Citations

Abstract Background Ten years after the original publication, the Centiloid framework is now broadly used to harmonize amyloid‐PET quantification, facilitate data sharing and comparison across cohorts, and even assist visual interpretation in clinical settings. We evaluated the global implementation of Centiloids by comparing their distribution and corresponding positivity thresholds across cohorts. Methods We gathered data from publicly available cohorts and reached out to investigators across the world to collect cross‐sectional Centiloids, demographic and clinical information, and visual read data. Gaussian mixture models (GMM, k=2) were fitted to Centiloid values for each cohort and cutoffs were calculated as mean + 2SD of the lower Gaussian. When visual reads were available, we determined Centiloid cutoffs that maximized correspondence with visual reads (Cohen's kappa). Data was combined across cohorts using random effects meta‐analyses. Results As of January 2025, we included 37 cohorts ( n = 41,678 participants) with heterogeneous pipelines, radiotracers, and clinical and demographic characteristics (Table‐1). The low Gaussian peaks ranged from ‐9 to 10CL; the meta‐analysis identified a common peak at 1CL. The second peaks were more heterogeneous (range=38‐102CL; meta‐analysis outcome=64CL). Across cohorts, the proportion of cognitively unimpaired versus impaired participants impacted the position of both peaks, with better separation in cohorts enriched in impaired individuals (Figure 1C). The meta‐analysis indicated a GMM‐based cutoff of 19CL (95%CI: 16‐21CL, Figure 1B); subgroup analyses showed no evidence of significant effect between single versus multicenter settings (17 versus 20CL, p = 0.30), MRI‐based or PET‐only processing (18 versus 19CL, p = 0.88), and no evidence of difference across radiotracers (Flutemetamol: 16CL; PIB: 17CL, Flutafuranol: 18CL, Florbetaben: 19CL, Florbetapir: 20CL, p = 0.78). In a subset of 29,496 participants with visual reads available, binary visual reads corresponded well to Centiloids (common kappa=0.86, Figure 2A). The visual read‐based cutoff of 24CL (95%CI: 21‐27CL, Figure 2B) maximized correspondence between visual read and quantification and was slightly higher than the GMM‐based cutoff. All meta‐analysis models showed high non‐random heterogeneity (I 2 >80%) across studies, suggesting non‐random differences in peaks and cutoffs. Conclusions Meta‐analysis‐based cutoffs align well with thresholds from the existing literature. High heterogeneity among studies underscores the need to investigate contributing factors, raising concerns about applying common cutoffs.

The success of living donor liver transplantation (LDLT) has bridged the growing gap between organ demand and availability in patients with liver failure or liver cancer. Safety of the living liver donor (LLD) is paramount, and astute intraoperative management plays a critical role in ensuring optimal outcomes for them. Given that intraoperative surgical and anesthesia practices vary widely across centers, the International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a global consensus conference in Toronto in March 2025 to develop guidelines for intraoperative management of the LLD. This manuscript details the recommendations on intraoperative considerations for the safety of LLD developed by Working Group II of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. Working Group II focused on intraoperative monitoring, fluid and ventilation strategies, surgical techniques for vascular and biliary division, surgeon and center-specific experience, and intraoperative crises planning. These guidelines aim to support both established and emerging LDLT teams to ensure high-quality and safe intraoperative care for the LLD.

Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.

Abstract Objective Lymphoepithelial carcinoma of the salivary gland (LECSG) is a rare malignancy. The purpose of this study is to evaluate the clinical features of LECSG with a focus on the role of Epstein‐Barr virus (EBV). Data Sources PubMed, Embase, Web of Science, institutional pathology Natural Language search tool. Review Methods Retrospective review of patients diagnosed with LECSG at a single institution and a systematic literature review. Full text articles in English were included. Results 285 cases of LECSG identified via literature review and an additional 10 within our institution. Most tumors were in the parotid gland (70.5%). Lymph node metastasis was observed in 28%. Most cases were in Asian or Inuit patients (70.5%). EBV association was positive in 52%, and 87.6% of these were in endemic populations. Treatment primarily involved surgical resection (65.8%), often combined with adjuvant therapy (50.2%). No significant differences in disease‐free survival (DFS) or disease‐specific survival (DSS) were observed by EBV status. Advanced tumor stage was associated with worse DFS ( P < .0001) and worse DSS ( P < .0001). Lymph node metastasis was also associated with reduced DSS ( P = .04). Independent predictors of poorer DFS and DSS included late tumor and endemic region of origin. Conclusion This comprehensive analysis of 295 salivary gland LEC cases provides valuable insights into the clinical behavior, pathological features, and treatment outcomes of this rare malignancy. The study highlights the potential role of EBV in tumor pathogenesis, particularly in endemic populations, and emphasizes the need for further research to establish optimal management strategies.

Abstract Objective Intraoperative parathyroid hormone (ioPTH) monitoring is crucial during parathyroid surgery to ensure chemical cure. However, delays in processing can prolong operative times. This study evaluates the effectiveness of a checklist to expedite ioPTH assay processes. Methods A multidisciplinary checklist was developed to standardize ioPTH collection and workflow. Thirty patients treated with use of the checklist were prospectively studied, while 30 patients treated without use of the checklist were retrospectively reviewed. Time intervals for post–15‐minute ioPTH assay results were compared. Results Thirty age‐ and sex‐matched patients were included in each group (n = 60) involving 5 surgeons. The intervention and control group had a mean baseline PTH of 140.9 and 130.3 pg/mL and a post–15‐minute ioPTH of 69.6 and 52.0 pg/mL, respectively. The mean time from sample collection to the post–15‐minute ioPTH assay result was significantly reduced in the intervention as compared to the control group (22.2 vs 33.3 minutes; P < .01). The proportional operative time spent awaiting ioPTH assay results was also reduced (24.4 vs 34.1%; P < .01). In subgroup analysis, a significant difference in the total operative time was found in adenomatous disease (68.0 vs 92.2 minutes, P < .05) but not four‐gland hyperplasia (119.3 vs 142.3 minutes). Discussion The implementation of a simple intraoperative checklist effectively reduces the overall ioPTH assay processing time, creating a more efficient surgical workflow. It is low‐cost and requires minimal additional resources. Implications for Practice This quality improvement intervention holds promise for broader adoption in parathyroid surgery to reduce delays and optimize patient care.

Abstract Background Ten years after the original publication, the Centiloid framework is now broadly used to harmonize amyloid‐PET quantification, facilitate data sharing and comparison across cohorts, and even assist visual interpretation in clinical settings. We evaluated the global implementation of Centiloids by comparing their distribution and corresponding positivity thresholds across cohorts. Methods We gathered data from publicly available cohorts and reached out to investigators across the world to collect cross‐sectional Centiloids, demographic and clinical information, and visual read data. Gaussian mixture models (GMM, k=2) were fitted to Centiloid values for each cohort and cutoffs were calculated as mean + 2SD of the lower Gaussian. When visual reads were available, we determined Centiloid cutoffs that maximized correspondence with visual reads (Cohen’s kappa). Data was combined across cohorts using random effects meta‐analyses. Results As of January 2025, we included 37 cohorts ( n = 41,678 participants) with heterogeneous pipelines, radiotracers, and clinical and demographic characteristics (Table‐1). The low Gaussian peaks ranged from ‐9 to 10CL; the meta‐analysis identified a common peak at 1CL. The second peaks were more heterogeneous (range=38‐102CL; meta‐analysis outcome=64CL). Across cohorts, the proportion of cognitively unimpaired versus impaired participants impacted the position of both peaks, with better separation in cohorts enriched in impaired individuals (Figure‐1C). The meta‐analysis indicated a GMM‐based cutoff of 19CL (95%CI: 16‐21CL, Figure‐1B); subgroup analyses showed no evidence of significant effect between single versus multicenter settings (17 versus 20CL, p = 0.30), MRI‐based or PET‐only processing (18 versus 19CL, p = 0.88), and no evidence of difference across radiotracers (Flutemetamol: 16CL; PIB: 17CL, Flutafuranol: 18CL, Florbetaben: 19CL, Florbetapir: 20CL, p = 0.78). In a subset of 29,496 participants with visual reads available, binary visual reads corresponded well to Centiloids (common kappa=0.86, Figure‐2A). The visual read‐based cutoff of 24CL (95%CI: 21‐27CL, Figure‐2B) maximized correspondence between visual read and quantification and was slightly higher than the GMM‐based cutoff. All meta‐analysis models showed high non‐random heterogeneity (I 2 >80%) across studies, suggesting non‐random differences in peaks and cutoffs. Conclusions Meta‐analysis‐based cutoffs align well with thresholds from the existing literature. High heterogeneity among studies underscores the need to investigate contributing factors, raising concerns about applying common cutoffs.

ABSTRACT Background Isolated chromosome 5/5q losses (–5/5q) without TP53 mutations are associated with favorable outcomes in myeloid neoplasms (MN) with <5% blasts. However, the clinical implication of concurrent −5/5q and TP53 aberrations in MN with ≥5% blasts is poorly understood. Methods Patients with TP53 ‐mutated MN carrying ≥5% blasts assessing the prognostic impact of ‐5/5q on 24‐month overall survival (OS24) were examined. Results Of 587 patients, 515 (88%) exhibited −5/5q overwhelmingly in the context of a complex karyotype (98.3% vs. 61.1% complex karyotype without −5/5q; p < .0001) and multihit TP53 allelic state (88.3% vs. 56.9%; p < .0001). Proportions of patients with blasts ≥20% were comparable between groups with and without −5/5q; p = 0.26. Notably, patients with −5/5q exhibited significantly fewer coalterations; p < .0001. Looking at outcomes, presence of −5/5q was associated with shorter median 24‐month overall survival (7.8 months vs. 11.2 months; p Log‐rank = .012), an effect restricted to subgroups with blasts <20% ( p = .039; N = 163), absent −7/7q ( p = .007; N = 225), or WHO5‐defined single hit allelic state ( p = 0.030; N = 91). Importantly, −5/5q retained independent adverse prognostic significance regardless of TP53 allelic state in a multivariable model. Furthermore, among the subset of 75 (13%) patients undergoing allogeneic stem cell transplantation, −5/5q predicted significantly shorter median 5‐year posttransplant survival (16.2 months vs. median not reached; p Log‐rank = .009). Conclusions These findings emphasize the independent prognostic relevance of chromosome 5/5q losses underscoring the clinical relevance of cytogenetic testing for −5/5q even in this high‐risk cohort.

ABSTRACT Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia‐like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC‐containing brain organoids in modeling neurodegeneration and cell‐cell communications have not been well investigated. In this study, iPSC‐derived MGCs are co‐cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient‐derived iPSCs ( APOE ε4/ε4 and presenilin 1). The AD EV‐stimulated co‐culture organoids are treated with EVs from healthy MGCs or co‐culture. Differential responses of the co‐cultured organoids and the MGCs to AD EVs are demonstrated. The co‐cultured organoids mitigated pro‐inflammatory gene expressions. EVs from healthy MGCs or co‐culture reduced the expression of IL‐12β , iNOS , TREM2 , and CASS4 , which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA‐sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV‐based cell‐free therapeutics for AD treatment.