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Low protein (LP) diets improve metabolic health in rodents and humans. In rodents, LP diets are typically implemented by replacing protein with carbohydrates like sucrose or cornstarch, keeping diets isocaloric. However, humans can choose from many different types of carbohydrate, and how dietary carbohydrate quality - the precise composition of the dietary sugars - impacts the response to dietary protein remains largely unexplored. Here, mice were fed control (21% protein) or LP (7% protein) diets with four different carbohydrate sources: sucrose, a 1:1 glucose/fructose mixture, glucose, or fructose. While LP diets improved metabolic health across all groups in male mice, carbohydrate quality also significantly altered specific health outcomes, with fructose-fed mice having the lowest body weight and adiposity of all control diets. In female mice, responses to LP diets were influenced by carbohydrate quality, with certain sugars inducing a stronger metabolic response to LP diets than previously seen. Finally, in female APP/PS1 mice, a model of Alzheimer's disease, we find that although LP diets reduce A-beta; plaque burden irrespective of carbohydrate type, dietary sugar type does influence spatial memory. Together, these results demonstrate that while dietary protein is a critical determinant of metabolic and neurological health, carbohydrate quality influences these outcomes in a sex-specific manner.

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

In this retrospective cohort study at a quaternary referral hospital, 829 adult patients supported by extracorporeal membrane oxygenation (ECMO) between January 1, 2014, and October 31, 2024, were screened for ventilator-associated pneumonia (VAP). The incidence of VAP in ECMO-supported patients was 17.7 per 1,000 ECMO days (venoarterial [VA] ECMO, 22.1 per 1,000 ECMO days; venovenous [VV] ECMO, 13.8 per 1,000 ECMO days). Median time from ECMO cannulation to diagnosis of VAP was 4 (interquartile range [IQR], 3–8; range 1–84) days. Gram-negative bacteria comprised most respiratory pathogens. A significant increase in minimum ECMO sweep was noted from 2 days before to 1 day after VAP diagnosis (0.79 L/min increase, p = 0.004). Only 38 of 153 patients (24.8%) met National Healthcare Safety Network (NHSN) VAP definitions. After creating a modified VAP definition, which included an ECMO sweep increase of 0.5 L/min as evidence of worsening respiratory status, 78 (51.0%) met the modified definition. Those who met the modified VAP definition had worse in-hospital (60.3% vs. 28.0%, p < 0.001), 30 day (33.3% vs. 17.3%, p = 0.023), and 90 day (53.8% vs. 25.3%, p < 0.001) mortality compared with those who did not meet the modified VAP definition. The incorporation of ECMO parameters into diagnostic criteria may improve detection sensitivity, but further validation is necessary before implementation.

Abstract Burke, AA, Saine, ND, King, EL, Fields, JB, Jagim, AR, Miller, AD, Green, BC, and Jones, MT. Longitudinal modeling of pitching workload and countermovement jump performance as determinants of fastball velocity and consistency in collegiate baseball pitchers. J Strength Cond Res XX(X): 000–000, 2026—Maintenance of four-seam fastball (FSFB) velocity across the baseball season is critical, yet the extent to which workload and neuromuscular status relate to velocity is unclear. Thus, aims of the current study were to assess the relationship between external pitching workload metrics and FSFB velocity; quantify within-season FSFB velocity; and examine how countermovement jump (CMJ) performance predicts FSFB velocity. Collegiate pitchers ( n = 8) completed weekly CMJ testing during a 15-week, 53-game season. Countermovement jump metrics included jump height (JH), reactive strength index–modified (RSImod), peak braking force, and peak propulsive force normalized to body mass. Workload variables (innings, total pitches, FSFB pitches) and FSFB velocity were evaluated via repeated measures correlation (RMCORR). A longitudinal heat map visualized velocity trends, and a hierarchical location–scale model assessed predictors of mean velocity and variance. Repeated measures correlation showed weak negative associations between FSFB velocity and innings ( r = −0.15, p = 0.11), total pitches ( r = −0.18, p = 0.05), and FSFB pitches ( r = −0.18, p = 0.05). Heat map analysis identified 3 distinct velocity clusters. Location model results indicated no predictors of mean velocity. The scale model showed JH ( γ = −0.060, p = 0.001) predicted reduced velocity variance, and RSImod ( γ = 3.800, p < 0.001) predicted increased variance. Findings suggest that velocity patterns varied across athletes, where greater workloads were negatively associated with FSFB pitch velocity. Further, CMJ performance related to velocity stability rather than mean velocity. Routine longitudinal monitoring and continued strength-power training are recommended to support FSFB velocity.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of heterogenous hematologic malignancies characterized by the proliferation of blood cells and consist of myelofibrosis, polycythemia vera, and essential thrombocythemia. The NCCN Guidelines for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the aim of providing recommendations for the comprehensive care of adults with these diseases. The panel of experts convenes at least once a year to discuss requested changes to the Guidelines and to evaluate emerging data. These Guideline Insights focus on some of the recent updates for myelofibrosis.

Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P&lt;0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

Background Intraoperative indocyanine green fluorescence angiography (ICG-FA) is increasingly utilized to assess bowel perfusion during colorectal anastomosis. Although recent multicenter randomized trials have yielded mixed findings, pooled randomized evidence and 2025 SAGES guidance indicate an overall benefit, particularly in left-sided and rectal surgery. However, acquisition protocols, interpretation criteria, and reported endpoints remain heterogeneous. Main message ICG-FA reflects the dynamics of an intravascular dye signal and is affected by injection technique, hemodynamic status, camera geometry, display mode, and platform-specific processing. Visual interpretation shows substantial interobserver variability. Thus, single fluorescence-intensity snapshots are unstable for comparison. In contrast, time-intensity kinetics and spatial heterogeneity measures are more reproducible and physiologically meaningful. Among reported kinetic metrics, the time ratio (TR = T1/2Max/Tmax) is promising. However, current evidence is preliminary and needs multicenter validation. Proposal We propose a practical minimum acquisition and reporting standard for colorectal ICG-FA studies as an expert-opinion framework for future consensus development. This includes consistent reporting of ICG administration, physiological status at assessment, imaging conditions, camera geometry, analysis methodology, measured outcomes, decision impact, and software/version details. We also describe other relevant approaches, such as laser speckle contrast imaging (LSCI), hyperspectral imaging (HSI), and artificial intelligence (AI)-assisted interpretation. Conclusions The key question is no longer only whether ICG-FA should be used, but how its signal should be acquired, quantified, interpreted, and reported. Better standardization should improve comparability, support multicenter validation, and clarify where perfusion imaging adds the greatest clinical value.

Abstract Background Glioblastoma (GBM) is the most common malignant primary brain tumor and is associated with a poor prognosis. Repurposed posaconazole (PCZ) has demonstrated efficacy in vitro by targeting key metabolic pathways. The aim of this study was to determine the neuropharmacological profile of PCZ in patients with GBM through a Phase 0 first-in-human trial for this indication (NCT04825275). Methods We conducted an open-label, non-randomized, parallel-arm trial in participants with primary or recurrent GBM. Patients in the treatment arm received oral PCZ for 7-10 days presurgically to achieve steady-state concentrations. Microdialysis catheters were implanted to measure interstitial drug levels. Postoperative tissue and fluid samples were analyzed to evaluate PCZ pharmacokinetics (mass spectrometry) and pharmacodynamics, including vascular density, apoptosis, and metabolite concentrations (lactate and pyruvate) compared to controls. Results The trial was closed early due to slow accrual, enrolling 2 participants in the PCZ arm and three in the control arm. No drug-related safety issues were observed. Although PCZ was undetectable in microdialysate fluid, it accumulated in tumor tissue, with concentrations showing an association with CD31-measured endothelial content. PCZ-treated tumors exhibited trends toward lower BCL2 expression indicative of increased apoptosis, and significantly lower pyruvate levels in the tumor periphery compared to controls. Plasma lactate levels in treated patients normalized to control levels over 24 h. Conclusions Despite limited accrual, this trial provides the first clinical evidence that oral PCZ accumulates in human GBM tissue and shows preliminary signals of metabolic modulation. These findings provide biological rationale warranting further clinical investigation, potentially utilizing direct tissue sampling rather than microdialysis.

Abstract Recent single-cell transcriptomic studies of follicular lymphoma (FL) have revealed heterogeneity among malignant B (MB) cells and selected components of the tumor microenvironment (TME), but have been constrained by relatively small sample sizes and a lack of spatial context. We performed comprehensive cellular profiling and spatial dissection of over five million cells by integrating single-nucleus RNA sequencing (snRNA-seq) from 182 samples (FL, n = 167; control, n = 15) with single-cell spatial transcriptomics (ST) from 386 samples (FL, n = 365; control, n = 21). After stringent quality control, 1,289,073 and 3,968,427 cells from snRNA-seq and ST data, respectively, were analyzed. Unsupervised clustering of snRNA-seq data identified 58 TME cell subtypes. To extend this classification to the ST dataset, we integrated snRNA-seq and ST data by co-embedding them into a shared principal component space, enabling robust batch correction and cell-type label transfer across modalities. Using this supervised annotation framework, ST data recapitulated 54 TME cell subtypes. MB, proliferating MB (MBprolif), and healthy B (HB) cells were classified using sample-level unsupervised clustering in ST. Macrophages exhibited previously uncharacterized heterogeneity in transcriptomic profiles and spatial distribution. We identified CXCL13-expressing macrophage subtypes with high intra- and peri-follicular abundance, termed follicular macrophages (FMs). Non-negative matrix factorization of intrafollicular cell fractions identified five TME archetypes: FM, follicular stroma, two follicular T, and HB archetypes. The FM archetype was enriched for intrafollicular macrophages, including FMs, and showed a significantly higher proportion of grade 3A/3B cases (53.4%) compared to other archetypes (≤16.5%). It was also associated with a higher frequency of high tumor burden requiring treatment initiation rather than a watch-and-wait (WW) approach. Among patients managed by WW, those with the FM archetype showed significantly shorter event-free survival (EFS) compared to those with non-FM archetypes, whereas this association was not observed among treated patients. The percentage of intrafollicular macrophages (IFMP) showed excellent predictive performance for the FM archetype (area under the curve: 0.90). IFMP calculated in a published multiplex spatial protein imaging dataset from an independent cohort of 242 FL patients validated the associations between high IFMP and both pathology grade 3A/3B and shorter EFS in WW patients. Consistently, spatial neighborhood and cell–cell communication analyses revealed co-localization of FMs and MBprolif cells, forming a distinct niche with activated signaling mediated by FM-derived CXCL13, APRIL, and BAFF. Our integrative multi-modal analysis defines previously unrecognized cellular heterogeneity and spatial architecture in FL and highlights macrophage-enriched follicular ecosystems associated with aggressive clinicopathological features, providing a framework for improved biological understanding and patient management. Citation Format: Yoshiaki Abe, Bijal Thakkar, Atish Kizhakeyil, Ashley Wilson, Andrew L. Feldman, Jared Henderson, Amy Ayers, Sara Borgschatz, R. Andrew Harkins, Priya Lakra, Daisuke Kaji, Jonathon B. Cohen, David Russler-Germain, Eric Mou, Francisco Vega, Jennifer Chapman, Giorgio Inghirami, Carla Casulo, Izidore S. Lossos, Jean L. Koff, Chijioke Nze, Peter Martin, Sergei Syrbu, Kiran Vij, David L. Jaye, James R. Cerhan, Christopher R. Flowers, Anne J. Novak, Richard Burack, Dai Chihara, Mamiko Sakata-Yanagimoto, Joshua Tobin, Xubin Li, Michael R. Green. Spatially resolved microenvironment profiling reveals distinct follicular lymphoma archetypes [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A049.