Citations

OBJECTIVE Chiari malformation type 1 (CM1) is the most common neurological disorder of the craniocervical junction. CM1 is characterized by cerebellar tonsillar herniation below the foramen magnum, causing CSF obstruction and neural compression. Patients with CM1 suffer from highly variable symptoms, progression, comorbidities, and outcomes, partly due to poor understanding of CM1 pathogenesis. In this paper, the authors present the only familial CM1 cohort study to statistically assess intrafamilial clinical phenotypes to date. METHODS Comprehensive medical, surgical, and family histories and neuroimaging were collected from families with multiple CM1-affected family members. Univariate analysis was performed for each symptom, comorbidity, or surgery to compare observed versus expected frequencies of affected patients with another CM1-affected family member with the same clinical characteristic. RESULTS Twenty-four new familial CM1 cases (totaling 57 patients with CM1) are presented. Intrafamilial similarities were identified for age of onset, symptoms such as headaches (p = 0.007) and neck pain (p = 0.018), neurological comorbidities such as syringomyelia (p = 0.003) and hydrocephalus (p = 0.0001), neurodevelopmental conditions such as dyslexia (p < 0.0001), and connective tissue disorders (CTDs) such as Ehlers-Danlos syndrome (p < 0.0001). CONCLUSIONS These results suggest that CM1 and its associated clinical phenotypes, including age of onset, clinical symptoms, neurological comorbidities, neurodevelopmental conditions, and CTDs, are genetically influenced. Whole-exome sequencing of CM1 patient-parent trios has the potential to identify the genetic determinants of CM1, with implications for neurosurgical management.

Abstract Background The urgent need for rapid fentanyl detection at the point-of-care originates from its involvement in a high number of overdose deaths, primarily due to illicit use. Given fentanyl's potency compared to traditional opioids, accurate and sensitive detection is critical. Current lateral flow assays (LFA) cannot detect single-digit concentrations and may yield false negatives due to their lower sensitivity. Herein, we evaluate the clinical performance of a novel LFA (InstaStrip Fentanyl Rapid Test (urine)) with 1 ng/mL cutoff for fentanyl and no cross-reactivity for norfentanyl, offering enhanced sensitivity for effective overdose prevention at the ED. Methods A total of 172 urine samples submitted for UDS analysis were used for comparison studies. Fentanyl concentrations were categorized in 5 groups to cover various concentration categories around the cutoff of the LFA (1 ng/mL). These categories are: drug-free (&lt;0.1 ng/mL, n=68), 0.1-0.5 ng/mL (n=14), 0.5-0.9 ng/mL (n=15), 1-1.5 ng/mL (n=9) and &gt; 1.5 ng/mL (n= 66). Concentrations were determined by in-house LC-MS/MS methods validated according to CLIA standards, with fentanyl concentrations quantitated in the ABSciex software. For LFA testing, 150 μL of urine was added to a reagent tube containing dried rabbit anti-fentanyl antibody conjugated gold nanoparticles. After 20 sec of brief shaking, a test strip was inserted into the test tube. After 5 min, qualitative results were read as follow: both the control and test lines were visible in negative results, whereas only the control lines were visible in positive results. Method comparison study of the LFA was conducted by three operators who were blinded to the LC-MS/MS results. Result comparisons were made between the LFA strip and LC-MS/MS results, as well as among different operators for the same samples. Results Of the 75 urine samples with LC-MS/MS fentanyl concentrations ≥ 1 ng/mL, 74 produced consistently positive results using the InstaStrip Fentanyl Rapid Test. Of the 97 urine samples with LC-MS/MS fentanyl concentrations &lt; 1 ng/mL, 96 produced consistently negative results using the InstaStrip Fentanyl Rapid Test. Using the LC-MS/MS as the gold standard method and 1 ng/mL as a cutoff, the clinical sensitivity of InstaStrip Fentanyl Rapid Test was calculated to be 98.67% (95% confidence interval (CI) 92.79-99.97%), and the clinical specificity was 98.97% (95% CI 94.39-99.97%). Consistent results among three operators were obtained for 100% of the “drug free”, “0.1- 0.5 ng/mL” and &gt; 1.5 ng/mL groups, whereas 93.3 % (14 out of 15) and 88.9% (7 out of 8) were obtained for the “0.5-0.9 ng/mL” and “1-1.5 ng/mL” groups, respectively. The two samples with a singlet discrepant result (1 false positive and 1 false negative) in the triplicate experiments contained fentanyl concentrations of 0.9 and 1.0 ng/mL respectively, which are very close to the cutoff value. Conclusions In this study, the InstaStrip Fentanyl Rapid Test (urine) demonstrated high clinical sensitivity (98.67%), high specificity (98.97%) and high reproducibility showing that it may be useful in screening and identifying patients with fentanyl overdose in minutes in an emergency setting. This would facilitate appropriate patient triaging for optimal clinical care.

AbstractMyhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016–2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence‐based guidelines in anticipation of disease‐specific therapies.

Abstract Background Abuse of fentanyl and its analogs is a major contributor to the opioid overdose epidemic in the United States, but detecting and quantifying trace amounts of such drugs remains a challenge without resorting to sophisticated mass spectrometry-based methods. Methods A sensitive immunoassay with a sub-picogram limit of detection for fentanyl and a wide range of fentanyl analogs has been developed, using a novel high-affinity antibody fused with NanoLuc, a small-size luciferase that can emit strong and stable luminescence. When used with human urine samples, the assay has a sub-picogram limit of detection for fentanyl, with results fully concordant with LC-MS. Results When applied to clinical samples, the novel chemiluminescence immunoassay can detect low positive fentanyl missed by routine screening immunoassays, with a limit of detection of 0.8 pg/mL in human urine. When applied to environmental samples, the assay can detect levels as low as 0.25 pg fentanyl per inch2 of environment surface. Assay turnaround time is less than 1 h, with inexpensive equipment and the potential for high-throughput automation or in-field screening. Conclusions We have established a novel assay that may have broad applications in clinical, environmental, occupational, and forensic scenarios for detection of trace amounts of fentanyl and its analogs.

We report a case of low‐grade fibromyxoid sarcoma arising within the median nerve. A 31‐year‐old woman presented with symptoms of carpal tunnel syndrome and an enlarging mass in her right palm over 1 year. MRI demonstrated a mass associated with the right median nerve with solid and cystic components. At surgery, the mass was located within the epineurium, could be bluntly dissected from the nerve fascicles, and was suspected to be a schwannoma. A 3.4 cm, tan‐pink, glistening, smooth, homogenous mass was submitted to pathology. Microscopically, the tumor was a solid and cystic circumscribed nodule with a dense fibrous pseudocapsule. The tumor cells were uniformly bland and spindle‐shaped, with small, hyperchromatic oval nuclei and were embedded in an alternating fibrous and myxoid stroma with a prominent curvilinear vasculature and perivascular sclerosis. The differential diagnosis for this lesion included myxoid neurofibroma, schwannoma, soft tissue perineurioma, low‐grade malignant peripheral nerve sheath tumor and low‐grade fibromyxoid sarcoma. The tumor cells expressed MUC4, GLUT‐1, and vimentin and were negative for S‐100 protein, epithelial membrane antigen, smooth muscle actin, desmin, claudin‐1, neurofilament and SOX10. Fluorescence in situ hybridization, with a break‐apart probe strategy, demonstrated FUS rearrangement, consistent in this morphological context with the low‐grade fibromyxoid sarcoma‐associated FUS‐CREB3L2 or FUS‐CREB3L1 fusions. Low‐grade fibromyxoid sarcoma is exceptionally rare in the peripheral nerve, with only a single previously reported case. Nonetheless, as our case illustrates, this entity must be included in the differential diagnosis of unusual intraneural mesenchymal tumors. As in all other locations, intraneural low‐grade fibromyxoid sarcomas should be excised with negative margins. Patients with this disease require long‐term clinical follow‐up, given this tumor's propensity for very late distant metastases to the lungs and other sites.

Abstract BACKGROUND Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a “resectability index” for each lesion by pooling responses from all 13 surgeons. RESULTS Neurosurgeons’ individual surgical goals varied significantly ( P = .015), but the resectability index calculated from the surgeons’ pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor ( R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes ( P < .01) and nonresectable residual ( P < .01), but not resectable residual. CONCLUSION In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials.