White, Jessica D.

Abstract Purpose This study explores how new residents experienced the transition to residency, examines factors that made the transition process more or less difficult, and identifies potentially modifiable program features that enhanced or would have enhanced transition experiences. Method The authors conducted a qualitative interview study of postgraduate year (PGY) 1 residents in emergency medicine, family medicine, general surgery, internal medicine, obstetrics and gynecology, pediatric and adolescent medicine, and psychiatry at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin between December 2020 and March 2021. Open-ended questions explored residents’ transition experiences. Interviews were audio-recorded, transcribed, coded inductively, and analyzed iteratively using general thematic analysis from an epistemologically constructivist perspective. Results Forty-five residents (25 women, 20 men) from 12 programs, 7 specialties, and 4 states participated. PGY-1 residents experienced the transition to residency as a confluence of overlapping and interconnected transitions that unfolded over time, spanned multiple life domains, and generated numerous personal and professional demands. Residents appraised demands based on their effects on patient care, professional growth, and personal well-being and struggled when coincident demands forced tradeoffs among these concerns. Residents who experienced many difficulties during the transition to residency reported high demands (eg, due to transition-related discontinuities, depleted resources from prior transitions or a difficult match experience, structural and systemic barriers, coincident personal or situational stressors) and/or fewer resources (eg, insufficient residency or life skills, limited social support, financial strain). Preparedness and supportive relationships eased the transition process. Residency program features that enhanced or would have enhanced the transition experience included monitoring and limiting overall demands, minimizing unhelpful and harmful demands, calibrating constructive demands, and increasing holistic support. Conclusions Study findings illuminate transition experiences of PGY-1 residents, reveal person-centered considerations to inform ongoing improvement efforts, and identify potentially actionable steps programs can take to improve resident transition experiences.

Abstract BACKGROUND High grade astrocytoma with piloid features (HGAP) is a newly recognized tumor with a distinct DNA methylation profile. Its clinical course, treatment response, and outcomes remain poorly understood. METHODS We conducted a retrospective cohort study across three Mayo Clinic sites including adults with a HGAP diagnosis confirmed by DNA methylation profiling. RESULTS 17 patients were included (median age 38 years, Q1, Q3: 29–59; 9 male). DNA methylation-based tumor classification using the NCI/Bethesda classifier (v2) indicated a match to HGAP with high confidence (calibrated score >0.9) in 14 cases and was suggestive in 3 cases. All had MAPK pathway alterations (NF-1 mutation in 11, FGFR1 mutation in 2, KIAA1549::BRAF fusion in 2, FGFR1 transcript variant suggestive of internal tandem duplication in 1, KANK2::NTRK2 fusion in 1). All tumors also had CDKN2A/B homozygous deletion and 9 lost ATRX expression. Tumors were infratentorial (n=8), supratentorial (n=7), and spinal (n=2) at initial presentation. First line treatment included surgery followed by chemoradiation with temozolomide (n=12), surgery followed by radiation (n=4), radiation alone (n=1), and surgery alone (n=1). Gross total resection was achieved in 3/17, 8/17 had subtotal resection and 5/17 had biopsy. 14/17 received a median RT dose of 5700 cGy (range, 4005–6000) in 30 fractions. The median follow-up duration was 34.9 months. 8 patients experienced disease progression. The median progression-free survival (mPFS) was 30.3 months (95% CI: 15.4–NR). 6/8 underwent surgery; 3/8 underwent RT. Systemic therapies were administered in 5/8 (lomustine, bevacizumab, pembrolizumab, temozolomide, trametinib, tovorafenib). 3/17 patients died due to progressive disease with an OS of 54.2, 94.6 and 17.4 months, respectively. The mOS for the whole cohort was 54.2 months (95% CI: 54.2-NR). CONCLUSION While the optimal management of this newly recognized entity has yet to be established, our cohort demonstrates a clinical behavior consistent with CNS WHO grade 3, aligning with current WHO interpretations.

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Introduction: The differential diagnosis of a spinal intradural extramedullary mass lesion is broad and includes meningioma, schwannoma, neurofibroma, leptomeningeal metastasis, and myxopapillary ependymoma. Though rare, lymphoma should be included in the differential diagnosis of a dural mass lesion. Case Report: A 38-year-old man presented with back pain that progressed over 1 month with associated focal tenderness over his mid to lower thoracic spine. He developed intermittent numbness of the bilateral lower extremities, nuchal rigidity, difficulty sleeping, and night sweats. A magnetic resonance imaging of the thoracic spine demonstrated a dorsal intradural extramedullary enhancing lesion from T7 to T10 extending outside the spinal canal. Dural thickening across the entire circumference of the spinal cord was noted. Computed tomography (CT)-guided biopsy of the thoracic lesion was performed, and pathology was consistent with follicular lymphoma. Fluorodeoxyglucose positron emission tomography:CT demonstrated no systemic disease. Bone marrow biopsy was negative for malignancy. Symptoms resolved with dexamethasone therapy. He was treated with bendamustine and rituximab with follow-up positron emission tomography:CT 2 months later demonstrating a complete response. Conclusions: Lymphoma can rarely present as an isolated dural lesion and should be considered in the differential diagnosis of intradural extramedullary spinal mass lesions. Prompt diagnosis and initiation of treatment can lead to complete response and resolution of symptoms.

We report a case highlighting key clinical, CSF, and imaging findings of recurrent pleomorphic xanthoastrocytoma with leptomeningeal spread.