Pharmaceutics

The aim of this study was to develop a framework for assessing the incremental value of decisions on drug amount, timing, input structure, cessation and restart. The LOGOS (Longitudinal Optimization of Global Outcomes and Strategies) approach combines matched nested regimen classes, mechanism-specific benchmarks and evidence requirements in a single longitudinal comparison. Thus, the contribution of additional regimen freedom is assessed separately from improvements due to different resources, constraints or evaluation horizons. Nested feasible classes have nondecreasing objective suprema, whereas a strict gain requires a feasible witness above a valid bound for the smaller class. The approach is illustrated through analytical examples of periodic smoothing, matched desensitization, relaxed exposure allocation, finite-course loading and safety after cessation. In a normalized finite Emax model, integrated benefit increased from 0.629606 for three equal boluses to 0.672945 after optimization of amounts, 0.677043 for an amount-and-time candidate and 0.679553 for a globally certified loading-maintenance-coast solution. The adjacent observed gains were 6.88%, 0.61% and 0.37%, respectively, and all schedules satisfied the full-tail injury bound. In addition, a periodic factorial example separated response curvature from a joint recovery and repair process, including a null case and results dependent on feasibility constraints. The LOGOS framework allows assessment of whether additional regimen flexibility improves benefit, provides no added value or restores feasibility. These dimensionless examples support conditional mathematical and model-based conclusions; clinical superiority and safe restart in patients have not been established.

Background: Although perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is the standard neoadjuvant regimen for resectable gastric and gastro-oesophageal junction adenocarcinoma, evidence describing treatment delivery in routine clinical practice remains limited, particularly regarding relative dose intensity (RDI) and treatment completion. Objectives: To evaluate real-world delivery of preoperative FLOT chemotherapy, including treatment completion, progression to surgery, RDI, toxicity and exploratory changes in estimated lean body mass (LBM). Methods: A retrospective single-centre service evaluation included consecutive patients receiving neoadjuvant FLOT during 2024. Outcomes included treatment completion, surgery, RDI, toxicity, pathological response and estimated LBM. Descriptive statistics were used. Results: Twelve patients were included (median age 68.6 years; 91.7% male). Eleven (91.6%) completed all four preoperative cycles and proceeded to surgery. Mean RDI was 76.7%. Pre-emptive dose capping was the predominant dose modification strategy, with only one reactive dose reduction. Two grade 3 adverse events occurred. Major pathological response (Mandard grade 1-2) was observed in 2/12 patients (16.7%). Mean estimated LBM declined from 54.3 to 53.4 kg. Greater LBM loss appeared to coincide with poorer clinical outcomes. Conclusions: High treatment completion and progression to surgery were achieved despite reduced RDI. These findings support prospective evaluation of strategies to optimise chemotherapy delivery while maintaining tolerability in routine clinical practice.

Nicotinamide riboside (NR), a precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), has been extensively studied following oral administration, while the longer-term safety and physiological effects of injectable NR remain less characterized. Following an initial in-clinic phase evaluating repeat intramuscular (IM) and subcutaneous (SC) administration of pharmaceutical-grade NR, participants transitioned to an at-home phase designed to assess the safety, feasibility, and exploratory physiological effects of repeated self-administered SC administration. Participants continued their assigned 50 or 100 mg dose group and self-administered NR subcutaneously 3 times weekly for approximately 90 days. Safety was assessed through adverse event (AE) monitoring, vital signs, and clinical laboratory health measures. Exploratory assessments included markers of mitochondrial bioenergetics, urinary biomarkers of oxidative stress, and participant-reported outcomes related to fatigue, sleep, pain, and quality of life. At-home administration of NR was generally well-tolerated, with no clear dose-dependent safety concerns identified over the study period. Further, participants were able to successfully self-administer repeated SC injections over the study period, demonstrating positive feasibility. Whole-blood NAD+ concentrations remained largely stable over time in both dose groups. MeScreen analysis demonstrated a reduction in GlycoATP at Day 30 and increases in the MitoATP/GlycoATP ratio at Day 30 and Day 90, signifying a preferential shift toward oxidative metabolism. These findings may be indicative of positive metabolic health shifts. Urinary oxidative stress profiling demonstrated heterogeneous temporal responses. Several lipid oxidation markers significantly declined at Day 30 but returned toward baseline at Day 90. Select markers of nucleic acid, nitrative stress, and advanced glycation end-product oxidation demonstrated more sustained reductions. These results for which the majority of measured oxidative stress markers improved suggest that NR injections may exhibit anti-oxidative characteristics. Validated participant-reported sleep and fatigue measures showed improvements. Self-reported facial skin improvement increased descriptively from 11.4% at baseline to 27.8% at Day 30 and 36.8% at Day 90; improvements noticed by others increased from 9.1% to 23.7%, while reported body-skin improvement increased more modestly, from 8.8% to 16.7%. As these outcomes were not designed or powered to establish efficacy or definitive clinical claims, the findings should be considered hypothesis generating and provide preliminary data to inform the selection of outcomes and design considerations for future randomized, placebo-controlled, adequately powered trials of SC NR administration.

Aims Rosuvastatin is commonly co-administered with ticagrelor in patients with acute coronary syndrome. Ticagrelor inhibits breast cancer resistance protein (BCRP/ABCG2), increasing rosuvastatin exposure and potentially the risk of rhabdomyolysis. This risk may be further influenced by age and the ABCG2 c.421C>A variant. We aimed to predict optimal rosuvastatin dosing with ticagrelor in elderly patients stratified by ABCG2 genotype using physiologically based pharmacokinetic (PBPK) modelling Methods PBPK models for rosuvastatin and ticagrelor were developed and validated in PK-Sim using clinical data from healthy adults, elderly patients, and individuals with wild-type or homozygous ABCG2 c.421C>A genotypes. Key parameters, including BCRP catalytic activity and age-dependent declines in CYP2C9 and CYP3A4 activity, were optimized. The drug-drug interaction model incorporated competitive BCRP inhibition by ticagrelor. Rosuvastatin steady-state exposure was simulated with half or quarter standard doses during ticagrelor co-administration, and exposure matching approach was used to identify optimal dosing. Results The PBPK models demonstrated good predictive performance across populations and genotypes. In young adults with the wild-type genotype, halving the rosuvastatin dose resulted in an AUC fold change of 1.44, supporting a half-dose strategy. In young homozygous variant carriers, half-dose co-administration produced comparable exposure (AUC fold change 0.78). In elderly wild-type individuals, a four-fold dose reduction achieved comparable exposure (AUC fold change 1.06), whereas elderly variant carriers required only a half-dose reduction (1.12). Conclusions PBPK modelling supported age- and ABCG2 genotype-specific rosuvastatin dosing with ticagrelor. Elderly wild-type patients may require a further dose reduction to minimise toxicity while maintaining therapeutic exposure.

Src family kinases (SFKs) constitute a major non-receptor tyrosine kinase class that regulate processes important for pregnancy. We profiled placental SFKs to assess cell-specific expression, tissue localization, and clinical associations in early-onset preeclampsia (PE). Placental SFK transcripts were analyzed using bulk RNA sequencing discovery (GSE203507; n=15 PE, n=15 controls) and external validation (GSE114691; n=40 PE, n=21 controls) cohorts. Single-cell and single-nucleus RNA sequencing atlases mapped cell-specific expression. Computational deconvolution and causal mediation analyses were applied to bulk datasets. Findings were cross-validated by real-time quantitative PCR (qPCR; n=9 early-onset PE, n=7 controls) and immunohistochemistry (IHC). Transcriptomic data showed that LYN was the sole SFK member consistently elevated in early-onset PE placentas across discovery (1.8-fold, FDR<0.01) and validation cohorts (2.2-fold, FDR<0.001). Elevation was verified by qPCR (p<0.0001) and remained significant after adjusting for clinical covariates. Placental LYN abundance correlated positively with maximum antepartum maternal systolic blood pressure (r=0.63, p<0.01). Single-cell transcriptome atlases demonstrated LYN enrichment in myeloid lineages, extravillous trophoblasts, and syncytiotrophoblast (SCT). Deconvolution and mediation analyses indicated that altered tissue composition and increased per-cell expression each accounted for approximately half of the PE-associated LYN increase. IHC localized Lyn protein to Hofbauer macrophages and the apical microvillar SCT membrane in PE placentas. We conclude that placental LYN expression is selectively elevated in early-onset PE and correlates with maternal blood pressure severity. Lyn localization to trophoblasts and placental immune cells suggests potential roles in mediating inflammation and hypoxia-associated signaling in PE pathogenesis.

Objective: Amphetamine (AMP) and its derivates are commonly prescribed for the management of attention-deficit/hyperactivity disorder (ADHD). This study aimed to 1) quantify AMP's transfer into human milk in lactating women receiving therapeutic doses and 2) contextualize infant exposure. Methods: Milk samples and dyad health histories of thirteen lactating women treated with varying doses of either mixed AMP, dextroamphetamine, or lisdexamfetamine were released for this study from the InfantRisk Human Milk Biorepository. Milk drug concentrations were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) and used to calculate standard relative infant dose (RIDmat) and RID standardized to the defined daily dose (RIDDDD) of 15 mg AMP base. Results: Average milk concentrations (Cavg) of AMP base ranged from 23.3 to 297.0 ng/mL and increased linearly (R^2 = 0.92) with maternal daily dose. The RIDmat ranged 3.6-10.8% and RIDDDD ranged 1.4-21.8%. The fitted regression line crossed the 10% RIDDDD threshold at 1.17x DDD, with the upper 95% prediction limit crossing at 0.84x DDD. No adverse event reported by the mother-infant dyads were attributed to AMP exposure, notably including absence of reduced milk supply. Conclusions:The levels of AMP observed in human milk followed a dose predictable manner. The average patient was predicted to remain below the 10% RID DDD safety threshold at total daily doses at or below approximately 28 mg of mixed AMP salts or 59 mg of lisdexamfetamine. Ninety-five percent of patients were predicted to remain below the threshold at or below approximately 20 mg and 40 mg, respectively.

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.

Background. Regulatory pressure to avoid confusingly similar drug names appears to have pushed manufacturers to coin more distinctive proprietary names, but no one has quantitatively analyzed this trend. Objective. To determine whether proprietary drug names became more orthographically distinctive (unusual in spelling) over time. Methods. We examined 1,321 US Food and Drug Administration (FDA) new molecular entity (NME) names (1985-2024), 2,769 FDA Orange Book trade names (1982-2026), 177,337 US pharmaceutical trademarks (1980-2026), and 1,273 generic names (1982-2025). Compared to prior names (including those already marketed) and ordinary English, we scored each name's character trigram (three-letter sequence) surprisal (statistical unexpectedness) and its edit-distance similarity to the closest existing names. Linear regression tested time trends, controlling for name length. Results. Mean NME trigram surprisal rose in every decade between the 1980s and 2020s, from 7.21 to 8.50 nats (natural-logarithm units, higher meaning less predictable), an 18% increase (b = 0.038, p < .001, R2 = 0.34). Half of 2020s names (7% in the 1980s) contained a letter sequence found in no common English word (e.g., Jesduvroq, Omvoh). Nearest-neighbor similarity fell after the early 1990s. Trademark data showed the same trend (b = 0.016, p < .001). Generic names showed a weaker trend (b = 0.011, R2 = 0.063). Conclusions. Over four decades, drug names became more orthographically distinctive, consistent with namespace crowding, deliberate efforts to avoid confusing names, and branding strategy. Because unfamiliar letter sequences can introduce other error pathways, increased distinctiveness does not necessarily imply improved safety.

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.

Background and Objective: Adding belzutifan to adjuvant pembrolizumab improved disease-free survival (DFS) in LITESPARK-022, but its durability beyond the 1-year treatment is unknown. Methods: Following a registered plan, we reconstructed individual patient data from published Kaplan-Meier curves of ten phase 3 adjuvant renal cell carcinoma trials. Within each trial, we estimated restricted mean survival time differences ({Delta}RMST), hazard ratios (HRs) before and after planned treatment ended, and DFS differences. Key Findings and Limitations: In LITESPARK-022 (central review), the 24-month {Delta}RMST was 1.34 months (95% confidence interval 0.73-1.95), and the belzutifan arm remained ahead after month 12 ({Delta}RMST increment 0.74 months/yr, 0.32-1.19). The HR was 0.55 (0.43-0.71) before month 12 and 1.16 (0.87-1.54) afterwards (post/pre ratio 2.10); investigator assessment showed similar attenuation. Similar ratios occurred in KEYNOTE-564 at its first interim analysis (2.02), whose benefit persisted, and in SORCE and PROTECT (2.09, 2.59), whose benefit faded. From months 12 to 30 (post hoc), the DFS difference changed by -3.7 percentage points (-8.1 to 0.8) with central review and 0.6 (-4.0 to 5.0) with investigator assessment. Data were reconstructed, and follow-up was short. Conclusions and Clinical Implications: Relative hazard reductions with belzutifan were greater before month 12; durability of the absolute DFS advantage is uncertain and assessment-dependent, so single-HR projections should be avoided.

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: 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.

Summary Background We used sequential target trial emulation (TTE) to examine associations between opioid analgesic initiation and adverse maternal and neonatal outcomes while accounting for gestational timing, time at risk, and potential confounding. Methods Using the Early Life Course platform, comprising linked population-based data for births in New South Wales, Australia (2013-2019), we emulated a new trial at each gestational week, comparing women who initiated a prescribed opioid analgesic with eligible non-initiators. Baseline covariates were balanced using inverse probability weighting. Weighted logistic regression estimated odds ratios (ORs) for neonatal outcomes, postpartum haemorrhage, and severe maternal morbidity. Pooled logistic regression estimated hazard ratios (HRs) for other maternal outcomes, combined across gestational weeks using fixed-effects meta-analysis. Sensitivity analyses assessed unmeasured confounding, exposure misclassification, and potential reverse causation. Findings Among 511,357 pregnancies, over 80% of opioid initiators received only one dispensing. Opioid initiation was not associated with increased risks of placental abruption (HR 0.94, 95% CI 0.75-1.16), severe maternal morbidity (OR 1.05, 0.97-1.11), postpartum haemorrhage (OR 0.98, 0.95-1.02), low Apgar score (OR 0.99, 0.87-1.08), small for gestational age (OR 0.90, 0.85-0.95), or neonatal abstinence syndrome (OR 0.98, 0.72-1.30). Risks were elevated for PPROM (HR 1.10, 0.98-1.23), preterm birth (HR 1.26, 1.19-1.33), severe neonatal morbidity (OR 1.08, 1.02-1.17), and perinatal death (OR 1.29, 1.10-1.52). Perinatal death estimates attenuated in analyses addressing potential reverse causation. Interpretation Using a TTE approach that accounted for gestational timing and time at risk, we found no appreciable increase in most maternal or neonatal outcomes following predominantly short-term opioid initiation. Elevated risks of preterm birth, perinatal death, and third-trimester PPROM may reflect causal effects or confounding by pregnancy-related indications. Studies using time-appropriate designs and detailed information on prescribing indications and their timing are needed to clarify these associations.

Background: Opioids remain the cornerstone of acute postoperative pain management but are associated with potentially serious adverse effects. We aimed to investigate the effect of oxycodone patient-controlled analgesia with adjunctive S-ketamine on pain after lumbar fusion surgery. Methods: In this secondary analysis, we examined oxycodone and S-ketamine exposure and PCA behaviour during the first 24 h. We assessed current pain versus subsequent PCA activity and whether the association between plasma oxycodone and adequate analgesia changed with postoperative time. Results: Plasma concentrations of administered drugs rose rapidly after PCA initiation, but variation was large. Metabolite concentrations accumulated over time. PCA attempt and delivered-dose rates decreased over postoperative time (RR 0.965 and 0.966 per hour, respectively; both P<0.001). Older age was associated with a lower delivered-dose rate (RR 0.905 per 10 years, 95% CI 0.829-0.987). Each 1-point higher current pain score was associated with more subsequent PCA attempts (RR 1.09, 95% CI 1.04-1.14) and delivered doses (RR 1.07, 95% CI 1.03-1.11). The oxycodone-analgesia association weakened over time [interaction P <0.001; odds ratios (Ors) per 10 ng/mL 1.16, 1.13, and 1.00 at 1, 4, and 24 h, respectively]. In active S-ketamine groups, including S-ketamine, norketamine, and 6-hydroxynorketamine concentrations left the pain-PCA association unchanged (RR 1.09 and 1.07) and preserved the time-dependent oxycodone association (ORs 1.30, 1.26, and 1.02). Conclusions: During PCA, drug exposure develops from patient-generated dosing histories while pain and recovery change. Current pain was associated with subsequent PCA activity, and the oxycodone-analgesia association was time-dependent.

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.

Background: Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice. Methods: This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain (NCT05235191). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with 30% or more pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups. Results: Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved 30% or more pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (rs=0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003). Conclusions: Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.

Purpose: Biochemical recurrence (BCR) after radical prostatectomy (RP) presents heterogeneous recurrence patterns and variable outcomes following salvage radiotherapy (sRT). We evaluated clinicopathologic determinants of PSMA-PET/CT detection, anatomical recurrence distribution, and biochemical disease-free survival (bDFS) following PSMA-PET-guided sRT. Methods: This retrospective single-institution study included 140 patients with BCR after RP who underwent Ga-PSMA-PET/CT prior to sRT with or without androgen deprivation therapy. PSMA-PET-positive findings were categorized as prostate bed only (PBO) or pelvic nodal involvement with or without the prostate bed (PLNI). Receiver operating characteristic (ROC) analysis, logistic regression, and Cox proportional hazards models were employed. Results: PSMA-PET detected locoregional recurrence in 77/140 patients (55%). On multivariable analysis, PSA at recurrence (OR=2.07; p=0.003) and age (OR=1.07; p=0.016) were the sole independent predictors of PSMA-PET positivity. ROC analysis yielded AUC=0.74 (optimal threshold of 0.58 ng/mL). Among PSMA-positive patients, PBO was associated with a longer time to BCR (tBCR) (37.5 versus 15 months; p=0.006). Seminal vesicle invasion (SVI) and pT-stage predicted PLNI on univariable analysis. Among 124 of 140 evaluable patients (median follow-up 31 months), estimated bDFS at 24, 36, and 60 months was 89.7%, 80.2%, and 54.1%, respectively. SVI (HR=2.39; p=0.031), EPE (HR=2.82; p=0.012), pT-stage (HR=1.64; p=0.021), and pN-stage (HR=1.83; p=0.045) were associated with increased failure on univariable Cox regression, though none retained independent significance. Conclusion: PSA burden and age independently predicted PSMA-PET detection. Recurrence patterns reflected disease behavior, as PBO was associated with longer tBCR. Adverse pathologic features were associated with pelvic nodal disease and reduced biochemical control; none remained independently predictive.

Open-loop insulin pump therapy depends on clinical expertise for dose initiation and titration. We developed a long short-term memory-based system, using 1738 treatment courses from 1641 patients with type 2 diabetes for initial prescribing and daily basal and bolus titration. Patient-grouped five-fold validation showed closer agreement with recorded prescriptions for subsequent titration than for initiation. Prospective evaluation in 97 patients from the model-directed arm of a randomized trial yielded a median derived time in range (3.9-10.0mmol/L) of 84.5%, with low hypoglycemic exposure. Favorable control extended to previously treated patients. Higher mean glucose during the first 24 hours was associated with poorer glycemic control thereafter. The association between distance from development data and glycemic outcomes was stronger when early glucose responses were included alongside baseline characteristics. These findings support model-directed pump dosing and highlight early treatment response as a clinically relevant signal for assessing applicability and identifying patients who may require additional oversight. Trial registration: ClinicalTrials.gov, NCT07066891.

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.

Pharmacological treatments targeting core autistic features remain limited. In neurotypical adults, cannabidiol (CBD) alters mismatch negativity (MMN), an electrophysiological marker of automatic auditory deviance detection that has been associated with autistic traits. The effects of CBD on MMN, as measured using electroencephalography (EEG), in autistic children remain unknown. This secondary analysis of a pilot randomised, double-blind, placebo-controlled crossover trial examined the effects of 12 weeks of oral CBD oil on MMN during a duration-deviant auditory oddball task. We hypothesised that CBD would produce more negative MMN amplitudes and shorter peak latencies relative to placebo. Nineteen autistic children (6-12 years, 8 female) received CBD (dose) and placebo in randomised order, separated by an 8-week washout. Age-adjusted linear mixed-effects models tested Time (baseline, follow-up) x Treatment (CBD, placebo) effects on mean MMN amplitude and peak latency separately at Fz and FCz. Exploratory Spearman correlations examined baseline associations between MMN and Developmental Behaviour Checklist-2 (DBC-2) Social Relating scores. At FCz, latency decreased following CBD but increased following placebo but did not survive FDR correction (p = .029, pFDR = .058) and no other interactions were significant. Higher baseline DBC-2 Social Relating scores were associated with more negative MMN amplitude at FCz (rho = -.58, pFDR = .028) and Fz (rho = -.59, pFDR = .028). These findings provide tentative evidence that CBD may modulate MMN latency in autistic children. Larger trials should clarify CBDs effects on MMN and further examine the association between MMN amplitude and social-relating difficulties.