Background: Preoperative biliary drainage is required for complicated malignant obstructive jaundice before pancreaticoduodenectomy (PD). However, the impact of internal (IntBD) versus external biliary drainage (ExtBD) on post-pancreatectomy clinical and oncological outcomes remains controversial. Methods: Systematic search of MEDLINE, EMBASE, CENTRAL, Web of Science, and ClinicalTrials.gov (through January 2025) identified studies comparing IntBD and ExtBD before PD. Meta-analyses were performed using random-effects modeling to calculate risk ratios (RRs), mean differences (MDs), and respective 95% confidence intervals. The primary outcome was overall postoperative morbidity; secondary outcomes included specific surgical complications and oncological endpoints. Results: 6832 patients from 31 retrospective cohort studies and 1 randomized trial were analyzed. ExtBD was associated with a lower overall complication rate after PD (RR: 1.31 [1.08–1.59]; P = 0.006). Post-pancreatectomy specific complications were reduced after ExtBD: pancreatic fistula (RR: 1.56 [1.29–1.90]; P < 0.00001), delayed gastric emptying (RR: 1.84 [1.19–2.85]; P = 0.006), and post-pancreatectomy hemorrhage (RR: 1.56 [1.12–2.19]; P = 0.01). Infectious complications, including biliary tract (RR: 2.40 [1.54–3.76]; P = 0.0001) and surgical site infections (RR: 1.39 [1.20–1.61]; P < 0.00001), were lower, length of hospitalization after PD was shorter with ExtBD (MD: 2.53 [0.20–4.86]; P = 0.03). Narrative analysis of long-term follow-up suggests similar distant metastases rates, but higher local recurrence (RR: 0.41 [0.32–0.55]; P < 0.00001) and lower 5-year overall survival (RR: 0.67 [0.50–0.90]; P = 0.007) of patients with periampullary cholangiocarcinoma treated with preoperative ExtBD compared with IntBD. However, long-term outcomes are biased through oncologically unbalanced cohorts. Conclusions: ExtBD was associated with lower postoperative morbidity after PD, whereas oncological outcomes remain uncertain. Given the low methodological quality and predominantly retrospective design of the included studies, these findings should be considered hypothesis-generating. Prospective trials are needed to clarify the optimal preoperative drainage strategy.

Background: Nasopharyngeal carcinoma (NPC), a frequent malignant tumor, exhibits a high propensity for both metastasis and recurrence. This study provided a comprehensive analysis of the burden, risk factors, and potential molecular mechanisms of NPC. Methods: Utilizing data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, we analyzed NPC burden in relation to age, sex, risk factors, and the sociodemographic index (SDI). The average annual percent change (AAPC) was computed through joinpoint regression. To assess causal links between risk factors and NPC, we employed two-sample Mendelian randomization (MR). Future NPC incidence trends (2022–2050) were projected using the Bayesian age–period–cohort model. We also elucidated the molecular mechanisms that trigger NPC by a bioinformatics analysis. Results: Global NPC mortality (AAPC: −1.817) and disability-adjusted life years (DALYs) rates (AAPC: −1.932) declined from 1990 to 2021. However, rising prevalence (AAPC: +0.317) and persistent high burden in East/Southeast Asia [e.g., Malaysia age-standardized incidence rate (ASIR): 6.09/100 000]. Socioeconomic disparities are widening, with low-SDI regions experiencing slower burden reduction. Projections suggest continued ASIR decline to 1.08/100 000 by 2050. MR analysis confirms smoking as a causal risk [current smokers odds ratio (OR) = 3.10; former smokers OR = 7.00, compared to never smoking], while Secretoglobin family 1A member 1 (SCGB1A1) downregulation emerges as a key mechanistic link-driving immunosuppression via Th2/Treg infiltration and hub genes (CXCL11, CD19). Conclusion: We innovatively constructed a closed-loop on NPC by multiple bioinformatic techniques. Global NPC mortality and DALYs have significantly declined, while this progress is counterbalanced by a rising prevalence and persistently high burden in East/Southeast Asia. Smoking was detected as a strong causal risk factor for NPC, while SCGB1A1 downregulation served as a novel key molecular driver of NPC pathogenesis.

Dear Editor, We read with great interest the study by Zhou et al[1], which demonstrates that isocucurbitacin B targets STAT3 to induce ferroptosis, reprogram mitochondrial metabolism, and enhance anti–PD-1 immunotherapy responses in triple-negative breast cancer using integrated multi-omics and spatial transcriptomic approaches. In the context of growing interest in ferroptosis-based therapeutic strategies and rational immunotherapy combinations to overcome resistance, this work addresses a timely and clinically relevant question. Nevertheless, several mechanistic and translational considerations warrant further clarification to strengthen causal interpretation and support the broader applicability of these findings. This study complies with the TITAN 2025 framework for transparent and ethical reporting of AI-assisted research[2]. While Zhou et al provide strong evidence that isocucurbitacin B binds STAT3 and suppresses its phosphorylation, whether STAT3 represents the dominant and rate-limiting driver of ferroptosis, mitochondrial rewiring, and anti–PD-1 potentiation remains insufficiently resolved. Their discovery pipeline nominates multiple credible signaling nodes beyond STAT3, yet mechanistic follow-through is largely monocentric, leaving open how much of the observed phenotype reflects on-target STAT3 biology versus scaffold-level polypharmacology typical of cucurbitacin-like compounds[3]. This distinction is consequential for translation, as target primacy directly informs exposure–occupancy relationships, biomarker prioritization, resistance liabilities, and rational combination design. Greater causal stringency could be achieved through orthogonal target validation and epistasis, including restoration with SH2-interface variants engineered to abrogate compound engagement, systematic assessment of activity in STAT3-null contexts with matched rescue, and proteome-scale target engagement demonstrating that STAT3 occupancy tracks with ferroptosis induction and immunotherapy sensitization. The multi-modal integration of transcriptomics, metabolomics, proteomics, and spatial profiling represents a major strength, yet it also concentrates inference risks that bear directly on translational credibility. In spatial analyses, region-of-interest ascertainment and treatment of ROIs as independent replicates can conflate within-tumor heterogeneity with between-subject effects, yielding pseudo-precision unless animals or patients are modeled as the true statistical unit with appropriate nesting[4]. This is not a technical footnote, as conclusions regarding reduced exhaustion, altered PD-1 axis activity, and metabolic reprogramming depend on whether significance is preserved after subject-level aggregation and hierarchical testing. Across modalities, pathway concordance may be further amplified by batch structure, analytic flexibility and multiplicity, and multiplicity when enrichment is repeatedly applied to correlated feature sets[5]. Explicit reporting of pre-specified contrasts, batch adjustment, and family-wise error control, together with subject-level orthogonal validation of key spatial signatures, would strengthen confidence that the reported immune and metabolic shifts reflect robust biological effects rather than analysis-dependent signal. The observed potentiation of anti–PD-1 therapy by isocucurbitacin B is translationally appealing, yet the current evidence remains largely correlative and does not define the minimal causal chain required to justify clinical extrapolation. Increased CD8⁺ T-cell infiltration and reduced exhaustion signatures are consistent with immune reinvigoration, but they do not establish whether ferroptosis constitutes the immunologically productive lesion that gates checkpoint sensitivity or whether both are parallel consequences of broader cellular stress and STAT3 pathway modulation[6]. Discriminating these possibilities requires necessity tests at the levels of both mechanism and effector, including CD8 depletion and targeted interruption of ferroptosis to determine whether the combination advantage is abolished[7]. Moreover, synergy claims in syngeneic models are inherently vulnerable to context dependence driven by baseline inflammation, tumor burden kinetics, and microbiota composition, all of which can shift checkpoint responsiveness across facilities. Demonstration of reproducibility in an additional immunocompetent model, together with reporting of key environmental covariates, would strengthen external validity and help define actionable conditions for isocucurbitacin B–based combinations in future trial design[8]. Collectively, clarifying target primacy, strengthening subject-level robustness of multi-modal inference, and establishing mechanism-based necessity for immunotherapy synergy would materially reinforce the translational foundation of this work. Addressing these issues would not only refine biological interpretation, but also inform biomarker development, patient selection, and rational combination strategies for ferroptosis-based immunotherapy. Such rigor is essential to ensure that promising preclinical synergy can be credibly advanced toward clinical testing and policy-relevant therapeutic decision-making.

To the Editor, We read with interest the randomized trial by Zhang et al[1] entitled “Effect of remimazolam on postoperative delirium in elderly patients undergoing major abdominal surgery: a randomized controlled Trial.” The use of blinded assessors with twice-daily validated assessments and reporting of both intention-to-treat (ITT) and per-protocol (PP) analyses are notable strengths. While postoperative delirium (POD) incidence did not differ significantly between groups [PP: 17.1% vs 19.7%; odds ratio (OR) 1.189, 95% confidence interval (CI) 0.688–2.057], and intraoperative hypotension appeared less frequent with remimazolam, we seek clarification on several points to aid interpretation, particularly given the variability of POD incidence across cohorts (10% reported in elective major abdominal surgery)[2]. First, although the trial was designed as a non-inferiority study (margin 5%, one-sided α = 0.025), the results are largely presented in terms of “no significant difference” based on P-values. For non-inferiority trials, interpretation hinges on the prespecified estimand and its CI relative to the margin. We suggest explicitly reporting the between-group risk difference and its 97.5% confidence interval in both ITT and PP populations, and stating clearly whether the upper confidence bound lies within the 5% margin. A simple figure showing the point estimate and confidence interval against the margin would further aid readers. Second, in the ITT population, baseline imbalances were reported for education level and diabetes – both plausibly related to cognitive reserve and POD risk. Although subsequent analyses identified education, American Society of Anesthesiologists (ASA) grade, age, and Mini-Mental State Examination (MMSE) as prognostic factors, it would be helpful to assess whether these imbalances materially affect the treatment estimate. We therefore suggest a covariate-adjusted sensitivity analysis (e.g., regression including education, diabetes, age, ASA grade, and MMSE) and reporting the adjusted effect alongside the primary analysis, particularly given an overall POD incidence of around 20%. This request is supported by cohort evidence linking education and perioperative vulnerability to POD risk[2–4] (college education: adjusted OR 0.35, 95% CI 0.13–0.91; ASA ≥3: OR 2.0, 95% CI 1.0–3.9). Third, the prespecified subgroup finding in patients aged ≥75 years is notable, with a significant interaction term (P for interaction <0.001) suggesting a higher POD risk with remimazolam. To fully appreciate the clinical relevance of this signal, readers would benefit from seeing the absolute POD rates and the corresponding absolute risk difference within this specific subgroup. Furthermore, as subgroup analyses are inherently sensitive to event counts and multiple testing, cautious interpretation is warranted. Age thresholds show strong associations with POD risk in prospective cohorts; for example, age ≥75 years independently increased POD risk (adjusted risk ratio (RR) 2.54, 95% CI 1.11–5.80) in a noncardiac surgery cohort[5]. Clarifying the interaction in this high-risk demographic is crucial for safe clinical application. Fourth, anesthetic depth was guided by bispectral index (BIS) targets (40–60). The manuscript appropriately acknowledges the uncertainty regarding BIS interpretation under remimazolam. If BIS values do not correspond equivalently to hypnotic depth across different agents, maintaining “similar BIS” may not ensure comparable cortical suppression. This has profound implications for both delirium risk assessment and the interpretation of hemodynamic outcomes. Data on total hypnotic drug doses or alternative depth-of-anesthesia metrics, if available, could provide valuable context. If BIS values under remimazolam reflect a different hypnotic state than under propofol, maintaining “similar BIS” might have resulted in disparate actual anesthesia depths, potentially confounding the comparison of delirium risk. Finally, methodologically, the handling of missing data through last observation carried forward (LOCF) and hot-deck imputation in ITT analyses, along with the exclusion of a notable proportion of patients (22/370) from PP analyses due to additional medications, raises questions about the robustness of the findings. The sensitivity of the primary conclusion to these assumptions, as well as the context of real-world co-interventions, would be valuable to discuss. Additionally, while POD assessment through postoperative day 5 captures most early cases, later-onset delirium associated with complications, ICU transfer, or sleep disruption might be missed, particularly with earlier discharge. This represents a recognized limitation in many POD studies. Moreover, hemodynamic “variability” (not merely the presence of hypotension) has been linked to POD in cohort evidence; for instance, mean arterial pressure variability was associated with POD severity (MAP variance OR 1.038 per 10 units, 95% CI 1.013–1.065) in a prospective cohort[6]. This trial offers valuable prospective evidence on the safety profile of remimazolam in elderly surgical populations. Addressing the aforementioned points would not only clarify the interpretation of the current data but also better guide the design of future trials and the optimization of anesthetic strategies for this novel agent in vulnerable geriatric patients. Ethical approval Not applicable. Consent Not applicable.

Dear Editor, We recently read with great interest the article entitled “FANS-UAS under local anesthesia for urinary stones with high risk postoperative urosepsis” by Zhang et al in your prestigious journal[1]. In this study, nephrolithiasis accompanied by asymptomatic bacteriuria (ASB) or asymptomatic pyuria (ASP) are considered urinary stones associated with a high risk of postoperative urosepsis (HR-POU). They found that retrograde intrarenal surgery (RIRS) assisted by flexible and navigable suction ureteral access sheath (FANS-UAS) under local anesthesia (LA) is feasible and safe for these HR-POU patients, and preliminary results indicate it may reduce the incidence of postoperative fever. These findings provide an attractive new option for stones with HR-POU. However, several issues merit further discussion. This study is compliant with the TITAN Guidelines 2025 – governing declaration and use of AI[2]. For patients with stone obstruction complicated by pyonephrosis or perinephric abscess, clinical priority is given to drainage methods such as ureteral stent placement or percutaneous nephrostomy[3]. Stone management is deferred to a second-stage procedure once the local infection has improved. However, this study performed first-stage FANS-UAS assisted RIRS on all 28 patients with kidney stones complicated by pyonephrosis without any discussion. Given the potential increased risk of infection following first-stage surgery, preoperative risk assessment and personalized treatment are particularly critical for these patients when opting for a primary surgery treatment plan. Based on the above, we recommend conducting a detailed analysis and discussion of the preoperative assessment and postoperative outcomes for patients with renal calculi complicated by pyonephrosis in this study. In most studies, general anesthesia (GA) is the preferred anesthetic type for RIRS[4]. The advantages of GA in kidney stone surgery include high patient compliance, controlled duration of anesthesia, and control over patient respiratory movements[5]. However, there are few studies evaluating the efficacy of LA during RIRS. This study found no significant differences between the two types of anesthesia in terms of surgical success rate, intraoperative bleeding, and operating time; however, patients in the LA group had a lower risk of postoperative fever. Furthermore, through comparative analysis of postoperative blood immune cells, the authors speculate that the cause may be attributed to the lack of significant impairment in immune function. It is our view that analyzing postoperative immune cells alone cannot fully elucidate the impact of primary surgical treatment under different anesthetic modalities on the immune function of patients with kidney stones. Instead, preoperative immune status should serve as the baseline, and different anesthetic techniques should be evaluated by comparing the degree of change in immune function before and after surgery between the two patient groups. During procedures performed under non-general anesthesia, unstable spontaneous breathing, uncontrollable coughing and sneezing reflexes, or patient movement that cannot be prevented during surgery due to inadequate analgesia may all negatively impact the successful completion of the surgical procedure. According to a study by Sahan et al, mucosal tears and hemorrhage occurred in 4.4% and 2.2% of patients in the regional anesthesia group, respectively[4]. In this study, three cases (0.8%) of patients undergoing LA experienced ureteral perforation. It is conceivable that the surgeon’s comfort level during procedures under local anesthesia would also be significantly reduced. Therefore, the safety and efficacy of RIRS assisted by FANS-UAS under LA require further discussion. In conclusion, this study pioneers an attractive new treatment option for patients with HR-POU kidney stones, but further prospective randomized controlled trials are needed to evaluate its safety and efficacy.

Background: Implant-based breast reconstruction is the most common postmastectomy approach, but the optimal combination of implant plane (prepectoral vs. subpectoral) and timing (immediate vs. delayed) remains controversial. Methods: We systematically searched five databases through March 2025 and included observational studies that compared immediate subpectoral breast reconstruction (ISBR), delayed subpectoral breast reconstruction, immediate prepectoral breast reconstruction (IPBR), and delayed prepectoral breast reconstruction (DPBR). We performed pairwise meta-analyses and Bayesian network meta-analyses (NMA) using R (version 4.4.1). To enhance interpretability, the surface under the cumulative ranking curve (SUCRA) was used to assess the probability that each strategy was the optimal choice for each prespecified outcome. Results: Thirty-one retrospective studies were included. In the NMA, no statistically significant differences were found among the strategies for overall complications, hematoma, or necrosis. Compared with ISBR, IPBR was associated with lower risks of reoperation and wound dehiscence. ISBR was associated with the greatest risk of implant loss. In terms of volume, direct evidence favored DPBR over IPBR, and the SUCRA suggested that delayed strategies are advantageous. No statistically significant differences were observed across the BREAST-Q “satisfaction with breasts,” “sexual well-being” scales, and pain. Conclusions: Across strategies, overall safety is broadly comparable. Prepectoral reconstruction tends to reduce the reoperation rate and capsular contracture rate, whereas subpectoral approaches have fewer constraints regarding flap quality. Delayed reconstruction better supports volume optimization and flexibility, whereas immediate approaches have lower follow-up demands and costs. Surgical planning should integrate flap quality, recovery burden, and patient goals for more individualized treatment selection.

Background: Electrosurgical pencils (ESPs) are essential in modern surgery; however, concerns remain regarding their exposure to surgical smoke and thermal tissue damage. This study quantitatively evaluated four ESPs with a particular focus on two critical aspects: surgical smoke generation and minimization of thermal damage to the surrounding tissues. Methods: Full-thickness incisions were made on the porcine dorsal skin using six instruments: scalpel, uncoated Bovie, coated Bovie, PlasmaBlade, and Duoblade (with and without suction). Surgical smoke was measured by particle counting, blood loss was quantified, and histological analyses (hematoxylin and eosin, Masson’s trichrome, CD3, and α-smooth muscle actin staining) were performed to assess the wound scar width and densities of CD3-positive lymphocytes and myofibroblasts. Results: Duoblades, especially those with suction, consistently produced the lowest level of surgical smoke, reducing particle counts by up to 96.1% compared to the uncoated Bovie. It also achieved the greatest reduction in blood loss (93.3% less than that of the scalpel) and resulted in the narrowest scar width among the ESPs. The wound scar width and densities of CD3-positive lymphocytes and myofibroblasts were reduced more rapidly in Duoblade-incised wounds than in those with other ESPs. Discussion: Device design and energy delivery significantly affect the surgical smoke and tissue outcomes. Duoblade dielectric heating and integrated suction provide superior environmental safety and wound healing, while maintaining excellent hemostasis. The Duoblade has a suction function that reduces the surgical smoke.

We read with great interest the article by Yang et al[1], published in the International Journal of Surgery entitled “Polyethylene terephthalate microplastics exposure enhances the risk of ulcerative colitis: insights from multiomics integration, machine learning, and molecular docking reveal intestinal toxicity mechanisms.” This study represents a valuable exploration into uncovering the association between polyethylene terephthalate microplastics (PET-MPs) and ulcerative colitis (UC), as well as their underlying molecular mechanisms. For the first time, the authors integrated interdisciplinary techniques including multiomics, machine learning, and molecular docking to identify four hub genes – CTSK, NAAA, PDE4B, and PFKFB3 – and ultimately validated the exacerbating effect of PET-MPs on intestinal inflammation through animal experiments, shedding light on the correlation between pollutants such as plastics and the pathological mechanisms of ulcerative colitis. We sincerely commend the authors for their innovative contributions in study design and technical application. Beyond their findings, we aim to put forward several supplementary considerations focusing on the completeness and rigor of the animal experimental design, with the goal of further enhancing the reliability and clinical translational value of the research conclusions. This commentary also adheres to the provisions of the 2025 TITAN Guidelines regarding the declaration and use of artificial intelligence in scientific manuscripts[2]. First, regarding the experimental grouping, it is recommended to add a standalone PET-MPs exposure group. The current study includes three groups: the control group, the DSS-treated group, and the DSS + PET-MPs co-administration group, but lacks a “PET-MPs gavage alone + normal drinking water” group. Consequently, it is challenging to clarify whether PET-MPs directly induce UC or merely exacerbate DSS-induced inflammation – specifically, the independent pathogenic role of PET-MPs in the absence of pre-existing intestinal damage remains undetermined. Adding a standalone PET-MPs exposure group would help establish a direct causal relationship between PET-MPs and UC, further validating the core conclusion that PET-MPs increase the risk of UC. Second, the current evidence base is primarily limited to observing the effects of a single PET-MP exposure dose (0.5 mg per mouse), with no systematic investigation across multiple dose gradients. This limitation may hinder the quantitative assessment of the risk of UC induced by PET-MPs. A core principle of toxicological research is to reveal the hazard threshold and intensity of pollutants through dose–response relationships[3]. Future studies are advised to incorporate comparative analyses of low, medium, and high dose groups, combined with multi-dimensional indicators such as hub gene expression levels, inflammatory factor concentrations, and pathological scores. Such an approach will facilitate the establishment of a more precise and clinically translatable quantitative understanding of PET-MP-induced UC risk, providing a scientific basis for environmental exposure risk assessment. Furthermore, as a chronic inflammatory disease in clinical practice, UC is characterized by an insidious onset and chronic progressive course[4]. Short-term exposure experiments are relatively unable to simulate the actual scenario of long-term human exposure to microplastics. In this study, the intervention period was set at 7 days, which is relatively short and not conducive to observing the effects of PET-MPs on intestinal inflammation, mucosal damage, intestinal microecology, and other aspects. Future studies should include a long-term observation phase, which will help establish a more comprehensive evidence base for the role of PET-MPs in the pathogenesis of UC. In summary, Yang and colleagues’ rigorous research provides valuable evidence for the association between PET-MP exposure and UC, as well as the underlying molecular mechanisms. However, addressing the three aforementioned limitations would enhance the scientific rigor and clinical translatability of future studies. We appreciate the authors’ significant contributions and look forward to more comprehensive advancements in this field.

Background: The value of radical prostatectomy (RP) in large volume and unresectable locally advanced prostate cancer (LAPC) or oligometastatic prostate cancer (OMPC) is largely unknown. This retrospective study aims to evaluate the conversion efficacy and safety profile of preoperative androgen deprivation therapy combined with docetaxel (A + D) in patients with large-volume (≥60 mL) and initially unresectable LAPC or OMPC. Methods: Patients with LAPC or OMPC from three large tertiary medical centers (between April 2017 and October 2024) were included. Eligibility criteria included prostate volume ≥60 mL, unresectability, and an expected survival of more than 5 years, as confirmed by two senior urologists and one radiologist. All patients received preoperative A + D therapy (≥3 cycles), followed by reassessment for RP feasibility with multimodal therapy discussion. The primary endpoint was surgical conversion rate. Secondary endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), overall survival (OS), PSA response rate, adverse events, pathological response, perioperative complications, urinary continence, and sexual function. Results: Among 31 enrolled patients, the mean age was 67.71 ± 6.69 years, and 29 (93.55%) successfully underwent RP. The mean follow-up duration was 42.83 ± 23.58 months (up to October 2024). Median PSA-PFS was 49 months (95% CI: 24.20–73.79 months), and median OS was not reached. Hematologic toxicity was the most common adverse event during chemotherapy. After A + D therapy, median prostate tumor volume decreased from 67.50 mL to 25.81 mL, and median PSA declined from 168 to 0.49 ng/mL. After RP, 11 patients (37.93%) experienced a downgrade in Gleason score, and 14 patients (48.28%) experienced a downgrade in T-stage. Positive surgical margins were found in 11 patients (37.93%). Perioperative complications included blood transfusion (11.11%), rectal injury (3.70%), lymphorrhea (7.41%), and fever &gt;38.5°C (3.70%). The 1-year urinary continence rate was 89.66%, while 100% of patients experienced sexual dysfunction. Conclusion: Preliminary data suggest that preoperative A + D therapy followed by RP may be integrated into multimodal management for large-volume, initially unresectable LAPC and OMPC, demonstrating promising conversion efficacy and clinical outcomes.