Citations

Abstract Background Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. Methods This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Results Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Conclusions Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

Abstract BACKGROUND Neurofibromatosis type 2-related schwannomatosis (NF2) is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS) as well as other nervous system tumors. Management decisions for NF2-related VS are typically predicated on tumor size, associated symptoms, patient age, and comorbidities. Observation, surgical resection, and stereotactic radiosurgery can be viable options. In patients with VS associated with NF2, vascular endothelial growth factor A (VEGF-A) inhibitor, bevacizumab, is a systemic treatment option. In this single institution study, we review our clinical experience in patients with NF2 who received bevacizumab for VS and evaluate the effect of bevacizumab treatment on VS growth and symptom progression. MATERIAL AND METHODS This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Three-dimensional volumetric data for VS were measured using manual segmentation with Visage PACS software under the direct supervision of a board-certified neuroradiologist. RESULTS Out of 76 patients with NF2 evaluated in the past 3 years, we identified 19 that received treatment with bevacizumab. Median age of NF2 diagnosis was 19 years (range 0.5-61) with a median NF2 phenotype severity score of 2 (range 1-3). Thirteen of these patients have discontinued bevacizumab, accounting for a median duration of 12.2 months (range 3.3-88 months) of bevacizumab treatment. Bevacizumab was discontinued due to hypertension (n=5), proteinuria and renal dysfunction (n=3), tumor progression (n=2), fatigue or other intolerance (n=2), or non-compliance (n=1). The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March 2023 (range 3.7-48.3 months). Fifteen patients had brain MRI data available to evaluate VS change during bevacizumab treatment, with partial response observed in 5 patients, stable disease in 8, and progression in 2. Ten of the 13 patients who stopped bevacizumab had MRI data to evaluate VS change following treatment termination. Within 6 months of bevacizumab discontinuation, 6 patients had rebound growth of their VS between 21-95% from their previous tumor volume, while 4 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. CONCLUSION Our single institution experience confirms that bevacizumab can slow progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

Abstract Background Bevacizumab is commonly used to manage cerebral edema associated with brain tumors. However, its long half-life poses challenges for patients requiring urgent surgery due to wound complications. We present a case of utilizing therapeutic plasma exchange (TPE) to remove bevacizumab in a patient with recurrent glioblastoma requiring urgent surgery. Methods A 58-year-old male with recurrent glioblastoma, IDH-wildtype, presented with clinical and radiographic concern for ventriculitis requiring urgent wound washout only 4 days after his last bevacizumab infusion. TPE was performed for 3 sessions after surgery using a centrifugation-based cell separator. Replacement fluids included normal serum albumin, normal saline, and fresh frozen plasma. Bevacizumab levels were quantified using an enzyme-linked immunoabsorbent assay before and after each TPE session. Results TPE effectively removed bevacizumab, enabling safe surgery without new complications. Plasma bevacizumab levels decreased from 1087.63 to 145.35 ng/mL (13.4% of original) by the end of the last TPE session. This decline is consistent with nearly 3 half-lives, which compares favorably to the expected timeline of natural decline given the 21-day half-life. Conclusions We report a complex clinical scenario of a patient requiring urgent wound washout 4 days after last bevacizumab infusion for CNS infection. Surgery was successfully performed without new complications with use of TPE to remove bevacizumab immediately following surgery. This case highlights the feasibility of this approach, which may be utilized effectively in patients requiring surgery after having recently received bevacizumab.

AbstractBackgroundTwo pathways that help explain cognitive health are 1) brain maintenance – referring to the relative absence of brain changes over time; 2) cognitive reserve – a property of the brain that allows for sustained cognitive ability in the presence of brain pathology. Both pathways influence cognitive aging and are best understood using longitudinal data. Our goal was to assess the effect of modifiable vascular/metabolic and lifestyle enrichment factors on these pathways using longitudinal brain changes measured on structural magnetic resonance imaging (MRI) and longitudinal cognitive decline. Lastly, we combined these pathways and their relationships in the same model.MethodWe identified 1250 participants from a well‐characterized sample of older adults from the Mayo Clinic Study of Aging with both longitudinal MRI and cognitive data. Linear mixed models were performed to assess the impact of modifiable factors on brain maintenance and cognitive reserve. Latent growth curve models (SEM) were used to assess the impact of brain structure and cognitive reserve on longitudinal cognition.ResultThe mean age of our sample was 78.8 years, with 45.4% female, and 27.1% APOE4 carriers. Mean follow‐up time was 4.0 years with a mean of 3.2 MRI scans per participant. Linear mixed models showed that poorer vascular/metabolic health (presence of vascular/metabolic conditions) was associated with lower cross‐sectional temporal region cortical thickness (‐0.014 (0.003), p<0.001) and lower global cognition (‐0.042 (0.018), p = 0.024). Higher estimated cognitive reserve at baseline as assessed by education/occupation composite (0.103 (0.01), p<0.001) was associated with higher global cognition. Unexpectedly, late‐life physical activities were related to lower global cognition (‐0.05 (0.007), p = 0.004). Our final latent growth curve SEM fit the data well showing temporal associations between unmodifiable characteristics, cognitive reserve, and brain structural pathways, as well as the influence of modifiable vascular/metabolic factors.ConclusionWe found that brain maintenance and cognitive reserve pathways were related to better cognition over time. We further showed that vascular/metabolic health impacts long‐term cognitive outcomes (i.e. cognitive aging) primarily through the brain maintenance pathway. These data provide a modeling scheme for future studies and can aid in assessing the pathways by which individual factors may influence cognitive aging.

Abstract Extra-neural metastasis in recurrent medulloblastoma, carries a potentially fatal outcome. No robust salvageable therapeutic strategy is present, for these clinical phenotypes. We present an 18-year male, who presented at the age of 8 years as a standard risk medulloblastoma and was treated with chemotherapy (as per ACNS0331) followed by craniospinal radiation. At first recurrence in the thoracic spine, he underwent a gross total resection of the tumor, followed by high-dose stem cell chemotherapy and focal radiation. The 2nd recurrence which occurred in the thecal sac 9 years later was treated with metronomic anti angiogenic chemotherapy with outcome a complete radiographic response. Third recurrence occurred in the liver, bone marrow, multiple bones of axial skeleton and sacrum. Molecular interrogation of the lesions showed a (non-WNT / non-SHH subtype) with absence of MYC or MYCN amplification or any other clinically significant biological aberration. He received local radiation to tumors, following which he developed severe myelosuppression. A bone marrow aspirate and biopsy showed greater than 95% involvement with medulloblastoma cells. He was treated with irinotecan and temozolomide. A dramatic response was noted after one cycle (with PET and MRI), with bone marrow involvement of less than 1%. He continues with that therapy. To-date no defined molecular profile is predictive of extra neural metastasis, and has been likened to a fatal outcome, most patients being declared for hospice care. Our patient with this unique clinical outcome, warrants extensive evaluation of these rare clinical phenotypes including methylation profiling and RNA sequencing, which might suggest, certain molecular aberrations which correlates with good response, even in these biologically aggressive variants.

e24089 Background: Little is known about risk and protective factors for dementia in cancer survivors. With increasing longevity due to improved cancer therapy, it’s prudent to study factors contributing to cognitive impairment in this patient population. Methods: We performed multivariable cox regression analyses to assess established risk factors for all-cause dementia (age, education, APOE4-status, social and physical activity engagement) in breast and prostate cancer survivors. Patients 50+ years old with pathology-confirmed cancer diagnosis at Mayo Clinic were identified from a longitudinal, population-based cohort – Mayo Clinic Study of Aging. Analyses were controlled for age, APOE4-status, education, and cancer treatment. Results: We included a total of 209 patients with breast cancer (mean age 75.4 years, 24% APOE4-positive, median follow-up 6.8 years) and 352 with prostate cancer (mean age 77 years, 26% APOE4-positive, median follow-up 6.4 years). 31 patients with breast cancer (15%) and 66 patients with prostate cancer (20%) were diagnosed with dementia at last follow-up. Older age was associated with increased risk for dementia (5-year increase – breast: hazard ratio (HR) 1.9 [95%CI 1.3-2.7, p = 0.001]; prostate: HR 2.4 [95%CI 1.8-3.2, p < 0.0001]). APOE4-positivity was associated with increased dementia risk in breast (HR 3.6 [95%CI 1.6-7.8, p < 0.002]), but not prostate cancer (HR 1.2 [95%CI 0.7-2.0, p = 0.5]). More education was associated with lower dementia risk in prostate cancer (education year: HR 0.91 [95%CI 0.84-0.98, p < 0.02]; education years > 12: HR 0.26 [95%CI 0.1-0.6, p < 0.001]). Physical activity engagement in mid-life was associated with lower dementia risk (prostate: HR 0.56 [95%CI 0.4-0.8, p < 0.005]; breast: HR 0.48 [95%CI 0.3-0.9, p < 0.02]). Conclusions: In this longitudinal, population-based study we found that some risk and protective factors for dementia in cancer survivors vary by cancer type. While advanced age is an expected dementia risk factor, there were mixed results for APOE4-positivity (increased risk only in breast cancer) and education (only protective in prostate cancer). Our results support further study into factors influencing dementia risk by cancer type in hopes of identifying preventative strategies.

TPS2082 Background: No drug has improved survival for patients with high-grade gliomas (HGGs) since temozolomide in 2005. Relatively little is known about the live response of in situ gliomas to therapeutic intervention. Phase 0 studies that leverage access to the live human glioma in situ, including via microdialysis to sample the live glioma microenvironment, provide an attractive and feasible solution to this problem. We performed intraoperative microdialysis to evaluate the extracellular metabolome of divergent regions in 15 HGG resections. Our data revealed a conserved metabolic signature of HGGs and a novel glioma-associated metabolite, guanidinoacetate (GAA). Pathways enriched in this tumor signature included methionine and polyamine metabolism. Although GAA is typically converted to creatine, we hypothesize that the high flux of ornithine through ornithine decarboxylase (ODC) results in excess GAA accumulation. As such, in a Phase 0 trial, we will evaluate in situ glioma responses to polyamine depletion via ODC inhibition (Difluoromethylornithine, DFMO), with or without blockade of polyamine uptake (AMXT 1501), to identify candidate extracellular biomarkers of target engagement and cytotoxicity. Methods: Patients will be recruited who are undergoing a clinically indicated subtotal resection for a known or suspected high-grade glioma (NCT05717153). At the end of the surgery, two microdialysis catheters will be implanted for post-operative microdialysis, one in residual tumor and one in brain adjacent to tumor for an internal control. Beginning on post-operative day (POD) 1, patients will be randomized to one of the following three groups, including administration of vehicle, DFMO (500 mg, PO, BID) and AMXT 1501 (600 mg, PO, BID): 1) DFMO + AMXT 1501 (POD1-5); 2) Vehicle (POD1–POD2), followed by DFMO + AMXT 1501 (POD3-POD5); 3) DFMO alone (POD1–POD2), followed by DFMO + AMXT 1501 (POD3- POD5). Throughout this time, extracellular metabolite levels of polyamines, guanidinoacetate, and glutamate will be quantified from microdialysate collected every two hours from intraoperatively implanted 100 kDA microdialysis catheters. The primary outcome of this study is to determine how polyamine depletion impacts extracellular intratumoral guanidinoacetate abundance. The secondary outcomes of this study are to (1) determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ, and (2) assess the feasibility of longitudinal microdialysis for pharmacodynamic analysis within live human gliomas in situ in the post-operative setting. Clinical trial information: NCT05717153 .

BACKGROUND AND OBJECTIVES: No new drug has improved survival for glioblastoma since temozolomide in 2005, due in part to the relative inaccessibility of each patientʼs individualized tumor biology and its response to therapy. We have identified a conserved extracellular metabolic signature of enhancing high-grade gliomas enriched for guanidinoacetate (GAA). GAA is coproduced with ornithine, the precursor to protumorigenic polyamines through ornithine decarboxylase (ODC). AMXT-1501 is a polyamine transporter inhibitor that can overcome tumoral resistance to the ODC inhibitor, difluoromethylornithine (DFMO). We will use DFMO with or without AMXT-1501 to identify candidate pharmacodynamic biomarkers of polyamine depletion in patients with high-grade gliomas in situ . We aim to determine (1) how blocking polyamine production affects intratumoral extracellular guanidinoacetate abundance and (2) the impact of polyamine depletion on the global extracellular metabolome within live human gliomas in situ. METHODS: DFMO, with or without AMXT-1501, will be administered postoperatively in 15 patients after clinically indicated subtotal resection for high-grade glioma. High–molecular weight microdialysis catheters implanted into residual tumor and adjacent brain will be used for postoperative monitoring of extracellular GAA and polyamines throughout therapeutic intervention from postoperative day (POD) 1 to POD5. Catheters will be removed on POD5 before discharge. EXPECTED OUTCOMES: We anticipate that GAA will be elevated in tumor relative to adjacent brain although it will decrease within 24 hours of ODC inhibition with DFMO. If AMXT-1501 effectively increases the cytotoxic impact of ODC inhibition, we expect an increase in biomarkers of cytotoxicity including glutamate with DFMO + AMXT-1501 treatment when compared with DFMO alone. DISCUSSION: Limited mechanistic feedback from individual patientsʼ gliomas hampers clinical translation of novel therapies. This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.

Abstract INTRODUCTION The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD‐mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low‐fat‐diet intervention. METHODS Prediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low‐fat American Heart Association diet or high‐fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6‐week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals’ microbiome and metabolome throughout the dietary interventions. RESULTS Participants with MCI on the MMKD had lower levels of GABA‐producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA‐regulating microbes Akkermansia muciniphila . MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase‐containing microbes and an altered bile acid pool, suggesting reduced gut motility. DISCUSSION Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut‐transit time.