Citations

Abstract Purpose To evaluate alcohol intake trends and identify demographic, clinical, lifestyle and socioeconomic factors associated with alcohol consumption in late survivorship among breast cancer survivors. Methods Individuals diagnosed with stage 0–3 breast cancer enrolled in the Mayo Clinic Breast Disease registry between 2014 to 2022 reported their average weekly alcohol intake at baseline (time of diagnosis) and at approximately four years post-diagnosis. Alcohol intake was divided into four categories and cross-sectional associations with demographic, clinical, and lifestyle factors were examined using Monte Carlo-based Fisher exact tests and multivariable multinomial logistic regression. Changes in alcohol consumption from baseline to Year 4 were evaluated using Bowker’s test of symmetry and multinomial models. Results Among 719 participants, alcohol intake 4 years post diagnosis closely resembled baseline patterns, with 30.2% of patients reporting no alcohol use and 48.8% of patients consuming 1–4 drinks per week. Younger age and current smoking status were strongly associated with higher intake at Year 4. Exercise and better physical health were associated with higher alcohol intake in univariable models, however not in adjusted models. From time of diagnosis to Year 4, 15.6% of patients decreased their alcohol intake, 10.2% increased alcohol intake, and 74.3% reported no change. Higher levels of mild intensity exercise were associated with an elevation in alcohol intake over time. Conclusion Alcohol consumption remained stable in late survivorship, in contrast to the initial decline in alcohol use during early survivorship seen in this cohort. Younger age and smoking were key associations with higher alcohol intake.

Abstract Background The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC (PPBC) subtype, identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. Methods We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women aged ≤40 years included in the Young Women’s Breast Cancer Study. We analyzed data using univariable linear regression and multivariable sliced inverse regression to account for higher order interactions among biomarkers. Results In keratin-rich segments, progesterone receptor (PR) (P = 1.00 × 10−4) and PTEN (P = 1.00 × 10−3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (P = 4.00 × 10−4), SMA (P = 1.00 × 10−4), and NF-1 (P = 1.00 × 10−3). In keratin-poor segments, univariable significant positive associations were found for PR (P = 2.00 × 10−4) and PTEN (P = 1.00 × 10−3), whereas CD20 (P = 3.00 × 10−4) and CTLA4 (P = 4.00 × 10−5) were negatively associated; multivariable significant associations were found for fibronectin (P = 3.00 × 10−5) and pan-Akt (P = 1.00 × 10−3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN, and CD20 were strongest among women with the shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA, and CTLA4 replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T-cell exhaustion signature previously linked to poor prognosis among premenopausal women. Conclusion These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.

Background: There is no consensus scoring system for staging and prognosis in hepatocellular carcinoma (HCC), which is the fourth leading cause of cancer-related mortality worldwide. Commonly used systems include the albumin–bilirubin (ALBI) score, the Barcelona staging classification (Barcelona Clinic Liver Cancer, BCLC), the Model for End-Stage Liver Disease (MELD), and the model to estimate survival in ambulatory HCC patients (MESIAH). Liver secretion of pseudocholinesterase (PCHE) has been linked to liver function but is poorly studied in the natural history of HCC. We evaluated whether serum PCHE level predicts HCC mortality and whether it enhances existing scoring systems. Methods: We conducted a retrospective cohort study of individuals diagnosed with HCC. We collected variables including PCHE level, clinical data used in scoring systems, and time to mortality or liver transplant. We then analyzed the association between these variables and survival using Kaplan–Meier curves, Cox proportional hazards regression models, receiver operating characteristic (ROC) curves, and area under the curve (AUC) calculations. Results: We identified 420 individuals with HCC who were tested for PCHE levels, with a follow-up time of more than 20 years. There was a strong inverse relationship between PCHE level and overall survival, with the lowest quartile having high mortality and poor outcomes. Low PCHE level was associated with hepatitis C virus (HCV) infection, vascular invasion, poor liver function, and a high likelihood of liver transplant. In contrast, the highest quartile was associated with metabolic dysfunction–associated steatotic liver disease (MASLD) as the underlying cause. Compared with validated scoring systems, ALBI, BCLC, MELD 3.0, and MESIAH, the PCHE level was an independent predictor of mortality. PCHE levels could predict 3-month survival as well as or better than the other scoring systems, with an AUC of 0.74. PCHE level could also predict mortality related to hepatectomy. The addition of PCHE level to MESIAH and ALBI scoring systems could further improve the ability to predict overall mortality in HCC. Conclusions: PCHE is a reliable stand-alone biomarker of HCC prognosis. It is an independent predictor of mortality and can improve the accuracy of existing scoring systems. Improved risk stratification could improve outcomes by informing treatment decisions regarding hepatectomy or other interventions.

Background: Discovering risk biomarkers in small benign breast disease (BBD) biopsies is constrained by scarce tissue and microanatomic heterogeneity of terminal duct lobular units (TDLUs). We tested whether tissue-sparing tissue microarray (TMA)–based Digital Spatial Profiling (DSP) can deliver reproducible, biologically coherent protein measurements across benign lobules and breast cancers (BCs), and how well DSP aligns with standard immunoassays. Methods: We performed a pilot using tissues from the Mayo Clinic BBD cohort using TMAs representing four contexts: terminal duct lobular units (TDLUs) from BBD biopsies preceding BC and matched BBD-controls, subsequent BCs, and BC-associated TDLUs. We profiled 79 proteins by DSP (37 retained after QC) and benchmarked against chromogenic IHC and OPAL immunofluorescence. Reproducibility was evaluated using intraclass correlation coefficients (ICCs), cross-platform agreement (weighted kappa), marker correlations, and mixed-effects models with false-discovery-rate (FDR) control. Results: We analyzed 368 BBD-TDLU cores (88 cases; 88 controls), 204 BC cores and 110 BC-associated TDLU cores. ICCs were highest in BC tissues, and lower in BC-associated TDLUs and BBD-TDLUs. Agreement was slight–to-fair in TDLUs but moderate (ER/PR) to substantial (BCL2) in BC. DSP recapitulated expected immunologic correlations (CD45 with T-cell, B-cell, and macrophage markers) and tissue-type gradients (BC > BC-associated TDLUs > BBD-TDLUs). Exploratory case–control differences in BBD-TDLUs did not persist after FDR control. Conclusions: TMA-based DSP is feasible in archival breast tissues and yields biologically coherent, cross-platform-benchmarked profiles that are particularly robust in BC, while conserving scarce TDLUS and clarifying current limits of single-marker risk stratification from benign lobules. These data provide a foundation for refined sampling and expanded panels in future TDLU-focused studies.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.

Abstract Background Breast cancer (BC) survivors frequently experience sleep disturbances, which may persist for many years after treatment. This study aimed to describe trends in sleep-related symptoms over time and identify factors that may be associated with sleep disturbances in BC survivors. Patients and Methods Adult patients from the Mayo Clinic Breast Disease Registry were surveyed annually for up to 7 years post-diagnosis. Sleep disturbance severity was assessed using numeric rating scales for difficulty falling and staying asleep. Data from 3354 unique patients were analyzed, excluding those with metastatic disease or recurrence. Univariable and multivariable analyses were performed at the 1-year survey timepoint to evaluate disease and patient-related factors that were associated with increased sleep-related symptoms, and these factors were also assessed in relationship to sleep-related symptoms over time. Results In multivariable analyses, more trouble falling asleep was associated with financial insecurity, higher clinical stage, more cigarettes smoked per day, and less weekly exercise. More trouble staying asleep was associated with older age, race, advanced education, financial insecurity, and higher clinical stage. Over time, there was a nonsignificant trend toward increased trouble falling asleep and fluctuations in trouble staying asleep. Higher clinical stage and receipt of radiotherapy were associated with decreased severity in trouble falling asleep over time, while more cigarettes smoked per day was linked to increased severity in trouble staying asleep. Conclusions These findings highlight the complex interplay of clinical, lifestyle, and demographic factors in sleep disturbances among BC survivors, underscoring the need for tailored sleep management strategies.

ABSTRACT Background & Aims Steatotic liver disease (SLD) is characterised by liver fat accumulation exceeding 5%. Lean body weight (BMI ≤ 25 kg/m 2 ) with non‐alcoholic SLD is a rare phenotype, and the balance of risks related to metabolic conditions or genetic predisposition, or the risk of progressive liver disease, is not known. This study evaluates clinical and genetic predictors of non‐alcoholic SLD and advanced liver disease in lean individuals. Methods We used International Classification of Disease codes, radiology and pathology review to identify 177 lean non‐alcoholic SLD cases (47 cryptogenic, 130 MASLD), 677 matched lean controls, and 3090 overweight/obese SLD cases in the Mayo Clinic Biobank and Tapestry databases. We performed case–control and cross‐sectional comparisons of clinical and genetic factors between these groups, using univariable and multivariable analyses. Results Lean individuals with non‐alcoholic SLD exhibited metabolic and genetic profiles that were intermediate between those of lean controls without SLD and overweight/obese SLD individuals, including intermediate rates of diabetes, hypertension, hyperlipidaemia and of homozygosity for the risk allele of PNPLA3 . Multivariable analysis indicated that diabetes was an independent predictor of SLD among lean individuals. Among lean individuals with non‐alcoholic SLD, those with metabolic‐associated SLD (MASLD), as compared to those with cryptogenic SLD (without metabolic risk factor), were more likely to be homozygous for risk alleles in GCKR . The Fib‐4 score, a tool for screening advanced liver disease in SLD, accurately predicted advanced fibrosis among lean individuals with non‐alcoholic SLD. Conclusion Diabetes serves as a primary predictor of non‐alcoholic SLD in lean individuals. These results support the recommendation to screen for SLD in patients with diabetes, regardless of BMI. The GCKR risk allele is associated with MASLD in lean individuals, and the risk factors for cryptogenic SLD remain unclear.

ABSTRACT Introduction Children with hepatoblastoma (HB) and other solid tumors frequently undergo intraoperative blood transfusion (IBT) with unknown impact on oncologic outcomes and scant data to guide transfusion in this population. This study tested the hypothesis that IBT is associated with poorer survival in children with HB. Methods A multicenter retrospective observational study of patients aged <18 years with HB who underwent primary tumor resection, including liver transplantation, from 2010 to 2019 was performed at 19 institutions. The association of IBT with risk of recurrence and death were determined using propensity score reweighted (PSR) Cox proportional hazards regression analyses. Results There were 338 patients identified who met inclusion criteria and had sufficient data for inclusion. Of those, 257 (76%) received IBT, including 253 (98%) who received packed red blood cells (pRBC), 84 (33%) who received plasma, and 28 (11%) who received platelets. IBT was associated with higher pretreatment extent of disease ( p < 0.001), presence of annotation factors (+VPEFR: 50%, n = 129 vs. 37%, n = 30, p = 0.035), and complex resections (extended, meso‐, or total hepatectomy: 54%, n = 139 vs. 27%, n = 22, p < 0.001); these differences were mitigated after applying propensity score weighting. Patients who received IBT had greater postoperative hemoglobin (g/dL) (median 10 (I8–11) vs. 9 (8–10), p = 0.013) and required more postoperative plasma and platelet transfusions ( p < 0.05). Median follow‐up was 4.4 (2.0–8.3) years. Compared with non‐IBT patients, those with IBT had higher incidence of death (PSR HR 2.35, 95% CI 1.10–5.02). Recurrence did not significantly differ across groups (PSR HR = 0.82, 95% CI 0.45–1.48). Conclusion IBT was associated with greater hazard of death. Postoperative hemoglobin levels suggested that unnecessary transfusions occurred and a pRBC‐focused approach to IBT led to coagulopathy. Development of optimal transfusion strategies for HB are needed to minimize unnecessary transfusions.

Abstract Background Up to 80% of persons with Parkinson's disease (PwPD) have dysphagia. However, existing studies are based on small cohorts and the relationship between dysphagia and other motor and nonmotor symptoms (NMS) remains incompletely understood. Objectives To evaluate the relationship between motor and NMS in PwPD with vs without dysphagia. Methods Among 20,365 PwPD in the Michael J. Fox Foundation database who completed ≥2 NMS surveys, 12,678 (62%) reported dysphagia on ≥1 survey. We examined associations between dysphagia and: (1) self‐reported motor symptoms (UPDRS Part II), other NMS, quality of life (QoL), comorbidity score, depression, and daily activities at baseline; and (2) development of new NMS. Results Compared to PwPD without dysphagia, those with dysphagia were more likely to have had PD for >5 years, more severe motor and NMS, higher comorbidity scores, and a greater impairment in daily activities ( P < 0.001). The prevalence of dysphagia increased with the severity of motor symptoms at the index survey ( P < 0.001). At baseline, all NMS were significantly associated with dysphagia. Compared to PwPD who did not have dysphagia, PwPD with dysphagia were at increased risk of developing every NMS, even after adjusting for ages at PD diagnosis and index survey, sex, cognitive impairment, UPDRS, NMS and comorbidity scores. For most NMS, the risk of progression was greater in those with cognitive impairment or elevated NMS scores. Conclusions Dysphagia in PwPD is associated with more severe motor and non‐motor symptoms, reduced QoL, and an increased risk of future NMS.

Objective: This study establishes objective benchmarks for robotic ileal pouch-anal anastomosis (IPAA) proficiency, evaluating individual surgeon learning curves using risk-adjusted cumulative sum (RA-CUSUM) analysis. Summary Background Data: IPAA is a standard surgical treatment for conditions like refractory ulcerative colitis; robotic assistance offers potential advantages. However, the robotic IPAA learning curve is not clearly defined. Conventional analyses often overlook significant inter-surgeon variability and patient-specific factors, hindering surgical training optimization. Methods: A multi-site retrospective analysis of 123 consecutive robotic IPAA procedures performed by 11 surgeons between June 2015 and December 2023 was conducted. Patient-related variables were used for risk adjustment, and RA-CUSUM charts were generated to assess 30-day complications, operative time, and length of hospital stay at both aggregate and individual surgeon levels. Results: Aggregate RA-CUSUM data indicated general improvement trends for operative time and length of stay, alongside higher-than-expected complication rates in the early phase. Disaggregated analyses at the individual surgeon level revealed significant heterogeneity in performance trajectories and learning patterns across all three outcomes, directly challenging the concept of a standardized, uniform learning curve. Although postoperative complication and length of stay outcomes did not significantly differ between surgeons, operative time varied significantly. Conclusions: The acquisition of skill in robotic IPAA is a highly individualized process, suggesting the traditional uniform learning curve model is insufficient for contemporary surgical education. These findings strongly advocate for a shift towards personalized training paradigms that incorporate deliberate practice, targeted feedback, and simulation to optimize learning and patient outcomes.