Journal of Cachexia, Sarcopenia and Muscle

Background: The organization of pancreatic cancer care may be associated with survival. Using health administrative claims data, we reconstructed the pathway from diagnosis to first-line therapy and examined associations of multidisciplinary team review and treatment at specialized centers with overall survival. Methods: Longitudinal historical cohort study using anonymized health administrative claims data from six Czech health insurance funds, covering approximately 17% of patients diagnosed with pancreatic cancer nationally between 2018 and 2020. Adults with an incident ICD-10 C25 record confirmed by imaging and histopathology were followed from the index date (the date of the first qualifying imaging or histopathological examination) until death, censoring, or 31 December 2021. Overall survival was analyzed using Kaplan-Meier methods and Cox regression adjusted for age and first-line therapy type. Results: Of 1,255 patients, 920 (73.3%) received first-line therapy and 266 (21.2%) died untreated. Among treated patients, 436 (47.4%) underwent multidisciplinary team review, 335 (36.4%) underwent surgery, and 667 (72.5%) were treated at a complex oncological center. Surgery was associated with longer overall survival than chemotherapy (age-adjusted hazard ratio [HR] 0.32, P < 0.001). Treatment at a complex oncological center was associated with longer overall survival (adjusted HR 0.77, 95% confidence interval [CI] 0.64-0.92, P = 0.004; crude median 532 versus 394 days). Multidisciplinary team review was not significantly associated with overall survival (adjusted HR 0.86, 95% CI 0.73-1.01, P = 0.073). Conclusions: Treatment at a complex oncological center was associated with longer survival, while fewer than half of patients had a recorded multidisciplinary team review. How care is organized, not only which therapy is delivered, is associated with outcome. The observational design and absence of key clinical covariates limit causal interpretation.

Background: The C-reactive protein-albumin-lymphocyte (CALLY) index integrates systemic inflammation, nutritional status, and immune function. We evaluated its association with survival in primary lung malignancies. Methods: Embase, PubMed, Scopus, and Web of Science were searched from inception to 18 September 2026. Risk of bias was assessed using the Quality In Prognosis Studies tool. Hazard ratios (HRs) were synthesized using random-effects models with restricted maximum likelihood estimation and Hartung-Knapp adjustment. Sensitivity analyses, subgroup analyses, and meta-regression examined robustness and heterogeneity. Results: Eleven studies contributed 13 cohorts to the overall survival (OS) analysis and 8 cohorts from seven studies to a combined recurrence/progression-free survival (RFS/PFS) analysis. Lower CALLY was associated with poorer OS (HR 1.78, 95% CI 1.49-2.12; I2=71.6%) and poorer RFS/PFS (HR 1.60, 95% CI 1.40-1.84; I2=0%). Associations persisted in leave-one-out analyses. No statistically significant subgroup differences were detected. Funnel-plot asymmetry suggested small-study effects for OS and RFS/PFS. Seven studies had moderate and four had high overall risk of bias. The certainty of evidence was rated as low for both OS and RFS/PFS, primarily due to risk of bias, heterogeneity, and endpoint indirectness. Conclusion: Lower CALLY was associated with adverse survival outcomes in the current synthesis. Methodological limitations and variation in biomarker measurement and endpoint definitions restrict interpretation. Prospective validation using standardized measurements and clinically coherent outcomes is needed to establish incremental prognostic value and clinical utility. Keywords: CALLY index; lung cancer; prognosis; overall survival; systematic review; meta-analysis

Background: Mitochondrial dysfunction is a hallmark of ageing and is implicated in the pathogenesis of sarcopenia. Genetically confirmed mitochondrial disease provides a biologically definitive model of impaired oxidative phosphorylation against which novel functional assessments can be validated. We investigated whether a brief, submaximal, non-ischaemic intermittent isometric handgrip exercise protocol combined with Near Infra-Red Spectroscopy (NIRS) could detect distinct muscle oxygenation signatures in mitochondrial disease and sarcopenia. Methods: Adults with genetically confirmed mitochondrial disease (n=10, 7 female) and group-matched controls (n=19, 11 female), underwent assessment of maximal grip force, handgrip relaxation kinetics and a 3-minute intermittent submaximal isometric handgrip test (40% maximal voluntary contraction, 1Hz contraction/relaxation) with continuous force recording at 2000Hz and simultaneous NIRS. Findings were compared with 23 community-dwelling older adults from the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse cohort (n=23, 13 female) including seven with probable or confirmed sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Results: Participants with mitochondrial disease demonstrated an attenuated reduction in tissue saturation index (TSI) during exercise compared with controls (TSI % {middle dot} s150-180s: -59.9 {+/-} 94.5 vs -175.1 {+/-} 128.4; p=0.02). Total haemoglobin (THb) responses did not differ between groups (p=0.10). In contrast, participants with probable or confirmed sarcopenia showed exaggerated reduction in TSI compared with non-sarcopenic participants (TSI % {middle dot} s150-180s: -256.5 {+/-} 146.0 vs -121.2 {+/-} 95.2; p=0.05), while THb responses remained similar. The association between sarcopenia and TSI differed by sex (interaction coefficient -240, p=0.016), with greater TSI reductions observed in males with sarcopenia. Differences in TSI between mitochondrial disease and control groups were independent of age and sex. No statistically significant associations were observed between THb responses and age, sex or force production. Conclusions: A brief, non-ischaemic handgrip exercise protocol combined with NIRS identified divergent muscle oxygenation responses in mitochondrial disease and sarcopenia. The attenuated TSI response observed in genetically confirmed mitochondrial disease is consistent with impaired oxygen utilisation secondary to defective oxidative phosphorylation, whereas the exaggerated TSI reduction observed in sarcopenia suggests a distinct physiological mechanism, potentially involving impaired oxygen delivery, reduced muscle efficiency, or both. This portable and non-invasive approach has significant potential as a physiological biomarker for mechanistic studies and clinical trials in ageing and neuromuscular disease. More broadly, our findings demonstrate how biologically defined rare diseases can provide a powerful framework for interpreting mechanisms in common heterogeneous age-related conditions.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling, which may extend to the central airways and alter tracheal morphology. Whether tracheal shape relates to disease severity, quality of life, functional capacity, or survival is not established. Objective: To determine whether CT-derived tracheal lumen eccentricity is associated with cross-sectional and longitudinal clinical outcomes in COPD. Methods: We analyzed 8,383 participants from the multicenter COPDGene study. At each axial cross-section of the trachea, lumen eccentricity ({epsilon}) was computed from the major and minor axis lengths, and the participant-level value was taken as the arithmetic mean across all tracheal slices; {epsilon} = 0 denotes a circular lumen and values approaching 1 denote progressively elongated ellipses. Baseline outcomes were spirometry, 6-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) total score, and modified Medical Research Council (mMRC) dyspnea score. Longitudinal outcomes were annualized change in FEV1 and all-cause mortality. Multivariable linear and Cox proportional hazards models were adjusted for [age, sex, race, BMI, smoking status, pack-years, scanner model]. Results: Tracheal eccentricity rose monotonically with severity of airflow obstruction (0.60{+/-}0.07, 0.61{+/-}0.07, 0.62{+/-}0.07, 0.64{+/-}0.08, and 0.64{+/-}0.08 in GOLD stages 0 through 4, respectively). Higher eccentricity was independently associated with lower FEV1 ({beta} = -0.30 L, 95% CI -0.47 to -0.14; p < 0.001), lower FEV1/FVC ({beta} = -0.06, 95% CI -0.09 to -0.04; p < 0.001), shorter 6MWD ({beta} = -15.7 m, 95% CI -25.2 to -6.2; p = 0.001), higher SGRQ score ({beta} = 16.9, 95% CI 11.2 to 22.5; p < 0.001), higher mMRC dyspnea score ({beta} = 0.4, 95% CI 0.1 to 0.6; p = 0.007), and accelerated lung function decline ({beta} = -23.8 mL/year, 95% CI -45.13 to -2.48; p = 0.029). Eccentricity was also associated with all-cause mortality (adjusted HR 1.81, 95% CI 1.01 to 3.26; p = 0.047). Conclusions: Tracheal lumen eccentricity is associated with worse quality of life, reduced functional capacity, accelerated lung function decline, and mortality in COPD, supporting central airway morphology as a candidate imaging biomarker.

Background: This study compared functional and cognitive trajectories in older women treated for early breast cancer with matched women without cancer. Methods: Data were derived from two Dutch cohorts: the CLIMB study (women aged 75 years and older with operable breast cancer) and the ISCOPE study (community-dwelling women aged 75 years and older without cancer). Breast cancer patients were matched 1:2 to controls on age and baseline functional or cognitive status. Functional status was assessed using the Groningen Activity Restriction Scale (GARS), and cognitive function using the Mini-Mental State Examination (MMSE). Longitudinal changes over 12 months were analyzed using both unadjusted and confounder-adjusted linear mixed models. Results: 168 breast cancer patients and 336 matched breast cancer-free controls were included with a mean age of 80 years. Most breast cancer patients had stage 0-I or II disease and received surgery and/or radiotherapy; 48% received adjuvant endocrine therapy, chemotherapy was rare (<1%). At baseline, both cohorts were comparable in age and functional or cognitive status, although there was a higher comorbidity burden in the control cohort. No significant differences in functional or cognitive decline were observed between the cohorts over 12 months. Conclusions: In older women, early breast cancer and its treatment did not lead to accelerated decline in functional status or cognitive function within the first year compared to matched older women without cancer. These findings suggest that, for relatively fit older patients, breast cancer treatment may not accelerate functional decline in the short term.

Introduction: Perioperative systemic therapy improves outcomes in gastroesophageal adenocarcinoma, but many patients do not receive postoperative treatment. We examined whether host characteristics and perioperative inflammatory and albumin changes provided information about adjuvant initiation beyond tumour pathology, and whether initiation was associated with survival and disease control. Method: This retrospective cohort included patients undergoing curative-intent resection for gastroesophageal adenocarcinoma at the McGill University Health Centre between 2006 and 2025. Sequential logistic models evaluated pathological characteristics, pre-treatment host variables and perioperative changes in CBC-derived neutrophil-to-lymphocyte ratio (cNLR) and albumin. Postoperative measurements preceded adjuvant initiation. Nested comparisons used matched complete cases. Day-90 landmark and time-varying Cox models assessed associations between adjuvant initiation and survival. Results: Among 243 patients, 78 (32.1%) did not initiate adjuvant therapy. Adding host variables improved apparent discrimination for initiation beyond pathology (AUC 0.672 to 0.763; P=0.002). Greater perioperative cNLR increase was associated with lower odds of initiation (adjusted OR 0.67 per unit increase in {Delta}log2; cNLR, 95% CI 0.47-0.95), whereas more favourable albumin change was associated with higher odds (OR 1.07 per g/L, 95% CI 1.01-1.13). Neither marker retained a clear independent association when modelled together. Adjuvant initiation by day 90 was associated with longer overall survival (adjusted HR 0.53, 95% CI 0.36-0.78) and disease-free survival (HR 0.57, 95% CI 0.39-0.84), with similar time-varying findings. Conclusion: Host inflammatory and albumin changes added information about adjuvant initiation beyond tumour pathology, and initiation was associated with longer survival. Prospective evaluation should determine whether host-directed perioperative strategies can improve postoperative treatment delivery.

Introduction: Fighting the ventilator (FV) is characterized by a patients active counteraction of respiratory gas flow across multiple breaths during mechanical ventilation. An effective ventilation is prevented during such episodes. The objective of this exploratory study was to evaluate clinicians knowledge, perception and agreement regarding this condition. Methods: In a cross-sectional online survey, medical professionals with experience in intensive care medicine (mostly neonatal and pediatric patients) responded to 11 questions covering various clinical aspects of FV. Results: All respondents were familiar with the phenomenon and assessed it to be clinically relevant. Neonates were perceived to be predominantly affected. Promoting factors of FV included inadequate sedation and ventilation-associated factors. In clinical practice, the participants identified FV by clinical evaluation, analysis of ventilator waveforms and capnography and used both pharmacological and non-pharmacological intervention strategies. There was no consensus concerning the English terminology of the condition. Only few respondents were familiar with local guidelines to manage FV. Conclusion: Although there was consensus on the relevance of FV, diagnostics and management strategies were highly heterogeneous. Many participants agreed that poor patient-ventilator synchrony was an important cause of FV. Future work should focus on characterizing and generating evidence on FV.

Despite recent evidence of the ability of systemic and organ-specific proteomic aging clocks to predict a large range of age-related diseases, their utility in cancer research remains largely underexplored. In this study, we evaluated the predictive ability of systemic and organ-specific proteomic aging clocks for (i) all-cause mortality, (ii) cancer-related mortality, and (iii) cancer incidence in a sample of Finnish twins (N = 401, mean age at baseline 62.3 years) with Olink proteomic data. Participants were followed for a mean of 10.6 years (SD +- 1.6), with estimates from four systemic and 18 organ-specific proteomic aging clocks calculated at baseline. Cox proportional hazards regression models adjusted for sex and age at baseline identified 15 proteomic aging clocks as significant predictors of all-cause mortality (Ncases = 28) after multiple testing correction (FDR < 0.05), with 11 remaining significant after lifestyle adjustment (Ncases = 27). For several clocks, effect sizes were large, with hazard ratios (HR) approximately doubling per one standard deviation (SD) increase in clock estimates. In predicting cancer-related deaths among participants without a prior cancer diagnosis at baseline (Ncases = 9), only the Immune clock showed a significant positive association after multiple testing correction in basic (HR = 2.94, 95% CI: 1.88-4.59) and lifestyle-adjusted models (HR = 3.31, 95% CI: 1.78-6.17). No associations with cancer incidence (Ncases = 34 basic, Ncases = 31 adjusted) survived multiple testing correction, although several nominal associations were observed. In conclusion, our findings suggest that proteomic aging clocks are strong predictors of all-cause and cancer-specific mortality, independent of lifestyle factors. Proteomic aging clocks may further serve as valuable tools for stratifying cancers by mortality risk.

PhenoAge, a blood-based biological aging clock, is associated with cancer outcomes, a finding taken as evidence that biological aging shapes prognosis. In 3,067 patients undergoing primary tumor resection, PhenoAge acceleration rose with tumor stage. One or two of its eight blood components, differing by cancer type, carried the prognostic signal, and replacing its general-population weights with equal weights did not weaken it. In cancer, PhenoAge may reflect disease burden rather than biological aging.

Although physical activity is associated with better physical functioning, the effects of initiating regular physical activity among older adults with persistent inactivity remain unclear. We conducted a sequential target trial emulation using Health and Retirement Study (HRS) data to estimate the effect of physical activity initiation versus noninitiation on incident mobility difficulty. Participants were included in the analysis if they were aged [&ge;]65 years at the previous wave, reported no regular physical activity at the previous two waves, and had no mobility, activities of daily living (ADL), or instrumental activities of daily living (IADL) difficulties at baseline. Stabilized inverse probability of treatment weighting was applied to adjust for measured confounding. Weighted cumulative incidence was then estimated with death treated as a competing event, and risk differences were calculated at approximately 2, 4, and 6 years. At 2 years, the cumulative incidence of mobility difficulty was 32.75% among initiators and 39.73% among noninitiators, with a risk difference of -6.98 percentage points (95% CI, -13.11 to -0.88). At 4 and 6 years, risk differences were -2.90 percentage points (95% CI, -9.77 to 4.29) and -5.44 percentage points (95% CI, -12.27 to 1.99), respectively. Initiating regular moderate or vigorous physical activity was associated with a lower risk of incident mobility difficulty at approximately 2 years among older adults with persistent inactivity. This difference was less evident at later follow-up, and no clear differences were observed for incident ADL or IADL difficulty.

Rationale: Conventional CT-derived pulmonary vascular metrics quantify vascular pruning but do not assess the spatial heterogeneity of vascular architecture. In COPD, peripheral microvascular pruning coexists with compensatory central vessel dilation, paradoxically preserving total vessel volume while reducing effective vascular penetration into lung parenchyma. Objectives: To develop and evaluate Vascular Proximity Coverage (VPC), a distance-based CT biomarker quantifying the spatial efficiency of pulmonary vascular distribution. Methods: This retrospective analysis included 7,881 COPDGene participants [PHASE] with complete vascular segmentations. VPC was estimated by integrating the area under the cumulative lung tissue coverage curve at distances of 0-10 mm from segmented vessel voxels. Multivariable models assessed associations with lung function, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, mMRC dyspnea score, and all-cause mortality over a median follow-up of [10.8] years, adjusting for demographics, smoking, emphysema, scanner type, and BV5. The cohort was stratified at median BV5 and VPC into concordant (high/high, low/low) and discordant (high-BV5/low-VPC, low-BV5/high-VPC) vascular phenotypes. Results: VPC declined across disease severity (5.82 {+/-} 0.50 [UNITS] in non-smokers to 5.21 {+/-} 0.64 in GOLD 4; p < 0.001). Among spirometrically normal smokers, current smokers had lower VPC than former smokers (5.31 vs. 5.68; p < 0.001). Each standard deviation decrease in VPC was independently associated with reduced 6MWD ({beta} = -16.8 m, 95% CI: -19.5 to -14.0), worse SGRQ ({beta} = 1.9, 95% CI: 1.4 to 2.4), and greater dyspnea (RR = 1.05, 95% CI: 1.03 to 1.08; all p < 0.001). The lowest VPC quartile was associated with 38% higher mortality than the reference quartile (HR = 1.38, 95% CI: 1.18 to 1.62; p < 0.001). The high-BV5/low-VPC phenotype showed 24% higher mortality than high-BV5/high-VPC (HR = 1.24, 95% CI: 1.08 to 1.42; p = 0.002) despite preserved vessel volume. Conclusions: VPC captures spatial heterogeneity of vascular architecture independent of vessel volume, is reduced in smokers without airflow obstruction, and identifies excess mortality risk among individuals whose total vessel volume appears preserved.

Background: Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders characterized by progressive lower-extremity weakness and spasticity, with or without additional neurological symptoms. Objectives: To characterize the molecular genetic spectrum, inheritance patterns, molecular finding rate, and clinical characteristics of HSP within a multicenter Canadian cohort. Methods: We investigated 671 patients from 423 families who met clinical criteria for HSP identified through the Canadian HSP (CanHSP) registry from 7 medical centers across Canada. Patients were evaluated using known HSP and HSP mimic gene panels, whereas unsolved and more recent patients underwent whole-exome sequencing (WES). 435 individuals underwent gene-panel testing and 485 underwent WES. Copy-number variants (CNVs) were assessed using ExomeDepth, and candidate CNVs using multiplex ligation-dependent probe amplification (MLPA). Results: Molecular findings were identified in 426 of 671 individuals (63.5%): 351 (52.3%) had HSP-associated findings, 70 (10.4%) HSP-mimicking disorders, and five (0.7%) other molecular findings; 245 (36.5%) remained unresolved. Candidate variants were found in 80 relevant genes, 36 of which were HSP-associated genes. The most frequently implicated genes were SPAST (22.5%), SPG7 (5.7%), ATL1 (5.2%), SPG11 (3.6%), and SPG8 (3.3%). Phenotypically, SPAST, ATL1, and SPG8 w[zg1.1]ere predominantly associated with pure HSP, whereas SPG7 and SPG11 more often showed complicated phenotypes, with prominent cerebellar involvement in SPG7 and cognitive and developmental features in SPG11. Conclusion: Patients in CanHSP present with genetic and phenotypic heterogeneity. Reanalysis and complementary approaches, including whole-genome, RNA, and long-read sequencing, may increase diagnostic yield.

Objective: to estimate reconsultation risk and trajectories after a new episode of musculoskeletal pain in children and young people (CYP), and to determine routinely recorded prognostic factors associated with reconsultation. Design: Population based retrospective cohort study. Setting: Clinical Practice Research Datalink (CPRD) Aurum, 2005-2021. Participants: CYP aged 8-18 years consulting primary care for a new musculoskeletal pain episode (no musculoskeletal consultation in prior 12-months). Main Outcome Measures: Musculoskeletal pain reconsultation within 12-months, and 3-year musculoskeletal reconsultation trajectories derived using latent class growth analysis. Prognostic factors selected from a literature search and two-year symptom histories (sample prevalence >1%) were examined using regression models (conditional logistic; multinomial). Results: Among 313,830 CYP with >12 months' follow-up, 32% reconsulted for musculoskeletal pain within 12 months. Among 240,384 CYP with >3 years' follow-up, three trajectories were observed: single episode (62%), early reconsultation (18%), and persistent reconsultation (20%). Older age; female gender; hip, knee, multisite and back pain on index; previous headache; previous abdominal pain; and analgesic prescribing were associated with higher reconsultation risk. Asian or Black ethnicity, and residing in more deprived areas, were associated with lower recorded reconsultation. Conclusion: Most CYP had no further recorded consultation, but 38% followed early or persistent reconsultation trajectories. Routinely recorded prognostic factors, particularly index pain side and prior pain/symptom history, may differentiate groups who could benefit from proactive follow-up. Lower recorded reconsultation among Asian and Black individuals, and living in more deprived areas, should not imply lower need and warrants equity-sensitive monitoring of access, health-seeking, and coding.

Background Immune checkpoint blockade (ICB) has become the standard of treatment for metastatic melanoma (MM). However, patients with melanoma brain metastases (MBM) are often excluded from clinical trials. Here we analyse patients within the real-world OxCITE cohort receiving ICB treatment for metastatic melanoma, with a focus on MBM, aiming to discern outcomes, prognostic factors and peripheral biomarkers. Methods Patients eligible for ICB treatment were recruited prospectively. Demographic, clinical and radiological data were collected from electronic patient records. Plasma samples were collected prior to the first cycle of treatment for plasma proteomic analysis. Results 307 patients were included, 81 of whom had MBM on commencing ICB. No difference in overall survival between patients with and without brain metastases was noted on multivariable analysis (HR=1.1, 95% CI 0.73-1.6, p=0.68), whereas hepatic metastases were associated with increased risk of death (HR 1.7, 95% CI 1.2-2.4, p=0.0019). Within the MBM group, steroid treatment (HR=2.5, 95% CI 1.3-5.0, p=0.006) was associated with poor OS, whilst treatment with single agent ICB (HR=1.9, 95% CI 0.86-3.9, p=0.11), symptomatic first presentation of MBM (HR=1.5, 95% CI 0.76-2.8, p=0.25) and anti-seizure drug treatment (HR=1.74, 95% CI 0.89-3.4, p=0.10) were not. Amongst all patients carriage of a BRAF mutation was associated with increased risk of MBM (OR 2.49, 95% CI 1.4-4.4, p=0.0007), and increased propensity to new brain metastases on ICB treatment (OR 2.5, 95% CI 1.1-5.9, p=0.036). Analysis of blood and plasma samples demonstrated that patients with MBM have altered haematological profiles, with raised NLR and increased plasma glial fibrillary acidic protein levels, reinforcing the distinct systemic features of MBM. Conclusions In this real-world cohort of patients receiving ICB for metastatic melanoma, the presence of MBM did not associate with worse OS. Conversely, baseline corticosteroid use was adversely prognostic. Intriguingly, plasma GFAP was significantly elevated in patients with MBM and correlated with the burden of intracranial disease, highlighting a potential role for GFAP as a candidate biomarker for MBM in high-risk surveillance. Our observations indicate the adversely prognostic weight historically attached to M1d disease is no longer applicable in the ICB era.

New prognostic biomarkers for oesophageal adenocarcinoma (OAC) may help treatment planning as current staging does not accurately predict survival for many patients. We used a 451 cancer-associated gene panel to assess genomic alterations associated with survival for a cohort of 65 OAC patients who underwent surgical resection without perioperative treatment, reflecting institutional practice at the time. Median age at operation was 72 years, 88% were male, median 32 lymph nodes were removed per patient, and minimum follow-up exceeded 11 years. TNM stages (pTNM, 8th ed.) were 14% stage 1, 14% stage 2, 45% stage 3, and 6% stage 4 (non-locoregional nodal metastases). Copy number changes were common, and somatic mutations were similar to those reported previously. Genetic associations with worse survival included amplification of CCND1 (HR=3.08, p=0.02), EGFR (HR=2.98, p=0.01), loss of ARID2 (HR=2.12, p=0.05), KMT2D (HR=1.99, p=0.07) and missense mutation within RYR1 (HR=2.68, p=0.01). This study identifies candidate genomic prognostic biomarkers in OAC using a cohort treated by surgery alone, enabling assessment of tumour biology independent of the confounding effects of peri-operative systemic therapy and radiotherapy. Several of the identified alterations are potentially targetable, supporting further investigation of genomic profiling to refine prognostication and guide treatment selection.

Deep learning (DL) applied to haematoxylin and eosin (H&E)-stained pathology images can predict microsatellite instability (MSI) in gastric cancer (GC). We evaluated its diagnostic accuracy and discriminative performance. PubMed, Embase, Cochrane Library and Web of Science were searched for studies applying DL to H&E images for MSI prediction in GC. The protocol was prospectively registered in PROSPERO (CRD420261503140). Risk of bias was assessed with QUADAS-2. Pooled sensitivity and specificity were estimated with a bivariate random-effects model, with subgroup analyses by validation strategy and data source; slide-level areas under the curve (AUCs) were pooled after logit transformation. Prespecified scenario analyses assessed robustness. Ten studies were included; seven independent datasets from six studies entered the primary synthesis. Pooled sensitivity, specificity and summary receiver operating characteristic AUC were 0.78 (95% CI 0.63-0.88), 0.85 (95% CI 0.77-0.90) and 0.89 (95% CI 0.86-0.91); nine studies contributed to the secondary AUC synthesis (pooled AUC 0.85, 95% CI 0.80-0.89). Hospital-derived cohorts showed numerically higher sensitivity (0.86) and diagnostic odds ratio (39.8) than TCGA-derived cohorts (0.71 and 11.5), but subgroup differences were limited by the small number of studies and substantial heterogeneity. DL models show good diagnostic accuracy for MSI prediction in GC, but clinical utility still requires confirmation in standardised multicentre, independent external and prospective studies.

OBJECTIVE: To describe (1) US emergency department-treated pickleball injury burden and the injury-to-participation measure among total players, with burden among adults aged 60 to 79 years as a descriptive subgroup, and (2) determine whether general internet search interest for 'pickleball' is also associated with total pickleball-related injuries. DESIGN: Ecological time series study, United States, 2014 to 2023. DATA SOURCES: National Electronic Injury Surveillance System (NEISS) emergency department microdata yielded 1,738 adjudicated pickleball cases, 921 of them orthopedic, weighted to an estimated 101,450 injuries nationally. Google Trends, English Wikipedia pageviews, and GDELT news volume served as general pickleball attention signals, with the Trends index for 'sourdough' as a negative control. Sports and Fitness Industry Association (SFIA) participation estimates supplied a total player denominator. MAIN OUTCOME MEASURES: Annual national injury estimates with design-based 95 percent confidence intervals; injury-to-participation measures; and correlations between total pickleball-related injuries and general pickleball attention signals before and after removing trend and seasonality. RESULTS: Estimated emergency department-treated pickleball injuries rose 17.5-fold, from 1,391 in 2014 (highly unstable) to 24,294 in 2023. 70 percent of adjudicated cases involved adults aged 60 to 79. During 2017-2023, injury estimates rose 4.0-fold and participation rose about 4.4-fold. No temporal trend was detected in the injury-to-participation measure (P=0.59). Search interest looked like an excellent proxy: in annual levels it correlated with total pickleball-related injuries at R=0.96, and Pickleball Wikipedia pageviews at R=0.98. However, so did searches for "sourdough", at R=0.76. Removing trend and seasonality left little (monthly residual R=0.084; year-on-year R=0.28 over 96 months, 2015-2023), and the seasons ran opposite, with injuries peaking in February and searches in July, such that, on 12-month mean profiles, the sourdough negative control fitted the injury season (R=0.96) while pickleball ran against it (R=-0.40). General pickleball search interest and pickleball news coverage remained correlated in year-on-year changes in 2017-2023 (R=0.64), whereas their corresponding correlations with total pickleball-related injuries in 2017-2023 were 0.25 and 0.20. CONCLUSIONS: The absolute burden of emergency department-treated pickleball injury has grown substantially, but the available surveillance data cannot resolve whether the sport has become more hazardous per participant. The observed rise is consistent with growth in exposure alone. The strong correlation between search interest and injury counts was not specific, the association was substantially attenuated after detrending, and the seasonal patterns were opposed. These descriptive results do not establish that search interest can substitute for injury surveillance, and series that rise together should not be assumed to be related.

Background Sporadic Parkinson disease (PD) lacks a molecular taxonomy that stratifies patients by dominant molecular drivers, limiting enrollment for disease-modifying trials, especially anti-inflammatory agents targeting NLRP3/NF-{kappa}B. Methods We developed ORIGIN-PD, an interpretable whole-blood transcriptomic classifier comprising 34 gene-level features and a composite low-expression score, with gene-level contributions organized into eight prespecified functional modules: midbrain dopaminergic (mDA) neuron identity/development, pathway-related, oxidative/mitochondrial, proteostasis, inflammation/ immunity, microglia, ncRNA, and other. Using LASSO regression on stringently quality-controlled whole-blood RNA-seq data from the Parkinson Progression Markers Initiative (PPMI) (Training Set: 204 PD and 92 controls; Locked Test Set: 51 PD and 23 controls), we assigned each patient a module-contribution profile. Module dominance was defined as >30% of total score. Results ORIGIN-PD discriminated PD from controls with high accuracy (Locked Test Set AUC 0.944, sensitivity 0.843, specificity 0.913). Among 255 sporadic PD patients, 49.4% exhibited a dominant module-contribution pattern, most frequently mDA neuron identity/development (22.0%), followed by pathway-related (11.8%), microglia/glial (7.5%), and inflammation/immunity (3.5%). Among the 50.6% with multi-module contributions, mDA neuron identity/development ranked in the top three in 62.8% of patients versus 35.7% for inflammation/immunity, indicating broader involvement of mDA neuron identity genes than inflammatory genes. The model showed high specificity against Alzheimer disease, ALS, and inflammatory controls. Conclusions ORIGIN-PD enables rational enrichment for NLRP3/NF-{kappa}B inhibitor trials by identifying patients with inflammatory involvement. In addition, the predominant contribution of the mDA neuron identity/development module, centred on WNT1, MSX1, NPM1, and LMX1B, identifies a larger patient subgroup with altered expression of mDA neuron identity module genes, suggesting that ORIGIN-PD may also be useful for patient enrichment in future trials of Wnt/{beta}-catenin pathway agonists. This dual-purpose framework provides a transparent, interpretable basis for pathogenic subtyping and precision enrichment in sporadic PD, with the aim of guiding disease-modifying therapy.

Background: Peripheral inflammation has been implicated in the pathophysiology of Parkinson's disease (PD), but its relationship with autonomic dysfunction remains unclear. Objectives: To explore the association between peripheral inflammation, assessed by the neutrophil-to-lymphocyte ratio (NLR), and autonomic function in patients with PD. Methods: We retrospectively analyzed 97 patients with PD who underwent 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy and differential blood cell counts. Associations of NLR with early and delayed heart-to-mediastinum (H/M) ratios, washout ratio, and the coefficient of variation of R-R intervals (CVRR) were assessed using Spearman's rank correlation and multivariable linear regression adjusted for age, sex, and disease duration. Results: No significant univariable correlations were observed between NLR and the autonomic measures. In multivariable analysis, higher NLR was associated with a lower early H/M ratio (B = -0.802, 95% CI -1.598 to -0.005, P = 0.049), whereas no significant associations were observed with the delayed H/M ratio, washout ratio, or CVRR. Sensitivity analyses showed a generally consistent direction of association, although the effect estimate was attenuated after exclusion of two influential observations and statistical significance was not consistently retained. Conclusions: Higher NLR was associated with lower early cardiac MIBG uptake after adjustment for age, sex, and disease duration in patients with PD. This exploratory finding raises the possibility of an association between systemic inflammation and sympathetic dysfunction in PD and requires confirmation in larger prospective studies.

Background: Neoadjuvant chemotherapy (NACT) facilitates de-escalation of breast and axillary treatment in breast cancer, but pathological responses may differ between the primary tumour and axillary lymph nodes. Understanding differential response is crucial for de-escalation strategies. Methods: This single university hospital retrospective study analysed operable breast cancers (cT1-cT3, cN0-cN3) treated with NACT (January 2013-November 2020). Two-tailed Fishers exact test or the Chi-squared test (for 2x2 comparisons) analysed concordance between breast and axillary pathological responses; Cox proportional hazards regression ascertained predictors of distant recurrence and survival; and logistic regression ascertained predictors of complete axillary response. Results: Among 413 patients (cN0=229; cN+=184) with a median age of 51, pathological response concordance between the breast and axilla was 81% (both pCR, 22.2%; concurrent residual disease, 58.8%). The cN0 group had a significantly higher ypN0 rate in breast pCR versus non-pCR (97.1% vs 80.8%, p<0.001). cN+ had axillary pCR concordant with breast pCR, compared to only 16.5% with residual breast disease. Breast pCR was the most significant predictor of axillary pCR (OR=11.6, p<0.001). Axillary pCR was highest in ER-/HER2+(66.7%) and triple-negative(46.9%) subtypes. Residual axillary disease was independently associated with the worst breast cancer-specific (HR=7.13, p=0.006) and overall Survival (HR=3.32, p=0.029). Kaplan-Meier analyses showed a trend towards worse survival outcomes with axillary residual disease, even with a breast pCR. Conclusions: In this limited series, breast pCR predicts axillary pCR in cN0 and cN+, particularly in HER2-positives and triple-negatives, supporting axillary de-escalation strategies in selected patients stratified by careful assessment of disease at the end of NACT.