Citations

Abstract Purpose Bevacizumab is an effective treatment for radiation necrosis; dose dependent radiographic and edema response data are lacking. Methods Multicenter, retrospective cohort study of adult patients with primary central nervous system tumors or brain metastases who received bevacizumab for radiation necrosis between June 2021 and July 2024. Patients were grouped by bevacizumab dose (7.5 mg/kg vs 10 mg/kg administered every three weeks). Primary outcome was edema response, assessed by a blinded neuro-oncologist. Secondary outcomes included contrast enhancing disease response, clinical response, adverse events, treatment discontinuation, and re-dosing for recurrent radiation necrosis. Analyses were performed with and without adjustment for tumor type. Results 104 patients were included (7.5 mg/kg, n = 53; 10 mg/kg, n = 51). Edema response differed between dosing groups in unadjusted analyses (p = 0.032), favoring the 7.5 mg/kg cohort; however, this association was attenuated after adjustment for tumor type. Contrast enhancing disease response did not differ between groups in either unadjusted or adjusted analyses (p = 0.43). Clinical response was higher in the 7.5 mg/kg group (65.2% vs 37.8%, p = 0.013). Tumor type differed significantly between cohorts (p < 0.001), with more primary CNS tumors in the 10 mg/kg group. Rates of adverse events, treatment discontinuation, and re-dosing were similar. Conclusions While lower-dose bevacizumab was associated with greater edema reduction in unadjusted analyses, this effect was attenuated after accounting for tumor type. Importantly, 7.5 mg/kg dosing appeared sufficient for achieving edema control and contrast enhancing disease response. These findings support an individualized approach to bevacizumab dosing in radiation necrosis and highlight the need for prospective, tumor-stratified studies.

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 &gt;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 The majority of pituitary neuroendocrine tumors (PitNETs) are effectively managed with medical therapy, surgery, and/or radiation therapy; however, a subset of pituitary adenomas exhibit aggressive behavior. Temozolomide is thought to be an effective treatment option for patients with PitNETs. METHODS We identified and retrospectively reviewed 11 patients with pituitary tumors treated with temozolomide. We then conducted a review of the literature, combining 114 previously published cases with our cohort. RESULTS 125 cases were identified with diagnoses of pituitary adenomas (n=45), aggressive pituitary tumors (n=61), and pituitary carcinoma (n=19) treated with temozolomide. 79 patients were male (68.1%) with a median age of 47.5 (range 9-72). A variety of tumor types were represented: 50 corticotroph adenomas (40.7%), 37 prolactinomas (30.1%), 22 hormone nonfunctioning adenomas (17.9%), 8 somatotroph adenomas (6.5%), 6 other functioning adenomas (4.9%), and 2 cases where the functional status was not mentioned. Median treatment duration was 9 cycles (n=91, 150-200 mg/m2 days 1-5, 28-day cycles; n=2, 75 mg/m2, days 1-21, 28-day cycles; n=1, 75 mg/m2 daily). 27 patients received concurrent therapy with a dopamine agonist/somatostatin analogue (n=10), other chemotherapy agent (n=9) or radiotherapy (n=8). Radiographic responses included stable disease (n=40), partial response (n=35), complete response (n=8), and progressive disease (n=30). Hormonal responses included complete response (n=13), partial response (n=32), and no response (n=16). 22 patients (47.8%; out of 46 patients where progression/recurrence was assessed) experienced progression/recurrence following temozolomide initiation with a median progression free survival (PFS) of 24 months. There was no significant association between MGMT methylation status and radiological or hormonal response. No unexpected toxicities were observed. CONCLUSION In this cohort, temozolomide was well-tolerated with a median PFS of 24 months. MGMT methylation status did not predict temozolomide response. Temozolomide is an option with a survival benefit for patients with PitNETs.

Abstract BACKGROUND Mixed histiocytic neoplasms with overlapping features of Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) are extremely rare and diagnosis may be delayed due to lack of awareness and complex histology features. METHODS We report a case of mixed ECD/RDD misdiagnosed as IgG4-related disease and review the literature. RESULTS A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence. MRI demonstrated a T2 hypointense enhancing epidural mass with spinal cord compression. Epidural biopsy showed fibrosis and non-specific inflammation. Given elevated serum IgG4 (170 mg/dL) and clinical findings, he was diagnosed with IgG4-related disease. He received high dose prednisone and etanercept without radiographic or clinical improvement. He then presented to our institution. Given high concern for RDD, he underwent FDG-PET CT which demonstrated an infiltrative process and FDG avid regions in the upper thoracic spinal cord, paranasal sinus, renal hilum, perivascular abdominal vessels, testicle, and multiple joint effusions. Biopsy of left testicle demonstrated CD163-positive histiocytes which coexpressed S100, cyclin D1, and OCT2, consistent with RDD. Biopsy of the left shoulder synovium demonstrated an atypical CD163-positive histiocytic infiltrate expressing Factor XIIIa, cyclin D1 and S100 (partial), and appeared negative for OCT2, consistent with ECD. The atypical histiocytes in both biopsies were negative for CD1a and BRAF V600E by immunohistochemistry. Genomic sequencing of the testicular tissue demonstrated a MAP2K1 (Q56P) alteration. He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. DISCUSSION This case expands on the phenotypic description of mixed ECD/RDD. Histiocytic neoplasms should be considered in the differential diagnosis of dural based lesions.

Abstract BACKGROUND CNS germinoma is typically treated with combination of chemotherapy and radiotherapy, with steroids used temporarily for symptom management. METHODS We report a case of CNS germinoma initially treated with steroid monotherapy with reduction in radiographic enhancement. RESULTS A 25 year old male initially presented with polydipsia and polyurea that improved with desmopressin, consistent with central diabetes insipidus. Brain imaging was unremarkable and he was lost to follow up. 3 years later, he developed progressively worsening bitemporal scotomas, intermittent binocular horizontal diplopia, reduced visual acuity, headaches, weight gain, and sexual dysfunction. MRI brain revealed enhancement of the pituitary stalk, optic chiasm and optic nerves, floor of the third ventricle, lateral ventricles, periventricular white matter, and anterior corpus callosum and fornix with associated T2 hyperintensity within the optic chiasm and adjacent brain parenchyma. Biopsy was consistent with germinoma. He was started on a dexamethasone taper beginning at 4 mg every 6 hours and plateauing at 4 mg twice daily. 3 weeks after steroid initiation, the areas of enhancement surrounding the frontal horns of the lateral ventricles showed reduction in size. DISCUSSION Reduced tumoral enhancement with steroid monotherapy is a well-known phenomenon in CNS lymphoma and has been reported in gliomas, attributed to direct induction of apoptosis in CNS lymphoma and alterations in the blood brain barrier via suppression of vascular permeability factors in both. This case adds to the scant literature regarding change in enhancement patterns with steroid monotherapy in CNS germinomas, which is likely related to a reduction in tumoral diffuse lymphocyte infiltration with steroid administration. The reduction in enhancement seen in multiple CNS mass-like pathologies emphasizes the importance of a tissue diagnosis for germinomas, as this steroid response is transient and not indicative of true tumor regression. Definitive treatment of germinomas is combination chemotherapy and radiation.

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.