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484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐ score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐ score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.

Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study. Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and &lt;100, and/or clonal BMPCs &gt;50% to &lt;60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months). At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P &lt;0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P &lt;0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P &lt;0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

Abstract Background Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. Methods TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. Results Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). Conclusions Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.