raters and 60 patients, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement (Gwet's AC1> 0.60). • Intra-rater agreement was substantial to almost perfect for eight of nine hematoma expansion markers. • Only the blend, fluid level, and swirl markers achieved substantial to almost perfect agreement across all three measures of reliability (inter-rater agreement, intra-rater agreement, agreement with the results of a reference reading).

Assessment of the impact of EHR heterogeneity for clinical research through a case study of silent brain infarction.

BACKGROUND: The rapid adoption of electronic health records (EHRs) holds great promise for advancing medicine through practice-based knowledge discovery. However, the validity of EHR-based clinical research is questionable due to poor research reproducibility caused by the heterogeneity and complexity of healthcare institutions and EHR systems, the cross-disciplinary nature of the research team, and the lack of standard processes and best practices for conducting EHR-based clinical research. METHOD: We developed a data abstraction framework to standardize the process for multi-site EHR-based clinical studies aiming to enhance research reproducibility. The framework was implemented for a multi-site EHR-based research project, the ESPRESSO project, with the goal to identify individuals with silent brain infarctions (SBI) at Tufts Medical Center (TMC) and Mayo Clinic. The heterogeneity of healthcare institutions, EHR systems, documentation, and process variation in case identification was assessed quantitatively and qualitatively. RESULT: We discovered a significant variation in the patient populations, neuroimaging reporting, EHR systems, and abstraction processes across the two sites. The prevalence of SBI for patients over age 50 for TMC and Mayo is 7.4 and 12.5% respectively. There is a variation regarding neuroimaging reporting where TMC are lengthy, standardized and descriptive while Mayo's reports are short and definitive with more textual variations. Furthermore, differences in the EHR system, technology infrastructure, and data collection process were identified. CONCLUSION: The implementation of the framework identified the institutional and process variations and the heterogeneity of EHRs across the sites participating in the case study. The experiment demonstrates the necessity to have a standardized process for data abstraction when conducting EHR-based clinical studies.

Publisher Correction: Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.

Inactivation of the protein complex 'mechanistic target of rapamycin complex 1' (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including 'protein kinase C delta' (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional 'target of rapamycin signaling' (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-ß. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-ß, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.

Natural Language Processing for the Identification of Silent Brain Infarcts From Neuroimaging Reports.

BACKGROUND: Silent brain infarction (SBI) is defined as the presence of 1 or more brain lesions, presumed to be because of vascular occlusion, found by neuroimaging (magnetic resonance imaging or computed tomography) in patients without clinical manifestations of stroke. It is more common than stroke and can be detected in 20% of healthy elderly people. Early detection of SBI may mitigate the risk of stroke by offering preventative treatment plans. Natural language processing (NLP) techniques offer an opportunity to systematically identify SBI cases from electronic health records (EHRs) by extracting, normalizing, and classifying SBI-related incidental findings interpreted by radiologists from neuroimaging reports. OBJECTIVE: This study aimed to develop NLP systems to determine individuals with incidentally discovered SBIs from neuroimaging reports at 2 sites: Mayo Clinic and Tufts Medical Center. METHODS: Both rule-based and machine learning approaches were adopted in developing the NLP system. The rule-based system was implemented using the open source NLP pipeline MedTagger, developed by Mayo Clinic. Features for rule-based systems, including significant words and patterns related to SBI, were generated using pointwise mutual information. The machine learning models adopted convolutional neural network (CNN), random forest, support vector machine, and logistic regression. The performance of the NLP algorithm was compared with a manually created gold standard. The gold standard dataset includes 1000 radiology reports randomly retrieved from the 2 study sites (Mayo and Tufts) corresponding to patients with no prior or current diagnosis of stroke or dementia. 400 out of the 1000 reports were randomly sampled and double read to determine interannotator agreements. The gold standard dataset was equally split to 3 subsets for training, developing, and testing. RESULTS: Among the 400 reports selected to determine interannotator agreement, 5 reports were removed due to invalid scan types. The interannotator agreements across Mayo and Tufts neuroimaging reports were 0.87 and 0.91, respectively. The rule-based system yielded the best performance of predicting SBI with an accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 0.991, 0.925, 1.000, 1.000, and 0.990, respectively. The CNN achieved the best score on predicting white matter disease (WMD) with an accuracy, sensitivity, specificity, PPV, and NPV of 0.994, 0.994, 0.994, 0.994, and 0.994, respectively. CONCLUSIONS: We adopted a standardized data abstraction and modeling process to developed NLP techniques (rule-based and machine learning) to detect incidental SBIs and WMDs from annotated neuroimaging reports. Validation statistics suggested a high feasibility of detecting SBIs and WMDs from EHRs using NLP.

Psoas Muscle Area and All-Cause Mortality After Transcatheter Aortic Valve Replacement: The Montreal-Munich Study.

BACKGROUND: Psoas muscle area (PMA) is a novel measure of frailty that can be efficiently measured from computed tomography images to help predict risk in older adults referred for transcatheter aortic valve replacement (TAVR). The objective of this study was to determine if PMA would be incrementally predictive of mortality and morbidity after TAVR. METHODS: The pre-TAVR computed tomography scans of 208 consecutive patients at 2 hospitals in Montreal and Munich were analyzed to measure the cross-sectional area of the left and right psoas muscles on a single axial slice at the level of L4. The primary outcome was all-cause mortality assessed according to sex-stratified Cox regression models adjusted for the Society of Thoracic Surgeons predicted risk of mortality. RESULTS: The mean age was 80.7 ± 6.8 years with 55% women and a total of 57 deaths over a mean follow-up of 504 days. PMA was lower in nonsurvivors compared with survivors among women (12.9 vs 14.5 cm(2); P = 0.047) but not men (21.7 vs 22.4 cm(2); P = 0.50). The association between PMA and all-cause mortality in women persisted after adjustment for Society of Thoracic Surgeons risk (hazard ratio, 0.88 per cm(2); 95% confidence interval, 0.78-0.99). An association between PMA and bleeding complications was seen in men (odds ratio, 0.78; 95% confidence interval, 0.62-0.97). Sensitivity analyses with PMA normalized to body mass index yielded similar results. CONCLUSIONS: This study has shown that PMA is a marker of frailty associated with midterm survival in women who undergo TAVR. Further research is warranted to pursue PMA as a prognostic marker and therapeutic target in this vulnerable population.