Citations

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

175 Background: BRAF V600E mutations occur in ~8–12% of metastatic colorectal cancer (mCRC) and are linked to poor prognosis, therapy resistance, and limited response to anti-EGFR monotherapy. While the BEACON trial established encorafenib plus cetuximab as standard, the added value of triplet regimens remains unclear. Clarifying the efficacy and toxicity of doublet vs triplet therapies is essential to optimize care in this high-risk group. Methods: Studies published across PubMed, Embase, and Google Scholar from inception till May 2025 with reported outcomes of the desired targeted therapies for BRAF V600E-mutated mCRC were screened and finally 12 studies included in this review. Data on efficacy parameters such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) as well as safety indicators such as adverse events (AEs), and discontinuation rates were extracted and analyzed. Results: In the ≥2nd-line setting, doublet and triplet regimens (doublet plus binimetinib) demonstrated improved outcomes compared with cetuximab plus irinotecan/FOLFIRI, with higher OS (7.2–9.2 vs 5.6 months), PFS (4.2–4.6 vs 1.5 months), DCR (65–75% vs 31%), and a comparable incidence of severe AEs (3–5% vs 4%). Panitumumab plus vemurafenib, also in the ≥2nd-line setting, reported an OS of 7.6 months, PFS of 3.2 months, and a DCR of 27%. In the 1st-line setting, the doublet regimen plus mFOLFOX6 with longer treatment duration (~50 weeks) showed improved outcomes compared with the doublet regimen plus higher-dose cetuximab, with higher OS (30.3 vs 19.5 months), PFS (12.8 vs 6.8 months), ORR (65.7% vs 45.6%), but also a higher incidence of severe AEs (46% vs 30%). Similarly, the cetuximab + vemurafenib + irinotecan regimen outperformed conventional chemotherapy (mFOLFOX6, FOLFOXIRI, or CAPOX) ± bevacizumab, with improved OS (25.3 vs 10–15 months), PFS (11.9 vs 7.5 months), ORR (63.2% vs 37–40%), DCR (94.7% vs 75%), and a lower rate of grade ≥3 AEs (34.2% vs 65%). Conclusions: The survival benefit observed with the doublet regimen was comparable to that of the triplet, but with lower rates of adverse events and treatment discontinuation, supporting current evidence that the doublet remains the preferred option for patients with BRAF V600E–mutated mCRC who have received one or more prior lines of therapy. Although adding conventional agents such as mFOLFOX6 to the doublet in the first-line setting improved OS, PFS, ORR, and DCR, this approach was associated with higher toxicity and discontinuation rates, raising questions about its overall benefit. Emerging data on vemurafenib in combination with cetuximab and conventional agents show promise, but further studies directly comparing encorafenib- versus vemurafenib-based regimens are warranted to optimize outcomes in this patient population.

Abstract Background Tau‐PET neuroimaging is increasingly applied to diagnose and stage, track progression, and assess response to putative disease‐modifying treatments in individuals with Alzheimer disease. However, it remains to be seen whether findings established in predominantly non‐Hispanic White (nHW) cohorts will generalize to Black and Latino participants who are underrepresented in dementia research. Method Community‐dwelling Black ( n = 83) and Latino participants ( n = 27) completed MRI (with quantification of white matter hyperintensity volumes), and amyloid‐ (PiB or florbetapir) and tau‐ (flortaucipir) PET brain imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Global and regional tau‐PET standardized uptake value ratios (normalized to the cerebellar crus) were determined in Black and Latino participants and compared with findings from an independent cohort of nHW participants ( n = 110), 1:1‐matched for age, sex, education, and global Clinical Dementia Rating®. Conditional logistic modeling compared 47 regions of interest, adjusted for false discovery rate. Relevant associations between flortaucipir retention and clinical outcomes were assessed using Spearman rank correlations. Result Eighty‐three Black (mean 72±10.8‐years‐old, 63% female, 33% cognitively impaired) and 27 Latino participants (mean 65.8‐years‐old, 56% female, 11% cognitively impaired) completed neuroimaging. Data were compared with findings in 110 matched nHW individuals. Global tau‐PET burden was similar between matched cohorts (Black and nHW participants, mean SUVR: 1.34±0.39 vs 1.36±0.37, p = 0.71; Latino and nHW participants, mean SUVR: 1.17±0.09 vs 1.20±0.11, p = 0.66). Lower flortaucipir uptake was noted in the caudate ( p = 0.005) and putamen ( p = 0.022) of Black/Latino participants (vs nHW), although differences attenuated following adjustment for white matter hyperintensity volume. Global flortaucipir retention increased with age (Black: Rho=0.31; Latino: Rho=0.46; nHW: Rho=0.27; p <0.05), amyloid Centiloids (Black: Rho=0.65; Latino: Rho=0.41; nHW: Rho=0.58; p <0.05), and cognitive impairment (i.e., Clinical Dementia Rating® Sum‐of‐Box scores, Black/Latino: Rho=0.31, p = 0.07; nHW: 0.76, p <0.001). Conclusion Tau‐PET patterns were similar across ethnoracial groups after adjusting for white matter hyperintensity volumes—a biomarker of small vessel disease. Flortaucipir retention increased with age, amyloid accumulation, and cognitive impairment across all cohorts. These findings affirm the clinical and research applications of tau PET in diverse cohorts. Acknowledgements : Flortaucipir precursor and technology was supported by Avid Radiopharmaceuticals.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Abstract Background Bedside cognitive screening tools intend to reliably and efficiently detect cognitive impairment in research, clinical, and community settings. Black American (BA) and Hispanic/Latino (H/L) adults obtain lower performance on widely used screeners, largely driven by demographics and structural and social determinants of health (SSDoH). This study characterized the performance of the Montreal Cognitive Assessment (MoCA) performance in a cohort of cognitively normal ethnoracially diverse adults while considering cohort‐specific factors that contributed to misclassification of impairment. Method Cognitively normal BA and H/L participants completed a comprehensive neurological assessment, neuropsychological testing, and MRI and amyloid‐ and tau‐PET imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Demographically adjusted MoCA cutoffs were applied to BA (MoCA ≤ 22) and WH/L (MoCA ≤ 24) subgroups. Hierarchical binary logistic regression assessed whether amyloid burden (Centiloid value) improved prediction of scoring below demographically adjusted MoCA cutoffs beyond demographic/SSDoH factors, including age, education, and Area Deprivation Index (ADI). Result Participants included 105 (47 WH/L, 58 BA/AA) cognitively normal adults (mean age = 64.71 years, SD = 8.91; 62.9% female) with average of 16.07 years of education (SD=2.35) and mild‐to‐moderate neighborhood disadvantage (mean ADI=47.60, SD=23.77). 40% of H/L participants (MoCA (≤ 24) and 17% of BA participants (MoCa ≤22) scored below demographically adjusted MoCA cut‐offs. For the H/L subgroup, the best fitting model included age, education, ADI, and amyloid burden ( R 2 = 0 .43, χ 2 = 10.98, p = 0.03). Age (OR=1.21, 95% CI: 0.986 – 1.487) and amyloid burden (OR = 0.83, 95% CI: 0.67 – 1.03) approached statistical significance as individual predictors ( p = 0.06, p = 0.09). In the BA/AA subgroup, the best fitting model included age, education and ADI only ( R 2 = 0.47, χ 2 = 9.06, p = 0.02), with education approaching significance as an individual predictor (OR=0.46, 95% CI: 0.21 – 1.01, p = 0.05). Conclusion Sociodemographic factors continued to drive low MoCA performance in cognitively normal individuals despite applying demographically adjusted cut‐off scores by subgroup. These factors differentially impacted performance among BA/AA and WH/L participants. Careful consideration of these factors is warranted to mitigate risk of overdiagnosing impairment based on cognitive screening across clinical and research settings.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Regenerative medicine is transforming how we restore tissue function, leveraging advances in cell and molecular biology, biomaterials, and engineered microenvironments. While there have been notable advances and rapid progress over the past few decades, ongoing challenges persist in the technical development and effective translation of these advancements to clinical care. This perspective highlights clinically promising examples and critically assesses present challenges in translating tissue regenerative medicine therapies from the bench to the clinic. We further examine the evolving landscape of regenerative medicine by describing strategies to optimize the cellular microenvironment, the impact of patient demographics, and the use of artificial intelligence to shape the future of this field.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.