Citations

Abstract Extracellular matrix (ECM) stiffening correlates with tumor invasion in various cancer types, including glioblastoma (GBM). Increased matrix stiffness promotes a migratory phenotype through dysregulation of cell-ECM bidirectional communication. Exposure to stiffer environments is sensed by cells, which then adapt in ways that promote invasive behavior. These adaptive changes are imprinted onto the cells and persist even after they are placed in new, softer microenvironments via a process known as “mechanical memory.” Mechanical memory is believed to be driven by mechanosensitive transcription factor activity and epigenetic remodeling. Glioblastoma recurrence is linked to the ability of cells to disperse and infiltrate the surrounding healthy tissue. Extracellular matrix stiffness in GBM is heterogeneous; it starts with a softer tumor core and becomes progressively stiffer toward the tumor’s edges, potentially promoting sustained tumor invasion through mechanical memory. This review discusses the role of ECM stiffness in cancer cell behavior and the implications of ECM stiffening in GBM. We then describe the findings associated with mechanical memory and relay underlying mechanisms currently understood to drive the preservation of mechanically primed phenotypes. Finally, we discuss how matrix stiffness can drive migratory phenotypes in GBM cells and the potential role that progressive ECM dysregulation at the tumor periphery can link the formation of invasive tumor niches to the aggressive, resistant, and mesenchymal-like phenotypes present in GBM recurrent tumors.

Abstract Early diagnosis and treatment are essential for improving outcomes of coccidioidal meningitis. While the detection of IgG by serologic testing of the cerebrospinal fluid (CSF) has been a mainstay of diagnosis for years, the diagnosis of coccidioidal meningitis in clinical practice can be very challenging due to suboptimal sensitivity of laboratory tests. We reviewed the results of the CSF diagnostic test results from the initial lumbar puncture in 110 patients with proven, probable, and likely coccidioidal meningitis from 1989 to 2024. One hundred four patients were diagnosed with coccidioidal meningitis on the initial CSF examination. The positivity rate of the first CSF testing was 89.1% (n = 64) for IgG by enzyme immunoassay, 62.2% (n = 98) for IgG by immunodiffusion, and 70.2% (n = 104) for IgG by complement fixation, 4.4% (n = 90) for fungal culture, 18.8% (n = 69) for polymerase chain reaction, and 33% (n = 21) for Coccidioides antigen. The non-specific fungal marker 1,3-β-d-glucan was positive in the CSF in 70.4% (n = 27) of samples. Contrasted brain magnetic resonance imaging identified leptomeningeal enhancement in 53.1%. Optimal detection of coccidioidal meningitis requires a combination of diagnostic modalities.

ABSTRACT Background & Aims Steatotic liver disease (SLD) is characterised by liver fat accumulation exceeding 5%. Lean body weight (BMI ≤ 25 kg/m 2 ) with non‐alcoholic SLD is a rare phenotype, and the balance of risks related to metabolic conditions or genetic predisposition, or the risk of progressive liver disease, is not known. This study evaluates clinical and genetic predictors of non‐alcoholic SLD and advanced liver disease in lean individuals. Methods We used International Classification of Disease codes, radiology and pathology review to identify 177 lean non‐alcoholic SLD cases (47 cryptogenic, 130 MASLD), 677 matched lean controls, and 3090 overweight/obese SLD cases in the Mayo Clinic Biobank and Tapestry databases. We performed case–control and cross‐sectional comparisons of clinical and genetic factors between these groups, using univariable and multivariable analyses. Results Lean individuals with non‐alcoholic SLD exhibited metabolic and genetic profiles that were intermediate between those of lean controls without SLD and overweight/obese SLD individuals, including intermediate rates of diabetes, hypertension, hyperlipidaemia and of homozygosity for the risk allele of PNPLA3 . Multivariable analysis indicated that diabetes was an independent predictor of SLD among lean individuals. Among lean individuals with non‐alcoholic SLD, those with metabolic‐associated SLD (MASLD), as compared to those with cryptogenic SLD (without metabolic risk factor), were more likely to be homozygous for risk alleles in GCKR . The Fib‐4 score, a tool for screening advanced liver disease in SLD, accurately predicted advanced fibrosis among lean individuals with non‐alcoholic SLD. Conclusion Diabetes serves as a primary predictor of non‐alcoholic SLD in lean individuals. These results support the recommendation to screen for SLD in patients with diabetes, regardless of BMI. The GCKR risk allele is associated with MASLD in lean individuals, and the risk factors for cryptogenic SLD remain unclear.

Background: Ischemic stroke remains a leading cause of morbidity and mortality worldwide. Cardioembolic sources account for a significant proportion of these events, necessitating accurate identification of underlying structural heart abnormalities. Traditionally, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) have been utilized for this purpose, although both have limitations. Cardiac computed tomography (CCTA) has emerged as a potential alternative, offering non-invasive imaging with high sensitivity and specificity for detecting intracardiac thrombi. Objective: This study aimed to evaluate the diagnostic yield of CCTA compared to TTE and TEE in detecting high-risk cardioaortic sources of embolism, including left ventricular (LV) thrombus, left atrial (LA) thrombus, valvular thrombus, and ulcerated aortic plaques, in patients with ischemic stroke. Methods: We conducted a retrospective, single-center cohort study at Mayo Clinic, Rochester, MN, including 426 ischemic stroke patients who underwent CCTA within 30 days of stroke onset between March 2019 and June 2023. We compared the diagnostic yields of CCTA, TTE, and TEE in detecting structural cardiac sources of embolism. Results: The overall diagnostic yield of CCTA for detecting high-risk cardioaortic sources was 15.5%. Specifically, CCTA identified LV thrombus in 2.3% of patients, LA thrombus in 4.0%, valvular thrombus in 2.8%, and ulcerated aortic plaques in 7.0%. In comparative analysis, CCTA demonstrated a higher yield than TTE (16.0% vs 3.5%, p < 0.001) and a comparable yield to TEE (25.3% vs 20.7%, p = 0.47) in detecting these sources. Conclusions: CCTA proved to be a viable option for identifying high-risk structural sources of cardioembolism in ischemic stroke patients. Its non-invasive nature, coupled with the ability to perform imaging soon after stroke onset, underscores its clinical utility. However, further prospective and blinded studies are required to validate these findings and fully establish the efficacy of CCTA in this context.

ABSTRACTThis report details a severe complication of phenol neurolysis in a diabetic patient, where phenol induced tissue necrosis can lead to severe cellulitis with ulceration that may prove difficult to treat. It emphasizes the importance of considering comorbidities when selecting phenol neurolysis for treatment of chronic pain.

Abstract Electronic portal imaging devices (EPIDs) have been in widespread clinical use for almost two decades due to favorable measurement characteristics such as fast image acquisition, high sensitivity and resolution, digital data format, long‐term stability, linear dose response, and large detection area. On‐board EPIDs are widely used as a quality assurance (QA) tool to monitor nearly every aspect of linear accelerator (linac) performance. In both the commercial QA equipment market and in clinical practice, there is a trend toward replacing conventional QA approaches with fully automated, EPID‐based QA tools. Despite widespread use, EPIDs are complex devices, and there has yet to be consensus or formal recommendations published by the AAPM for their use in routine linac QA. Task Group 330 (TG‐330) was, therefore, formed to provide guidelines and recommendations for physicists on the safe and appropriate use of EPIDs for linac QA. In particular, the report: (a) provides a comprehensive review of the characteristics and limitations of EPIDs as time‐resolved measurement devices and dosimeters; (b) summarizes the application of EPIDs for linac QA; (c) provides recommendations on efficient and effective implementations of EPID‐based QA techniques; (d) describes risks associated with the use of EPIDs for linac QA and provides examples of how risk analysis can be used to ensure the safe use of EPIDs for linac QA. Many of the guidelines in this report are drawn from the literature that is included in the references and from the collective experience of the task group members. This report does not provide recommendations on the implementation of EPID‐based patient‐specific IMRT or VMAT QA, which is the topic of AAPM's report from AAPM TG‐307.

ABSTRACT Introduction Laryngotracheoesophageal clefts (LTEC) are aspiration‐related lesions often assessed using swallow studies and symptoms like respiratory or feeding difficulties. However, these indicators are unreliable predictors of disease severity. Lung inflammation and injury, though significant concerns, are rarely and inconsistently evaluated or reported. As a result, the correlation between swallow study findings and actual pulmonary disease remains unclear. Methods A retrospective cohort of children with LTEC seen in our Aerodigestive Program between October 1, 2012, and September 30, 2023, who underwent videofluoroscopic swallow study (VFSS) or flexible endoscopic evaluation of swallowing (FEES) were included. Data collected included clinical history, risk factors, BAL, chest CT, impedance probe, VFSS/FEES findings, and FOIS‐P/I scores at baseline and follow‐up. Results Eight‐two subjects identified. Lung inflammation and bronchiectasis were common and correlated. Clinical factors, impedance probe, and the presence/severity of swallowing abnormalities on VFSS/FEES were not predictive of lung disease. Fifty‐seven patients underwent LTEC repair for a range of indications, only 49% based on CT and/or BAL findings. Of 57 children who had LTEC repair, only 49% were based on CT or BAL findings. LTEC repair was associated with modest improvement feeding and swallowing. Discussion Children with LTEC have a high prevalence of inflammatory lung disease and injury and undergo repair for a variety of reasons. Swallow studies detect functional swallowing issues but do not reliably identify lung disease. Despite this limitation, LTEC repair is linked to improved feeding and swallowing in some patients, though not all benefit.

Background: Gluteus medius tears and atrophy cause lateral hip pain, limp, and functional impairment. We developed the “broken wing sign,” a novel physical examination test for detecting gluteus medius tendon tears and muscle degeneration. This study evaluated its diagnostic accuracy and clinical utility against magnetic resonance imaging (MRI) and intraoperative findings. Methods: We prospectively examined 59 patients (75 hips; mean age, 69.5 ± 10.8 years; 48 women) with suspected hip abductor insufficiency. The broken wing sign was tested with patients prone, the knee flexed at 90°, and the hip actively extended. A positive sign involved ≥10° of compensatory external hip rotation, visible as an inward drift of the foot, indicating gluteus medius (and resulting internal rotation) weakness. MRI served as the reference standard for classifying gluteus medius integrity as no tear, partial, full-thickness, or massive. Fatty infiltration was graded (Goutallier grades 0 to 4), quantified, and analyzed for a correlation with the examination findings. Diagnostic accuracy metrics were calculated. Results: The broken wing sign demonstrated high accuracy (sensitivity, 81.8%; specificity, 80.0%; positive predictive value [PPV], 91.8%; negative predictive value, 61.5%; diagnostic odds ratio, 17.8). An external rotation threshold of ≥30° yielded 100% specificity and 100% PPV for a tear. The sign detected acute tears with no or minimal fatty infiltration (100% sensitivity for massive tears). The degree of the external rotation angle was strongly correlated with muscle atrophy with fatty infiltration, showing 88.0% sensitivity for Goutallier grade ≥3 and 100% sensitivity for grade 4. Conclusions: The broken wing sign is clinically useful for diagnosing gluteus medius tendon tears and muscle atrophy, particularly massive tears and advanced fatty degeneration. It effectively guides MRI utilization and surgical planning, serving as a valuable initial diagnostic tool in the clinical setting. Level of Evidence: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Importance The prognosis of advanced pancreaticobiliary tumors is poor. Next-generation sequencing (NGS) of tissue samples is utilized to identify actionable alterations, but there are occasional limitations due to inadequate tissue acquisition. Circulating tumor DNA (ctDNA) is an alternative method, but its correlation with tissue-based NGS remains unexplored. Objectives To assess the mutation concordance (mCR) rates between ctDNA and tissue testing for patients with pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CC) and to evaluate how ctDNA performs as a treatment response biomarker. Design, Setting, and Participants This retrospective cohort study was conducted among patients with PDAC and CC treated at academic institutions from January 2014 to January 2025. Patients underwent ctDNA testing using 1 platform and tissue NGS testing using 2 platforms. Main Outcomes and Measures mCR, which measures the shared gene alterations observed by both ctDNA and tissue-based NGS testing, was calculated using the Spearman correlation for PDAC and CC. The performance of ctDNA as a treatment response biomarker was assessed by comparing serial ctDNA data with restaging scans and cancer antigen 19-9 levels in patients with PDAC. Results Our cohort included 790 patients: 570 with advanced PDAC (265 [46.5%] female; median [IQR] age, 64 [33-84] years) and 220 with advanced CC (95 [43.2%] female; median [IQR] age, 66 [42-88] years). Overall, 461 patients with PDAC (80.9%) and 192 patients with CC (87.2%) underwent ctDNA testing, while 239 patients with PDAC (41.9%) and 70 patients with CC (31.8%) had tissue NGS testing. Among patients with PDAC, 85 of 130 patients (65.4%) showed shared specific gene alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.47 (95% CI, 0.28-0.62; P &amp;lt; .001). For patients with CC, 32 of 48 (66.7%) had shared alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.56 (95% CI, 0.35-0.70; P &amp;lt; .001). A subgroup analysis of patients with PDAC who underwent serial ctDNA testing suggested that new TP53 subclones and increased ctDNA variant allele frequency levels of TP53 and KRAS were associated with higher odds of progressive disease (eg, increased TP53 frequency: odds ratio, 7.28; 95% CI, 2.15-24.66; P = .001). Conclusions and Relevance In this cohort study of patients with pancreaticobiliary tumors, there was a significant mCR between ctDNA and tissue NGS testing. Additionally, results suggest that ctDNA might detect resistant clones and enable assessment of treatment response.