Citations

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 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 Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation’s effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

ABSTRACT Background Treating Mycobacterium avium complex (MAC) infection pre‐lung transplant (LT) can be challenging to treat, given prolonged therapy and side effects. The impact of pre‐transplant MAC treatment on recurrence and outcomes post‐LT remains unclear, especially in patients with interstitial lung disease (ILD) who have a median survival of less than 2 years. Methods We performed a retrospective cohort study of adult LT patients at the Mayo Clinic who had positive MAC sputum cultures pre‐LT. The cohort was stratified and compared based on the type of treatment (complete, partial, or no treatment) for MAC pulmonary infection. The primary outcome was MAC recurrence post‐LT, and secondary outcomes were mortality, FEV‐1, and FVC at 1‐year post‐LT. Results Among the cohort of 47 patients, 9 (19.1%) were partially treated and 11 (23.4%) were completely treated for MAC infection pre‐LT. Post‐transplant MAC pulmonary infection recurrence occurred in eight (17%) of the total cohort, with four (14.8%) in the non‐treated, four (44.4%) in the partially‐treated, and none (0%) in the completely treated patients ( p = 0.026). There was no difference in mortality in patients who had MAC recurrence post‐transplantation (13% vs. 9.7%, p > 0.9) and those who were completely or partially treated, compared to non‐treated (0% vs. 13% vs. 13%, p > 0.9). The FEV1 and FVC at 1‐year post‐LT did not differ by the pre‐transplant treatment or post‐transplant MAC recurrence status. Conclusion The role of treatment for MAC infection pre‐transplant is questionable, especially in patients with diseases like ILD who may not have enough wait time to complete therapy.

Background: Macromastia causes significant physical and psychological distress in adolescents. Although reduction mammaplasty alleviates these symptoms, the mental health impact of macromastia in younger populations remains underexplored. This systematic review and meta-analysis aimed to evaluate mental health and quality of life outcomes in adolescents/young women undergoing reduction mammaplasty. Methods: A systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted from inception to September 2024. Studies reporting mental health or quality of life outcomes through the BREAST-Q, Short Form-36, Rosenberg Self-Esteem Scale, and Eating Attitudes Test were included. Odds ratios and mean difference with 95% confidence intervals were pooled using a random-effects model. Heterogeneity was assessed with I 2 statistics. The Risk of Bias in Nonrandomized Studies of Interventions tool was used to assess study quality. Meta-analysis was performed on 4 BREAST-Q domains. Results: Of 701 articles identified, 8 observational studies involving 660 patients were included. Pooled BREAST-Q scores postsurgery showed significant improvements across all 4 domains. Improvement in Short Form-36, Rosenberg Self-Esteem Scale, and Eating Attitudes Test scores was noted in individual studies, though meta-analysis was limited by incomplete data. Conclusions: These results indicate that reduction mammaplasty significantly improves the physical, psychosocial, and sexual well-being of adolescents/young women with macromastia.

Background: Pre-clinical animal studies have demonstrated improved cerebral blood flow and neurological survival with Automated Head Up Position (AHUP) cardiopulmonary resuscitation (CPR) as compared to flat conventional (C) CPR. AHUP CPR consists of 1) automated head and thorax elevation 2) active compression decompression CPR and 3) an impedance threshold device. Subsequently, observational propensity-matched studies of out-of-hospital cardiac arrest (OHCA) patients demonstrated a time-dependent association between survival with intact neurological function (SNF) and application of AHUP CPR. However, comparison of AHUP CPR outcomes with contemporaneous C-CPR controls is lacking. Hypothesis: Use of AHUP CPR for OHCA by first responder agencies will demonstrate a higher incidence of SNF compared to C-CPR outcomes from a national registry Methods: Data from the previous 5 years (2020-2024) from an AHUP-CPR Registry comprised of OHCA patients routinely treated by first responders with AHUP CPR were compared with data from the Cardiac Arrest Registry to Enhance Survival (CARES). Patient demographics, arrest characteristics, ROSC, SHD, and SNF were recorded. SNF was defined as a Cerebral Performance Category 1 or 2 at hospital discharge. A two-sample test of proportions was used for outcome comparisons. Results: Nine AHUP registry sites (MN, FL, TN, IL, OK, VA, AL, IA, MI) were included. Summary 5-year demographics (Table 1) and clinical outcomes (Table 2) are presented. For 2020-2024 AHUP sites, the average time (mm:ss, SD) from 9-1-1 call to start of CPR was 9:09 (4:37) and time to start of AHUP CPR was 12:46 (5:57). The AHUP registry had a higher 5-yr incidence of SNF versus the CARES registry (difference 2.8%, 95% CI 1.8-3.8, p < 0.00001). This difference was consistent year over year (Figure 1). Secondary outcomes of sustained return of spontaneous circulation and survival to hospital discharge in the AHUP registry were also significantly higher than CARES registry data (Table 2). Conclusions: Over a 5-year period, an unadjusted analysis of aggregate data from two OHCA patient registries demonstrated that the incidence of survival with intact neurological function was higher in patients treated with AHUP CPR as part of first responder care versus patients treated with more conventional CPR methods.