Citations

Abstract Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1 —a core adaptor in the CME complex—was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.

Study Design. Post hoc analysis of prospectively-collected data. Objective. To identify factors predicting the most (and least) satisfaction following surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data. Patient satisfaction affects long-term outcomes after surgery but the preoperative factors that influence postoperative satisfaction have not been well studied in patients with CSM. Methods. We conducted a post hoc analysis of prospectively-collected data from the Quality Outcomes Database (QOD) CSM registry cohort. Baseline and surgical characteristics were compared for patients with CSM reporting the most [North American Spine Society Satisfaction Score (NASS) 1] and least (NASS 4) satisfaction 24 months postoperatively. A multivariable logistic regression model was constructed using backward stepwise elimination to determine significant predictors of most versus least satisfaction. Twenty-four-month patient-reported outcomes (PROs) were compared. Results. Overall, 1141 patients were prospectively enrolled with 948 (83.1%) reaching 24-month follow-up. Of these, 699 met prespecified inclusion criteria: 610 (87.3%) were most satisfied and 89 (12.7%) were least satisfied. Though there were mean improvements in all 24-month PROs for the most satisfied cohort ( P <0.001), there were no significant improvements in 24-month PROs for the least satisfied cohort ( P >0.05). Using multivariable logistic regression modeling, a preoperative symptom of upper extremity weakness (OR=2.5, P =0.003), subjective myelopathy (OR=2.0, P =0.04), absence of numbness complaints (OR=2.2, P =0.003), symptom duration under 12 months (OR=1.6, P =0.047), Caucasian race (OR=2.3, P =0.001), participation in activities outside of the home (OR=2.0, P =0.04), anterior approach (OR=2.3, P <0.001), and higher baseline quality of life (OR=4.0, P =0.01) were predictive of the most satisfaction. Conclusion. Compared with the least satisfied, those most satisfied following surgery for CSM more often had a preoperative symptom of arm weakness, subjective myelopathy, the absence of numbness complaints, symptom duration under 12 months, higher baseline quality of life, and participation in activities outside of the home. Compared with a posterior approach, an anterior approach was associated with the most satisfaction. Taken together, early surgical treatment--before myelopathic symptoms significantly impact one's quality of life--may be considered to optimize patient satisfaction following CSM surgery.

Abstract Objective Current clinical risk models were developed for longer-term breast cancer risk stratification and therefore have limited utility for predicting short-term (1-year) breast cancer risk. This study evaluates the performance of a mammogram-based artificial intelligence (MB-AI) risk model for predicting breast cancer diagnosis within 1 year in high-risk women. Methods This retrospective case-control study included 340 women who underwent supplemental MRI screening within 1 year following a negative mammogram, of whom 101 (29.7%) developed breast cancer and 239 (70.3%) remained cancer-free during the same interval. Artificial-intelligence–assigned absolute 1-year risk scores, Tyrer–Cuzick (TC) lifetime and 10-year scores, and Gail lifetime and 5-year scores were analyzed. Model discrimination was evaluated using receiver operating characteristic (ROC) curves. Sensitivity, specificity, and predictive values were estimated at optimal cutoffs. Subgroup analyses examined model performance across genetic, menopausal, reproductive, and tumor-based strata. Results The MB-AI model demonstrated the highest overall discriminative ability (area under the curve [AUC] = 0.812), with strong performance in extremely dense breasts (AUC = 0.976). By comparison, TC lifetime (AUC = 0.625) and Gail lifetime (AUC = 0.668) models showed modest discrimination, while TC 10-year and Gail 5-year models did not discriminate (AUCs ≤0.49). Subgroup analyses showed consistent performance across clinical and pathological categories. The MB-AI model also showed an AUC comparable to that of previously developed AI models. Conclusions A mammogram-based AI model demonstrated improved performance compared with traditional clinical risk models for predicting breast cancer diagnosis within 1 year in women undergoing supplemental screening. These findings support that AI-based approaches may reflect both short-term risk and early imaging features of occult disease and suggest further investigation of AI as a complement to existing risk stratification strategies.

ABSTRACT Introduction Chronic gastroduodenal disorders remain challenging to manage, and new diagnostic approaches are needed to better delineate underlying causes and guide therapeutic decisions. Body Surface Gastric Mapping (BSGM) technologies combine high‐resolution gastric myoelectrical activity measurements with symptom and psychological profiling to provide mechanistic insights into gastric motor and sensory dysfunction. An International Working Group convened to derive the first consensus classification of BSGM phenotypes (the “Auckland Classification”). Methods A Technical Group conducted a systematic literature and clinical database review to identify objective test biomarkers and candidate disease mechanisms. Evidence was synthesized across 50 studies (primarily in gastroparesis, chronic nausea and vomiting, and functional dyspepsia), and BSGM phenotypes were mapped to existing treatment guidelines. Subsequently, iterative review and development of consensus was performed by a Consensus Group composed of international clinical experts familiar with BSGM. Eleven statements underlying the classification were then derived and circulated as a final survey to establish agreement. Results Six BSGM phenotypes were endorsed: three defined by myoelectrical abnormalities (Dysrhythmic, High Frequency, and Low Meal Response) and three by characteristic symptom associations (Sensorimotor, Continuous, and Delayed Onset Symptoms). Published studies plausibly linked these phenotypes to mechanisms including interstitial cell of Cajal depletion, vagal impairment, hypomotility, visceral hypersensitivity, gut‐brain dysregulation, and small bowel dysfunction. Phenotypes were also mapped to existing mechanism‐based treatment guidelines. Ten out of the eleven statements had > 80% agreement. Conclusions The Auckland Classification, derived by international consensus, presents a structured framework for BSGM‐defined patient phenotypes. Evidence and mechanism‐based treatment options are suggested for each phenotype to provide a foundation for research, further validation, and a pathway for integrating BSGM into clinical care.

Abstract: Cardiovascular disease (CVD) remains the leading cause of death worldwide. While advances in treatment have improved outcomes, the greatest gains in public health will come from primary prevention. Risk stratification is the foundation of CVD prevention. Traditional tools, such as pooled cohort equations (PCEs) and SCORE2, do not capture non-traditional risk factors and individual variability, driving efforts to refine existing approaches. We critically discuss emerging risk determinants for primary CVD prevention. Coronary artery calcium scoring can reclassify CVD risk but has limitations related to cost, access, and unvalidated improvements in clinical endpoints. Biomarkers such as apolipoprotein B and lipoprotein(a) may identify residual risk beyond LDL-C, particularly in patients with lipid discordance, but remain underused due to uncertain thresholds and the lack of prospective triallevel outcome data. Trials of colchicine in primary prevention have yielded mixed results, making the role of targeting inflammation unclear in CVD prevention. Polygenic risk scores can stratify genetic risk but face challenges in sensitivity, specificity, and generalizability. Multiomics approaches, while offering the promise of deeper phenotyping, lack established clinical applications and consensus on when their use is appropriate. Artificial intelligence may allow better prediction across cohorts but requires broader validation. Clonal hematopoiesis of indeterminate potential, a marker of inflammation and age-related CVD risk, lacks evidence supporting routine screening or intervention in younger, asymptomatic individuals. The proliferation of new risk stratification tools poses a key challenge: determining when additional data meaningfully alter clinical decisions. Until robust outcome-based evidence emerges, risk enhancers should guide, but not dictate, therapy in selected patients.

Radiation therapy is central to the management of gynecological cancers, including endometrial, cervical, ovarian, and vaginal malignancies. Despite advances in photon-based techniques, treatment-related toxicity remains significant owing to the anatomical proximity of pelvic targets to critical organs at risk (OARs), including the bowel, bladder, and bone marrow. Proton beam therapy exploits the Bragg peak to deliver a precise dose at depth with minimal exit dose, potentially reducing OAR exposure. This review develops the physical principles, dosimetric evidence, and early clinical data for proton therapy in gynecological malignancies, including cervical, endometrial, ovarian, vaginal, and vulvar cancers. Major focus is given to clinical conditions where conventional brachytherapy is not practical, and proton therapy may offer the greatest advantages, such as reirradiation for recurrent disease, post-operative pelvic irradiation, and extended field nodal treatment. This review also emphasizes current constraints that have slowed down wide clinical implementation, such as the lack of mature prospective data, cost, and accessibility. Finally, we emphasize future directions, including well-designed comparative trials, integration with systemic and immunotherapies, and adaptive treatment strategies. As the body of accumulated evidence evolves, the proton beam therapy potential for the treatment of gynecological malignancies has tremendously increased due to its role in safety and personalization of radiation treatment.

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

Abstract Background Tafamidis is a near-complete transthyretin kinetic stabiliser for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). It is administered orally, once daily, and has demonstrated a statistically significant reduction in mortality at 30 months vs placebo. Purpose Report findings from patients who received up to 7.5 years treatment with tafamidis in the phase 3 trial and its long-term extension (LTE) study. Methods In ATTR-ACT, patients were randomised (2:1:2) to blinded tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months. Patients continued their blinded tafamidis dose into the up to 60-month LTE study, until commercial prescription availability, or study termination. Those who received placebo in ATTR-ACT were randomized (2:1) to blinded tafamidis meglumine 80 mg or 20 mg in the LTE study. All patients were subsequently switched to open label tafamidis free acid 61 mg (bioequivalent to meglumine 80 mg). Outcomes were assessed over the entire 90-month follow-up. Results Of the 264 patients randomised to tafamidis in ATTR-ACT, 173 completed the trial and 170 continued to receive tafamidis the LTE study (Taf/Taf group). Of 177 patients randomised to placebo in ATTR-ACT, 85 completed the trial and 82 initiated tafamidis in the LTE study (Pbo/Taf group). Over a median follow-up of 54.2 months in the Taf/Taf group and 30.5 months in the Pbo/Taf group, incidence of all-cause mortality (ACM) was 54.5% and 71.2%. Median time to ACM was 47.5 and 30.3 months, resulting in a hazard ratio of 0.62 (95% CI: 0.49-0.79; P=0.0001; Figure). Incidence of cardiovascular-related mortality (CVM) was 42.0% and 57.1% in the Taf/Taf and Pbo/Taf groups. Median time to CVM was 47.6 and 30.3 months, resulting in a hazard ratio of 0.61 (0.47-0.81; P=0.0005). The total annual rate of all-cause hospitalisation in the LTE study was 0.69 in the Taf/Taf group and 1.14 in the Pbo/Taf group, and the total annual rate of cardiovascular-related hospitalisation was 0.36 and 0.63. Among patients remaining at each LTE study visit and with available data, improvement in New York Heart Association functional classification was more commonly seen in the Taf/Taf vs Pbo/Taf group. Mean observed reduction from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary score was significantly smaller in the Taf/Taf vs Pbo/Taf group at most LTE study visits. Treatment-related adverse events occurred in 11.2% of the Taf/Taf and 23.2% of the Pbo/Taf groups during the LTE study and were consistent with the known safety profile of tafamidis. Conclusions With up to 7.5 years of follow-up data, this analysis of ATTR-ACT trial and its LTE study is the longest reported to date for an ATTR-CM population treated with disease-modifying therapy. Findings demonstrate better long-term outcomes including survival, hospitalisation rates, quality of life, and heart failure symptoms with long-term tafamidis treatment. For image description, please refer to the figure legend and surrounding text.

Abstract TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer’s disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.