Citations

Abstract Quantifying urine protein is critical for detecting and monitoring kidney disease. However, screens for proteinuria are unable to detect low levels of albuminuria. For this reason, our institution has long measured urinary total protein and osmolality on routine urinalysis specimens (RUS) and calculated a predicted 24-hour protein excretion (PER) based upon the protein to osmolality ratio (POR). Within the last decade, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been approved by the United States Food and Drug Administration (FDA) as a treatment for adults with type 2 diabetes mellitus, and these agents appear to be beneficial for many forms of proteinuric renal disease and confer renal protection. Therefore, we investigated whether the expected glucosuria and increase in urine osmolality while on SGLT2i would significantly alter the POR, and hence predicted PER, via a retrospective analysis of residual timed and randomly collected urine specimens. Between January 1st, 2014, until January 29th, 2025, 5820 patients with nearly contemporaneous (collected within one week of each other) timed collections and RUS were identified that included 5656 not on SGLT2i (Cohort A) and 164 patients prescribed SGLT2i (Cohort B). Total protein concentrations were assessed using a Roche Cobas c701 by using benzethonium chloride. The osmolality was determined via freezing point depression using a Precision Systems Inc Multi-OSMETTE, whereas glucose measurements were made using either an Arkray AX-4030 with AUTION Stick 9EB test strips or a Clinitek Status with Multistix 10 SG reagent strips. Predicted 24-hour protein results were then calculated from the POR using a published formula based upon prior clinical studies: 10(x·[log(protein/osmolality)]+y where x is 0.908 or 0.953 for males and females, respectively, and y is 2.8254 or 2.9739 for males and females, respectively. In Cohort A, there was good correlation between the predicted and measured 24-hour PER (Spearman correlation coefficient, ρ = 0.78), although the predicted PER underestimated the measured PER (Passing-Bablok regression, y = 1.54x-20.97 mg/24 hr). Importantly, a strong correlation (ρ = 0.93) and similar distribution (p=0.17) were found between the predicted and measured PER in Cohort B, with a much-reduced proportional bias (y = 1.06x+62.96 mg/24 hr). Furthermore, comparison of the difference between the predicted and measured PER between the two cohorts demonstrated the same prediction accuracy (p = 0.65), with a median difference (interquartile range) of 79 mg/24 hr (256) and 109 mg/24 hr (480) for Cohort A and B, respectively. Finally, a strong correlation (ρ = 0.85), similar distribution (p = 0.23), and little bias (y = 0.96x+28.14 mg/24 hr) existed between the predicted and measured PER for all patients with overt glucosuria (urine glucose ≥1000 mg/dL, n = 348). In summary, these data suggest that the established formula for predicted PER on RUS is equally valid for patients on or off SGLT2i, and that this result is a useful clinical estimating tool.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Abstract Glioblastoma (GBM) and Alzheimer’s disease (AD) are devastating, age associated disorders with no cure. Epidemiologic data has established an inverse comorbidity between AD and cancer, including GBM, with up to a 50% reduction of cancer incidence in AD patients. While the underlying biology remains unclear, myeloid cells, which are central players in both neurodegeneration and tumor immunity, may serve as a mechanistic link. We hypothesize that myeloid cells activated by pre-existing AD pathology suppress tumor growth more effectively than homeostatic microglia. In this study, age-matched APPNL-G-F/MAPT double knock-in (henceforth “AD”) and wildtype (WT) mice received orthotopic xenografts of syngeneic GBM cell lines (GL261, SB28) (n=15/sex/genotype). We observed a significant survival difference, with AD mice living an average of 20% longer than WT mice (p<0.0001). In vivo luciferase imaging revealed impaired engraftment of tumor cells in AD mice compared to WT a week post-engraftment (p<0.05). At the microscopic level, tumors in AD mice were found to have nearly 2-fold the amount of tumor-infiltrating myeloid cells (p<0.01), with the proportion of anti-tumoral “activated” myeloid cells also being greater (p<0.05). Tumors in AD mice were found to have markedly higher immune infiltrate at the tumor rim and margin (p<0.001). We also observed striking astrogliosis (GFAP+) and microgliosis (P2RY12+) in both the tumor rim (p<0.05) and margin (p<0.01) in AD animals. This robust glial response was significantly higher in AD mice bearing tumor compared to both WT mice bearing tumor and sham AD mice. Lastly, we utilized a luciferase stain to visualize tumor cells that invaded beyond the bulk tumor. We found that both the quantity (p<0.01) and invasion distance of tumor cells (p<0.05) was lower in AD mice. We demonstrate that an AD-induced inflammatory microenvironment antagonizes glioma growth, providing a foundation for novel GBM treatment strategies that potentially exploit these immune signals.

Abstract The 5-year survival rate for metastatic melanoma (MM) is 35% with rates increasing to ~50% with immune checkpoint blockade (ICB) treatment. Unfortunately, melanoma brain metastases (MBM) develop in nearly half of MM patients and often relapse rapidly following ICB treatment. MBM resistance to ICB can be attributed to tumor-associated macrophages (TAM). Transcriptional profiling of MM revealed that TAMs possess a lipidated phenotype suggesting that aberrant lipogenic processes confer ICB resistance. Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that is overexpressed in MM and may cause TAM lipidation. SCD serves as an attractive target for inhibition and combination with ICB for treating MBM. We hypothesize that SCD overexpression produces lipid-rich tumor cells that trigger a phenotypic switch towards immunosuppressive lipid-laden macrophages (LL-Mø). Clinical correlation analysis was conducted to assess SCD expression with ICB response. scRNA-seq data of MBM were analyzed to assess TAMs exhibiting lipidated phenotype. Phagocytosis and lipid transfer was assessed via macrophage and melanoma co-culture using time-lapse microscopy. In-silico modeling and LC-MS/MS was performed to assess blood brain barrier (BBB) penetrance of two small molecule inhibitors of SCD (SCDi): MTI-301 and MF-438. Clinical correlation analysis of MM patients revealed high SCD expression associated with decreased survival of patients treated with ICB. scRNA-seq analysis of MBM revealed upregulation of de novo lipogenesis and cholesterol uptake transcripts within TAM populations. Time-lapse co-culture studies reveal rapid lipid accumulation in macrophages. In-silico modeling predicted SCDi BBB penetration and was corroborated by LC-MS/MS. MBM are notoriously difficult to treat due to poor drug penetrance into CNS and unique microenvironment. We demonstrate that macrophages reprogram towards immunosuppressive LL-Mø, which can be exploited for anti-tumor targeting. The potential for SCDi to synergize with ICB in MBM may improve patient outcomes. MTI-301 is approved for first-in-human clinical trial starting end of 2025.

Abstract BACKGROUND While most meningiomas are classified as low-grade tumors with indolent behavior, a subset is characterized by a more aggressive clinical course and patients undergo repeated resections and courses of radiation. Once these therapies fail, prognosis is poor and progression-free survival (PFS) rates at 6 months (PFS-6) are estimated to only be 43.6% for WHO grade 1 and 38% for WHO grade 2/3 meningiomas. Effective medical therapies are limited. Somatostatin receptor 2 (SSTR2) is expressed in a majority of meningiomas and represents a suitable treatment target. [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) is an SSTR2-targeted radioligand therapy, established as standard of care in the treatment of certain neuroendocrine tumors. Two ongoing non-randomized studies of 177Lu-Dotatate in meningiomas have reported encouraging efficacy compared to historical benchmarks. METHODS/STUDY DESIGN The MOMENTUM-1 study (RTOG 3523, NCT#06955169) is a multicenter, randomized, open-label study of 177Lu-Dotatate in adult patients with progressive intracranial WHO grade 1-3 meningiomas. Up to 130 eligible subjects are randomized in a 2:1 fashion to 177Lu-Dotatate at 7.4 GBq (200 mCi) every 4 weeks for 4 (+2 optional) doses or standard of care (SOC) medical therapy as defined by the protocol and deemed appropriate by the local investigator. Treatment responses are assessed by gadolinium-enhanced MRI brain and [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET imaging. At time of progression, cross-over from the SOC to the interventional treatment arm is allowed. The primary endpoint is PFS. Secondary endpoints include PFS-6, OS-12, OS, response assessments (ORR, DCR), safety/tolerability, and patient-reported outcomes. RESULTS/CONCLUSION MOMENTUM-1 is a multicenter, randomized, open-label, phase II study of 177Lu-Dotatate in adult patients with progressive WHO grade 1-3 meningioma. This clinical trial is expected to start enrolling patients in the United States in the third quarter of 2025. Details on study design, eligibility criteria for subject enrollment and study site eligibility criteria will be presented.

Abstract BACKGROUND [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET is a promising imaging modality for post-operative meningioma delineation and outcome assessments following stereotactic radiosurgery. However, its utility for response assessment following other meningioma therapies, including somatostatin receptor 2 (SSTR2) targeting [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) therapy is insufficiently understood. Here we report the 68Ga-Dotatate PET results, prospectively obtained in patients with treatment-refractory meningioma who enrolled in a phase 2, open-label clinical trial (NCT03971461) evaluating the radiopharmaceutical 177Lu-Dotatate. METHODS Patients underwent 68Ga-Dotatate PET during screening and 24±2 weeks following treatment with 177Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI and 68Ga-Dotatate PET using lesional Krenning score and lesional to superior sagittal sinus (SSS) maximum standardized uptake value (SUVmax) ratio (SUVR (lesion/SSS)). RESULTS Eight patients with 16 lesions were assessed. By RANO criteria, the best radiographic response was stable disease (SD) in 7 patients (14 lesions) and partial response (PR) in 1 patient (2 lesions). Krenning score was assessed in 14 lesions (Krenning 4/3/2/1 in 3/4/5/2 lesions). Following 177Lu-Dotatate, Krenning score was reduced by ≥1 point in 9 and remained stable in 5 lesions. SUVR (lesion/SSS) was evaluated in 16 lesions. Compared to baseline, SUVR (lesion/SSS) at 6 months was partially reduced (PR, ≥50%) in 2 lesions, minimally reduced (MR, <50% and ≥25%) in 3 lesions, and stable (SD, <25% reduction and <25% increase) in 11 lesions. CONCLUSIONS 68Ga-Dotatate PET is a promising imaging biomarker in patients with advanced meningioma. Treatment with 177Lu-Dotatate led to substantial reduction in SUVR (lesion/SSS) in a subset of patients. In contrast to other reports, 68Ga-Dotatate assessments were generally concordant with post-gad T1 based MRI assessments per RANO. Updated results in an expanded group of patients will be presented.

Abstract IDH-wildtype diffuse astrocytic gliomas with lower-grade histological features alongside specific genomic alterations (e.g., TERT promoter mutation, EGFR amplification, gain Chr7/loss Chr10) are presently diagnosed as glioblastoma, IDH-wildtype (GBM) under WHO 2021 criteria. Previous analyses categorized these into “early/evolving” or “surgically undersampled” GBMs. However, it remains unclear whether these tumors share identical clinical and prognostic features with histologic GBM. Data from IDH-wt molecular GBMs across six institutions were aggregated. Astrocytic IDH-wt tumors of any grade that lacked necrosis or microvascular proliferation on initial histopathology yet exhibited molecular alterations consistent with WHO 2021 GBM diagnosis, were included. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups based on overall survival (OS). Among the 264 patients included, the median age was 60 years (IQR: 51-67), with 162 (61%) being male. Additionally, 210 (80%) were diagnosed since 2016, and 216 (82%) received chemoradiation plus adjuvant temozolomide (GBM-SOC). The median follow-up period was 3.9 years (95% CI: 3.4, 4.6). Identified univariate risk factors for worse survival included older age, biopsy-only status, EGFR amplification, absence of initial adjuvant treatment, low post-operative KPS, and tumor histologic grade of 3. RPA divided patients into four distinct survival groups (p<0.0001). The “best” risk group comprised lower grade (<=2) tumors (n=58, median OS (mOS): 40 months (95% CI: 33, NA)). The “second best” group included Grade 3 patients receiving GBM-SOC without steroids during initial RT (n=139, mOS: 25 months (95% CI: 22, 28)). The “second worst” group encompassed Grade 3 patients who were on steroids during initial RT while receiving GBM-SOC (n=38, mOS: 15 months (95% CI: 13, 20)). The “worst” group contained Grade 3 tumors that had not undergone SOC (n=29, mOS: 9 months (95% CI: 4, 26)). These data show that histologic features and treatment are strong indicators of patient outcomes.

Abstract BACKGROUND The phase III ECOG-ACRIN E3F05 trial tested whether combined therapy with radiation and concomitant followed by adjuvant temozolomide is more effective than radiation alone in patients with grade II gliomas. The study incorporated 1p/19q analysis but predated assessment of IDH mutational status. We previously reported that the addition of temozolomide to radiotherapy significantly improved overall survival in grade II gliomas, with similar hazard ratios in co-deleted (0.56) and non-codeleted (0.53) tumors. Herein we incorporate the results of DNA methylation profiling to examine outcomes in IDHmt, non-codeleted subjects as well as co-deleted ones. METHODS All 172 subjects underwent 1p/19q co-deletion analysis as a stratification factor, 1p and 19q deletion analysis was performed on formalin-fixed paraffin-embedded (FFPE) gliomas by Fluorescent In Situ Hybridization (FISH) following standard methods, 97/172 (56.3%) had tissue with 60% or more tumor content available for DNA methylation profiling using Heidelberg classifier v12 and Bethesda Classifier 2.0 to ascertain classification as IDH mutant glioma and alternative evaluation of 1p/19q co-deletion status. RESULTS Of the 172 subjects, 74 (43.0%) had 1p/19q codeletion by FISH, 38 (22.1%) were IDHmt without codeletion, 14 (8.1%) were IDHwt, and 46 (26.7%) were non-codeleted with unknown IDH status (these include n=4 pts originally classified as 1p/19q undetermined). With a median follow-up of 130 months, the addition of TMZ to RT improved OS in patients with IDHmt, non-codeleted tumors (HR 0.15 (0.03-0.74)) and 10-year OS from 39% to 80%. In codeleted tumors, the addition of TMZ improved OS (HR 0.51 (0.19-1.42)) and 10-year OS from 68% to 90%. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and IDHmt, non-co-deleted grade II gliomas.

Abstract BACKGROUND Patients with primary brain tumors often have very complex histories, but an accurate understanding of their care timeline is critical to provide the best care possible. Extracting pertinent facts from the medical record can be time consuming and frustrating. We sought to apply generative AI large language models (LLM) to this problem in order to supply providers with concise, accurate, and focused data including graphs and tables. METHODS After evaluating multiple LLMs, GEMINI 2.5 Pro was selected. Prompt engineering was iteratively refined across a range of patients to generate concise outputs using tables, graphs, and prose to describe timing of chemoradiation, tumor markers, procedures, and trends in MRI results. The model inferred BT-RADS scores from the MRI report prose. Using a 5-point Likert scale, neuroradiologists assessed the AI-output both prospectively and retrospectively comparing it to the medical record. LLM’s compared AI summaries to source material. RESULTS Six neuroradiologists each ranked 25 prospective patient outputs as accurate (82%/16%/1%), useful (94%/6%/0%), trustworthy (86%/13%/1%), and satisfactory (86%/10%/1%) for Likert ratings of highly agree/agree/neutral, respectively. No responses were disagree or highly disagree. Interobserver agreement was high (Gwent AC2 > 0.95). The LLM evaluation of referenced portions of the record determined > 85% of summary statements were supported by source documents. While users estimated time savings of a 1-10 minutes per case, they felt the greater benefit was having more organized data presented efficiently. CONCLUSIONS AI summaries of the medical record of complex patients with primary brain tumors give providers an accurate, well-organized display of the pertinent facts necessary for high quality care and save time in chart review. These summaries, which are generated early each morning, have been found to be helpful and are now being incorporated into our clinical practice and multidisciplinary tumor board.