In response to the COVID-19 pandemic, many medical schools suspended clinical clerkships and implemented newly adapted curricula to facilitate continued educational progress. While the implementation of these new curricula has been described, an understanding of the impact on student learning outcomes is lacking. In 2020, the authors followed Kern’s 6-step approach to curricular development to create and evaluate a novel COVID-19 curriculum for medical students at the University of California San Francisco School of Medicine and evaluate its learning outcomes. The primary goal of the curriculum was to provide third- and fourth-year medical students an opportunity for workplace learning in the absence of clinical clerkships, specifically for students to develop clerkship-level milestones in the competency domains of practice-based learning and improvement, professionalism, and systems-based practice. The curriculum was designed to match students with faculty-mentored projects occurring primarily in virtual formats. A total of 126 students enrolled in the curriculum and completed a survey about their learning outcomes (100% response rate). Of 35 possible clerkship-level milestones, there were 12 milestones for which over half of students reported development in competency domains including practice-based learning and improvement, professionalism, and interpersonal and communication skills. Thematic analysis of students’ qualitative survey responses demonstrated 2 central motivations for participating in the curriculum: identity as physicians-in-training and patient engagement. Six central learning areas were developed during the curriculum: interprofessional teamwork, community resources, technology in medicine, skill-building, quality improvement, and specialty-specific learning. This analysis demonstrates that students can develop competencies and achieve rich workplace learning through project-based experiential learning, even in virtual clinical workplaces. Furthermore, knowledge of community resources, technology in medicine, and quality improvement was developed through the curriculum more readily than in traditional clerkships. These could be considered as integral learning objectives in future curricular design.
ObjectiveWe combined diffusion MRI (dMRI) with quantitative T1 (qT1) relaxometry in a sample of school-aged children born preterm and full term to determine whether reduced fractional anisotropy (FA) within the corpus callosum of the preterm group could be explained by a reduction in myelin content, as indexed by R1 (1/T1) from qT1 scans.Methods8-year-old children born preterm (n = 29; GA 22–32 weeks) and full term (n = 24) underwent dMRI and qT1 scans. Four subdivisions of the corpus callosum were segmented in individual native space according to cortical projection zones (occipital, temporal, motor and anterior-frontal). Fractional anisotropy (FA) and R1 were quantified along the tract trajectory of each subdivision and compared across two birth groups.ResultsCompared to controls, preterm children demonstrated significantly decreased FA in 3 of 4 analyzed corpus callosum subdivisions (temporal, motor, and anterior frontal segments) and decreased R1 in only 2 of 4 corpus callosum subdivisions (temporal and motor segments). FA and RD were significantly associated with R1 within temporal but not anterior frontal subdivisions of the corpus callosum in the term group; RD correlated with R1 in the anterior subdivision in the preterm group only.ConclusionsMyelin content, as indexed by R1, drives some but not all of the differences in white matter between preterm and term born children. Other factors, such as axonal diameter and directional coherence, likely contributed to FA differences in the anterior frontal segment of the corpus callosum that were not well explained by R1.
Meningiomas are the most common primary intracranial tumors, but meningioma metastases are rare. Accordingly, the clinical workup, diagnostic testing, and molecular classification of metastatic meningioma is incompletely understood. Here, we present a case report of multiply recurrent meningioma complicated by liver metastasis. We discuss the patient presentation, imaging findings, and conventional histopathologic characterization of both the intracranial lesion and the metastatic focus. Further, we perform multiplatform molecular profiling, comprised of DNA methylation arrays and RNA-sequencing, of six stereotactically-guided samples from the intracranial meningioma and a single ultrasound-guided liver metastasis biopsy. Our results show that DNA methylation clusters distinguish the liver metastasis from the intracranial meningioma samples, and identify a small focus of hepatocyte contamination with the liver biopsy. Nonetheless, DNA methylation-based classification accurately identifies the liver metastasis as a meningioma with high confidence. We also find that clustering of RNAsequencing results distinguishes the liver metastasis from the intracranial meningiomas samples, but that differential gene expression classification is confounded by hepatocyte-specific gene expression programs in the liver metastasis. In sum, this case report sheds light on the comparative biology of intracranial and metastatic meningioma. Furthermore, our results support methylation-based classification as a robust method of diagnosing metastatic lesions, underscore the broad utility of DNA methylation array profiling in diagnostic pathology, and caution against the routine use of bulk RNA-sequencing for identifying tumor signatures in heterogeneous metastatic lesions.
INTRODUCTION Vestibular schwannomas (VS) can cause significant morbidity from cranial neuropathies and mass effect. Broad molecular differences have been described for intracranial versus spinal axis schwannomas, but little is known about the molecular heterogeneity of VS or predictors of recurrence. METHODS A total of 66 sporadic VS from 59 consecutive patients with available tissue who underwent initial resection (44), resection for recurrence after prior surgery (5), resection for recurrence after prior stereotactic radiosurgery (SRS) (11), or resection after both prior surgery and prior SRS (6) at a single institution from 2003 to 2017 were profiled using 850 K DNA methylation arrays (median follow-up: 4.2 yr, median volumetric resection: 91%). A total of 24 VS were further characterized using RNA sequencing. Molecular subtyping was performed using differential-DNA methylation analysis and validated using transcriptomic data. Preoperative magnetic resonance imaging (MRI) studies were centrally reviewed by a board-certified neuro-radiologist. RESULTS NA methylation profiling revealed 2 novel subgroups of VS, delineated by enrichment of neural crest genes (31 tumors) or immune genes (35 tumors). Neural crest-enriched VS were more likely to show reduced diffusion on MRI (P < .01), while immune-enriched VS were more likely to show cystic changes (P < .05), mass effect (P < .01), and edema (P < .05). Immune-enriched VS were significantly more likely to be adherent to the brainstem and left as residual at the time of resection. A total of 15 immune-enriched VS (43%) had prior SRS, while only 2 neural crest-enriched VS (6%) had prior SRS (P < .001). Hypomethylation of G protein-coupled estrogen receptor 1 (GPER) promoter was prognostic for local failure in multivariate regression irrespective of primary treatment modality (P < .0001). CONCLUSION VS are comprised of 2 molecular subgroups characterized by differential enrichment of neural crest or immune genes. VS treated with prior SRS are associated with immune-enrichment. GPER promoter hypomethylation is prognostic for VS recurrence. These data illuminate the biology of VS and shed light on potential molecular therapies.
OBJECTIVE Tumors compressing the trigeminal nerve can cause facial pain, numbness, or paresthesias. Limited data exist describing how these symptoms change after resection and what factors predict symptom improvement. The objective of this study was to report trigeminal pain and sensory outcomes after tumor resection and identify factors predicting postoperative symptom improvement. METHODS This retrospective study included patients with tumors causing facial pain, numbness, or paresthesias who underwent resection. Trigeminal schwannomas were excluded. Logistic regression, recursive partitioning, and time-to-event analyses were used to report outcomes and identify variables associated with facial sensory outcomes. RESULTS Eighty-six patients met inclusion criteria, and the median follow-up was 3.1 years; 63 patients (73%) had meningiomas and 23 (27%) had vestibular schwannomas (VSs). Meningioma patients presented with pain, numbness, and paresthesias in 56%, 76%, and 25% of cases, respectively, compared with 9%, 91%, and 39%, respectively, for patients with VS. Most meningioma patients had symptoms for less than 1 year (60%), whereas the majority of VS patients had symptoms for 1–5 years (59%). The median meningioma and VS diameters were 3.0 and 3.4 cm, respectively. For patients with meningiomas, gross-total resection (GTR) was achieved in 27% of patients, near-total resection (NTR) in 29%, and subtotal resection (STR) in 44%. For patients with VS, GTR was achieved in 9%, NTR in 30%, and STR in 61%. Pain improved immediately after tumor resection in 81% of patients and in 92% of patients by 6 weeks. Paresthesias improved immediately in 80% of patients, increasing to 84% by 6 weeks. Numbness improved more slowly, with 52% of patients improving immediately, increasing to 79% by 2 years. Pain recurred in 22% of patients with meningiomas and 0% of patients with VSs. After resection, the Barrow Neurological Institute (BNI) facial pain intensity score improved in 73% of patients. The tumor diameter significantly predicted improvement in BNI score (OR 0.47/cm larger, 95% CI 0.22–0.99; p = 0.047). Complete decompression of the trigeminal nerve was associated with qualitative improvement in pain (p = 0.037) and decreased pain recurrence (OR 0.08, 95% CI 0.01–0.67; p = 0.024). CONCLUSIONS Most patients with facial sensory symptoms caused by meningiomas or VSs experienced improvement after resection. Surgery led to immediate and sustained improvement in pain and paresthesias, whereas numbness was slower to improve. Patients with smaller tumors and complete decompression of the trigeminal nerve were more likely to experience improvement in facial pain.
BACKGROUND Vestibular schwannomas (VS) are tumors arising from cranial nerve Schwann cells and show variable outcomes after treatment, including oscillation in size for many years after radiosurgery. To understand the unique biology of VS, we performed multiplatform molecular profiling to develop a single cell atlas of VS and reveal that VS exists on a molecular axis defined by neural crest and immune genes. METHODS Sixty-six sporadic VS with available tissue for molecular profiling from 59 consecutive patients at a single institution were included. 850K DNA methylation arrays and RNA sequencing were used to profile both primary (76%) and recurrent (24%) tumors. Single nuclei RNA sequencing of 7 tumors and single cell RNA sequencing of 3 tumors and cell lines were used to define the cellular composition of VS and heterogeneous changes in molecular programs following irradiation. Molecular subtyping was performed by hierarchical clustering of differentially-methylated DNA probes and validated using transcriptomic data. Mechanistic experiments were performed using cultured human schwann cells and human vestibular schwannoma cells, confocal microscopy, CRISPR interference, proteomic mass spectrometry and lymphocyte migration assays. RESULTS Multiplatform genomic profiling and machine learning revealed that VS is comprised of two distinct molecular subtypes characterized by heterogeneous cell populations. Neural crest enriched VS express primary cilia and are associated with misactivation of the Hedgehog pathway. Consistently, we find that the Hedgehog pathway antagonist vismodegib blocks the growth of human Schwann cells. Irradiation epigenetically reprograms tumors and cell lines to reduce ciliary length, attenuate Hedgehog signaling, activate senescence pathways, and express cytokines and apolipoproteins that recruit lymphocytes and macrophages to immune enriched VS. CONCLUSIONS Our data reveal novel molecular subtypes of VS and establish a framework for understanding how irradiation modifies the epigenome and tumor microenvironment.
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