Search Results (5,243)

Lipid nanoparticles (LNPs) have emerged as a groundbreaking delivery platform, revolutionizing the development of nucleic acid-based medicines for gene delivery and gene therapy. This review provides an insightful industrial perspective on the production process of LNPs, focusing on cutting-edge manufacturing equipment, downstream processing and the crucial transition from laboratory to large scale. While LNP production in the discovery phase relies on a small scale (µL to mL) for screening various LNP formulation candidates, transferring to preclinical (up to hundreds of mL) and clinical/commercial scales (up to liters) requires a robust and reproducible manufacturing process. Thus, mixing technologies throughout these scales must be carefully selected and require precision, scalability and high reproducibility to meet the target quality of the LNP drug product. Key mixing technologies in mRNA-LNP production primarily include microfluidic systems and impinging jet mixers (IJMs). In this review, we discuss key critical process parameters (CPPs) in LNP preparation, including flow rate ratio (FRR) or total flow rate (TFR), in relation to associated critical quality attributes (CQAs) across multiple manufacturing scales. We further assess the impact of downstream processing, specifically tangential flow filtration (TFF), on the formulation’s CQAs. In particular, the review highlights the importance of maintaining CQAs along each step of the process and emphasizes the role of robust analytical methods in ensuring product quality and safety. Additionally, we touch on current challenges associated with these advanced delivery vehicles, such as their long-term stability, and introduce the readership to innovative stabilization strategies aimed to extent LNP shelf-life. Full article

Background/Objectives: Sarcomas are rare, highly heterogeneous malignancies comprising more than 100 subtypes. Their nonspecific clinical presentations, frequent misdiagnosis, and limited access to specialized expertise contribute to prolonged routes to diagnosis. Prolonged diagnostic intervals are associated with worse clinical outcomes, yet determinants of time to diagnosis remain insufficiently characterized. Therefore, the aim of this study was to examine clinical, health system, and socioeconomic determinants of time to diagnosis among patients with sarcoma. Methods: We conducted a global cross-sectional survey through the Sarcoma Patient Advocacy Global Network (SPAGN), including 1803 patients and caregivers across 19 languages. Collected data included sociodemographic characteristics, tumor-related factors, healthcare access, and diagnostic timelines. Associations between patient-, tumor-, and system-level variables and time to diagnosis were assessed using multivariable linear regression. Missing data were handled using multiple imputation. Results: The median time to diagnosis was 92 days (interquartile range (IQR): 31–245). Patient-reported barriers to care were strongly associated with prolonged diagnostic intervals. Female gender was independently associated with longer care intervals, while patients from low/lower-middle-income countries reported shorter diagnostic times. Tumor characteristics, age, and stage at diagnosis were not independently associated with time to diagnosis. Conclusions: Timely and accurate sarcoma diagnosis remains a global challenge. Prolonged routes to diagnosis appear to be driven by modifiable structural and socioeconomic factors, including misdiagnosis, limited specialist expertise, and unclear referral pathways, rather than tumor-related characteristics. These findings highlight the need to enhance awareness, streamline referral processes, and expand access to specialized care to reduce avoidable prolonged routes to diagnosis and improve patient outcomes worldwide. Full article

Background: The global demographic shift towards an aging population has driven a steady, exponential increase in the utilization of cardiac implantable electronic devices (CIEDs). Consequently, device-related infectious complications have emerged as a leading cause of morbidity and healthcare expenditure. Patients in their eighth decade of life—octogenarians (aged 80–90 years)—represent an exceptionally high-risk demographic due to the compounding factors of physiological frailty, immunosenescence, and complex multi-morbidity. Despite this growing demographic, their specific clinical presentations, microbiological profiles, and procedural outcomes following infection remain poorly defined in the current literature. This study aimed to comprehensively compare the clinical characteristics, pathogen distribution, and in-hospital outcomes of CIED infections in an octogenarian cohort against a younger patient population. Methods: We conducted a robust retrospective cohort analysis of 383 consecutive patients treated for confirmed CIED infections at one major tertiary referral center (Heidelberg University Hospital) between January 2002 and December 2022. The cohort was stratified by age into octogenarians (n = 76) and a younger control group (n = 307). We systematically extracted and compared data regarding baseline clinical presentation, chronic comorbidities, detailed microbiological cultures (pocket, blood, and extracted leads), and definitive in-hospital outcomes, primarily mortality and length of stay. Results: The octogenarian cohort exhibited a significantly heavier comorbidity burden, notably higher rates of coronary artery disease (51.3% vs. 29.6%, p < 0.001), systemic hypertension (55.3% vs. 38.1%, p = 0.007), and chronic obstructive pulmonary disease (7.9% vs. 1.6%, p = 0.003). Furthermore, therapeutic systemic anticoagulant use was substantially more prevalent in the elderly group (60.5% vs. 45.0%, p = 0.015). Octogenarians presented overwhelmingly with localized generator pocket infections (73.0% vs. 30.0%, p < 0.001) but paradoxically also demonstrated higher rates of systemic bacteremia and sepsis (26.3% vs. 15.0%, p = 0.019). Microbiological analysis revealed a unique pathogen profile, with Staphylococcus capitis found with significantly higher frequency in the generator pockets of the elderly cohort. Remarkably, despite possessing a higher average lead burden (2.1 vs. 1.2 leads) and extreme comorbidity profiles, octogenarians demonstrated no statistically significant differences in in-hospital mortality (3.9% vs. 4.2%, p = 1.000) or overall length of hospital stay (14.7 vs. 17.2 days, p = 0.386) when compared to the younger cohort. Conclusions: Octogenarians suffering from CIED infections display highly distinct clinical and microbiological profiles, characterized predominantly by elevated rates of localized pocket infections, specific opportunistic pathogens, and a severe underlying comorbidity burden. Crucially, our findings indicate that with the application of modern extraction and management protocols, advanced age alone does not intrinsically correlate with increased in-hospital mortality. Future prevention and perioperative management strategies tailored to this rapidly expanding demographic must heavily prioritize the mitigation of pocket-related complications, particularly considering the high prevalence of concurrent anticoagulation therapy. Full article

Background: Most penicillin allergy labels are documented in early childhood and result from events of low risk for allergy. In Germany, evidence-based strategies to evaluate the likelihood of a true penicillin allergy are still lacking. As general practitioner input is indispensable regarding required resources for the implementation of successful delabeling strategies in outpatient care, a mixed-methods study in Baden-Württemberg, Germany explored untapped delabeling potential and conditions for successful initiatives based on their experiences, to support preservation of penicillin as a treatment option and prevent resistance development. Methods: A cross-sectional convergent mixed-methods study was conducted with an online survey and semi-structured interviews. The survey link and invitation to participate in an interview was sent to randomly selected publicly available e-mail addresses. Survey data were analyzed descriptively. Qualitative data were analyzed inductively based on thematic analysis. Results: n = 101 survey questionnaires and n = 15 interviews were analyzed regarding relevance, experiences, framework conditions, and potential approaches to delabeling. All participants with limited recollection of the index reaction. Most participants considered delabeling a highly relevant topic in general practice. Delabeling efforts were discouraged by lack of time, expertise, and remuneration, and uncertainty due to missing guidelines. Taking a sufficient medical history and, if necessary, subsequent testing were seen as one approach to delabeling. For a standardized approach in primary care, patient and care provider education, precise guideline recommendations, and delabeling expert teams were suggested. Conclusions: The findings mirror aspects already identified in international research. A nationwide survey with general practitioners could confirm that addressing necessary resources and systemic adjustments would support effective penicillin allergy delabeling in outpatient care. Full article

Background: Sebaceous carcinoma (SC) is a rare malignant cutaneous malignancy. Methods: A multicenter retrospective study of 213 German patients with SC diagnosed between 2008 and 2024 was conducted. Data were extracted from the Baden-Württemberg Cancer Registry. Cases were separated into ocular and extraocular SC. Their demographic, clinical, and treatment-related characteristics were compared and influences on overall survival (OS) analyzed. Results: Most patients were elderly (median age: 79 years), with a male-to-female ratio of 2:1. Extraocular SC was more common in men, while ocular SC was more frequent in women. Most tumors were diagnosed at stage I, and microscopically controlled excision was the primary treatment modality (81.4%). Sentinel lymph node biopsy (2.3%), lymph node dissection (1.9%) and systemic therapy (1.4%) were only documented in a minority of cases. Survival analysis (median follow-up 3.2 years) revealed a median OS of 61.4 months in the entire cohort. No significant survival difference was observed between ocular and extraocular SC (64.8 vs. 53.7 months; p = 0.490), and multivariable analysis confirmed no prognostic impact of tumor localization (HR 1.4, 95% CI 0.85–2.4). Age was the only independent predictor of outcome, with strongly increased risk in patients aged 70–79 years (HR 4.4, 95% CI 1.01–19.2) and ≥80 years (HR 16.1, 95% CI 3.91–66.1). Prior malignancies, including MTS-like tumors and hematological neoplasms, were not independently associated with overall survival. Conclusions: In this multicenter cohort, sebaceous carcinoma showed no survival difference between ocular and extraocular disease, with age emerging as the main independent prognostic factor. Prior malignancies and tumor characteristics, including histologic grade, were not independently associated with outcome. Microscopically controlled excision appears to be an effective treatment option. Full article

Understanding the genetic changes that allow avian influenza A viruses (IAVs) to switch their natural hosts and establish productive infection in humans is important for pandemic risk assessment. Adaptations in the IAV polymerase are required to overcome species-specific restrictions imposed by host ANP32 proteins. Notably, avian virus polymerase is generally only poorly supported by human ANP32 proteins due to species-specific differences. Consequently, efficient polymerase adaptation to the binding interface of human ANP32 requires distinct amino acid changes, such as PB2 E627K. A separate adaptation, PB2 M631L, has recently been reported in mammalian-adapted IAV; however, its functional role across divergent viral lineages and its relationship to host ANP32-dependent adaptation remain incompletely defined. Here, we examine PB2 M631L in the polymerases of a 1918 pandemic strain, a recombinant contemporary H1N1pdm09, and a recent clade 2.3.4.4b H5N1 virus. Using polymerase activity and protein-interaction assays, we show that PB2 M631L enhances polymerase activity and ANP32 binding in human—but not avian—contexts, and that this effect is conserved across multiple viral backgrounds. In H1N1pdm09, PB2 M631L also increased virus replication in mammalian cells. These findings indicate that PB2 M631L contributes to enhanced polymerase compatibility with human ANP32 proteins and are consistent with a role in adaptation across multiple influenza virus lineages. Our results highlight how analysis of historical pandemic strains can inform risk assessment for future emerging viruses. Full article

Iron oxide nanoparticles have emerged as multifunctional compounds with prominent potential in cancer theranostics, particularly in photothermal therapy (PTT) and photodynamic therapy (PDT). Their unique electronic and crystal structures, such as the dispersion of Fe²⁺ and Fe³⁺ ions and d-orbital splitting, contribute to their magnetic and catalytic properties. In PTT, Fe₃O₄ nanoparticles exhibit moderate near-infrared (NIR) absorption and photothermal conversion efficiency, which can be enhanced through adjustments in particle size, surface modification, and combinations with other components. In PDT, Fe₃O₄ nanoparticles demonstrate intrinsic peroxidase-like catalytic activity, facilitating Fenton and photo-Fenton reactions that generate reactive oxygen species (ROS), including hydroxyl radicals (^•OH), thereby amplifying oxidative stress in cancer cells. These nanoparticles can also function as carriers for photosensitisers (PS), promoting targeted delivery and enhanced ROS generation. Multifunctional nanomaterials that integrate Fe₃O₄ with other therapeutic agents and targeting ligands have demonstrated synergistic antitumour effects through amplified photothermal, photodynamic, chemodynamic, and chemotherapeutic mechanisms. Despite certain drawbacks, such as relatively low NIR absorption and challenges in optimising delivery and light activation, ongoing improvements in Fe₃O₄-based nanoplatforms present significant potential for enhancing treatment outcomes and the precision of cancer therapy. This article systematically explores the synergistic role of Fe₃O₄ nanoparticles in PTT and PDT, encompassing their magnetic and catalytic characteristics. Additionally, it focuses on multifunctional hybrid nanoplatforms that combine Fe₃O₄ with targeting or imaging agents, highlighting their potential to enhance therapeutic precision. Full article

Objectives: Oral health-related quality of life (OHRQoL) reflects the functional and psychosocial impacts of oral conditions on daily life. In low-resource settings such as rural Tanzania, limited access to dental care and preventive services may increase the burden of oral disease. This study assessed the association between clinical oral health conditions and OHRQoL among schoolchildren in rural Tanzania. Methods: A cross-sectional study was conducted among 293 schoolchildren at Igelehezda Primary School, Ilembula, Tanzania. Clinical examinations assessed dental caries using the DMFT index and oral hygiene using the OHI-S index. OHRQoL was measured with the Child Oral Impact on Daily Performances (C-OIDP) questionnaire. Behavioral data included sugar intake, number of daily meals, and toothbrushing-related symptoms. Associations between clinical, behavioral factors and OHRQoL were analyzed using descriptive statistics, bivariate tests, and multiple linear regression (p < 0.05). Results: All 293 children completed the study (mean age 12.2 ± 1.2 years; 157 females, 136 males). Mean DMFT was 2.7 ± 4.1, with 80.5% free of untreated caries, and mean OHI-S indicated good oral hygiene (0.4 ± 0.6). Most participants were periodontally healthy (68.3%). Toothache, gum pain, or bleeding during brushing were reported by 26.0–31.6%. Eating was the most affected daily activity (42.7%). Missing teeth, toothbrushing-related symptoms, and consumption of high-sugar sweets were significantly associated with higher C-OIDP scores (p < 0.05), while a higher number of daily meals was associated with fewer impacts. Conclusions: Missing teeth, toothbrushing-related symptoms, and high sugar intake were associated with greater impairment in daily life, particularly affecting eating. These findings highlight the need for preventive and educational oral health interventions in rural, resource-limited settings. Full article

Background/Objectives: Patients involved in high-energy accidents (HEAs) are frequently admitted for inpatient surveillance despite normal clinical examination and imaging, although the yield of this practice is uncertain. This study evaluated the frequency and nature of clinical events, interventions during surveillance and missed injuries in such low-risk patients and explored potential predictors. Methods: Retrospective study at a Level I trauma center including patients ≥18 years admitted between January 2022 and September 2023 solely due to HEA mechanism, without apparent injury requiring inpatient treatment. Baseline characteristics, clinical presentation, imaging findings, and laboratory values were extracted. Outcomes included additional diagnostics, new diagnoses, therapeutic interventions, and missed injuries. Patients with eventful and uneventful stays were compared using univariate statistical tests. Results: Among 363 included patients, 86.0% experienced an uneventful stay. Fifty-one patients (14.0%) had an eventful stay, most commonly requiring additional radiological examinations (8.5%) or blood tests (6.9%). New diagnoses occurred in 6.6%, and 6.1% received additional therapeutic interventions. Missed injuries were detected in 3.9%, including two potentially life-threatening injuries (0.6%). No robust predictors for missed injuries were identified. Established predictors of missed injuries from broader trauma populations were absent in this selected low-risk cohort. However, individuals after bicycle accidents were significantly more likely to experience any event during their stay (p = 0.009). Conclusions: Inpatient surveillance of patients without apparent injury after HEAs has a low overall yield but occasionally identifies clinically significant conditions. As no reliable predictors for adverse events were found, selective admission remains challenging. Hybrid models combining short-term observation with structured outpatient reassessment may represent a resource-efficient alternative for low-risk patients. Full article

Background/Objectives: Tinnitus and hyperacusis can occur together or in isolation, with hyperacusis being associated with tinnitus much more frequently than vice versa. This striking correlation between tinnitus and hyperacusis prevalence implies that there might be a common origin, such as (hidden) hearing loss, and possibly interrelated neural mechanisms in the pathological development of those two conditions. Here, we propose such interrelated pathological mechanisms. Methods: This is a theoretical work based solely on considerations and published data. Results: We propose a model localized in the dorsal cochlear nucleus (DCN) of the brainstem, based on classical mechanisms of Hebbian and associative plasticity known from classical conditioning. Specifically, our model proposes that hyperacusis results from the synaptic enhancement of cochlear input to the DCN, whereas chronic tinnitus results from the synaptic enhancement of somatosensory input to the DCN. Specific conditions leading to one or the other condition are discussed. Conclusions: Our model predicts that hearing loss leads to chronic tinnitus, while noise exposure (which may also cause hearing loss) leads to hyperacusis. We would like to emphasize that our aim with the proposed model is not to provide a self-contained theoretical construct, but to stimulate thought regarding possible pathological causes of tinnitus and hyperacusis that have not yet been investigated. Individual assumptions that cannot yet be substantiated by the existing literature are intended to provide impetus for future experimental studies. Full article

Background: Glioblastoma is an extremely aggressive brain tumor that diffusely infiltrates white matter and alters large-scale brain connectivity. Most prognostic models focus on localized tumor features and clinical variables, overlooking broader effects on the brain’s structural connectome. This study addressed this limitation by integrating graph-theoretical analysis of preoperative diffusion tensor imaging (DTI)-derived structural connectomes with machine learning (ML) to improve prediction of overall survival (OS) in newly diagnosed glioblastoma. Methods: Preoperative DTI data from 871 glioblastoma patients from the UPenn-GBM and UCSF-PDGM cohorts were processed to construct whole-brain structural connectomes weighted by tract count and quantitative anisotropy (QA). Global and nodal graph-theoretical network metrics were extracted and combined with demographic and clinical information. Ten ML models were trained and validated on 784 patients (90% of the cohort). The three best-performing algorithms were tested on a held-out cohort of 87 patients (10%). Results: Random forest, adaptive boosting, and KStar showed the strongest validation performance. In held-out internal testing, random forest models using degree and QA-weighted strength achieved accuracies of 0.862 and 0.874, with AUROCs of 0.929 and 0.909, for predicting OS beyond one year. Strength and clustering coefficient were key predictors, with over two-thirds of significant nodes localized in the temporal lobe, particularly the parahippocampal, and superior, middle, and inferior temporal gyri. Conclusions: Graph-theoretical quantification of structural brain network disruption combined with ML allows accurate prediction of OS in glioblastoma. These results support a network-based conceptualization of the disease and indicate that connectome-derived metrics may complement established prognostic frameworks. Full article

Prostate cancer is one of the most prevalent malignancies among men and remains a major clinical challenge due to the complex tumor microenvironment. Understanding gene expression dynamics at both cellular and spatial levels is essential for improving therapeutic strategies. In this study, we performed an integrated multi-omics analysis using single-cell RNA sequencing and spatial transcriptomics. scRNA-seq data from 15 prostate samples, including 8 normal and 7 tumor tissues, were analyzed to characterize distinct cellular populations. Spatial transcriptomic profiling was conducted on three FFPE prostate tissue sections, including adjacent normal tissue, acinar cell carcinoma, and invasive adenocarcinoma, using the standard 10x Genomics Visium FFPE platform (55 µm capture spots). Single-cell analysis revealed heterogeneity among epithelial, stromal, and immune cell populations, highlighting complex signaling networks in which myeloid cells may contribute to tumor progression through immune suppression and epithelial adaptability. Spatial transcriptomic analysis further identified region-specific expression patterns and spatially restricted tumor niches, including the regional establishment of TXNIP and BIRC3 as genes associated with metabolic stress and inflammatory survival pathways. The spatial colocalization of BIRC3 with tumor vasculature in invasive carcinoma tissue suggests a novel interaction. Our discoveries using an integrated single-cell and spatial transcriptomic approach reveal a high-resolution molecular map of prostate cancer with spatial features that may provide further therapeutic investigation. Full article

Background: Cardiac implantable electronic device (CIED) lead perforation is a rare but potentially catastrophic complication. As global device implantations increase, understanding the clinical spectrum and optimal management of this complication is essential. This study characterizes the clinical presentation, diagnostic strategies, and outcomes of lead perforation over a 25-year period. Methods: A retrospective analysis was conducted on 32 patients diagnosed with CIED lead perforation between 2000 and 2025 at a high-volume center. Perforations were classified by timing: acute (<24 h), subacute (1–30 days), and chronic (>30 days). Data included demographics, comorbidities, imaging modalities, and procedural interventions. Results: The mean patient age was 76.0 ± 11.7 years, with a mean body mass index (BMI) of 25.5 ± 3.4 kg/m². Subacute presentation was the most frequent (59.3%, n = 19), followed by acute (28.1%, n = 9) and chronic (12.5%, n = 4) cases. The right ventricle was the primary site of perforation (90.6%). While chest X-rays served as an initial screening tool in 62.5% of cases, diagnosis relied on multimodal imaging, with Computed Tomography (CT) providing definitive confirmation in 31.3% of the cohort, particularly when lead parameters remained stable. Management was risk-stratified based on hemodynamic status. The majority of patients (71.9%, n = 23) underwent successful transvenous lead removal via simple traction. However, 25% (n = 8) presented with hemodynamic instability, and 21.9% (n = 7) suffered from cardiac tamponade. These high-risk cases required surgical intervention, including sternotomy (n = 4), thoracotomy (n = 2), or pericardiotomy (n = 3). Notably, 62.5% of hemodynamically unstable patients were on oral anticoagulants. All patients survived to discharge, with no in-hospital mortality. The median length of hospital stay was 3 days. Conclusions: CIED lead perforation often presents subacutely with subtle clinical signs. CT imaging has emerged as the gold standard for definitive diagnosis. While percutaneous transvenous removal is safe and effective for stable patients, immediate surgical backup is vital, as patients—particularly those on anticoagulation—can deteriorate rapidly. Full article

Objectives: To evaluate Sodium Magnetic Resonance (²³Na MR) images of prostate cancer (PCa) and quantify tissue sodium concentration (TSC) based on internal references. Methods: Forty-six patients with clinically suspected prostate cancer were included into a prospective study. The patients underwent multiparametric MRI and an additional ²³Na MRI examination of the prostate, performed at 3T (Magnetom Skyra, Siemens Healthineers, Erlangen, Germany) using a dual-tuned ¹H/²³Na body-coil (Rapid Biomedical, Rimpar, Germany) to acquire a 3D radial density-adapted ²³Na sequence. Three-dimensional regions of interest (ROI) were defined within the femoral blood vessels, which were used as an internal reference for TSC quantification. Prostate zones and tumor ROIs were defined and TSC was evaluated for each ROI. Results: TSC quantification based on femoral blood vessels demonstrated good stability since mean absolute TSC difference between right and left regions of interest in the blood vessels was 3.3 ± 2.2 mM. TSC in the peripheral zone (40.7 ± 6.0 mM) was significantly higher than in the transition zone (37.5 ± 5.7 mM). Nine suspicious lesions (PI-RADS 4 and 5) were identified in eight men, all with biopsy-proven PCa with Gleason scores of ≥3 + 3. TSC in prostate cancer was significantly lower than in contralateral healthy regions, 32.2 ± 5.5 mM and 36.1 ± 3.9 mM, respectively (p = 0.018). Conclusions: TSC quantification of prostate tissue based on internal references is feasible and reliable. TSC was significantly decreased within prostate cancer, which represents a quantitative imaging biomarker that could potentially improve PCa characterization and risk stratification. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor survival outcomes. Resection is the sole definitive management; however, most PDACs are diagnosed with unresectable disease including metastatic, locally advanced (LAPC) or borderline resectable (BRPC). Recently, neoadjuvant therapy has demonstrated potential in downstaging these tumours for resection. This literature review explores current and novel approaches in the management of BRPC and LAPC. Methods: A systematic search of Medline, Embase, Cochrane Central and Emcare databases was conducted on 7 April 2025. Inclusion criteria were primary articles that explored current and novel therapies that led to downstaging of BRPC and LAPC to resection, as well as resection outcomes and oncological outcomes associated with this. Articles that explored other pancreatic cancer subtypes or either resectable or metastatic disease were excluded. All meta-analyses were performed using a random-effects model based on the inverse variance method. Results: A total of 88 studies involving 8585 patients were included in the review, predominately from retrospective studies (57%, n = 50). Neoadjuvant regimens incorporating chemotherapy or radiotherapy, whether sequential or concurrent, demonstrated the highest proportions of R0 resections with N0 status. Overall, most modalities showed evidence of survival benefit following resection compared to non-operative management, with pooled differences demonstrated for chemotherapy alone (HR 0.33, 95% CI 0.25–0.44) and sequential chemotherapy and radiotherapy (HR 0.49, 95% CI 0.25–0.95). However, no significant differences between these modalities were demonstrated. Other modality-specific conclusions regarding survival benefit could not be elucidated. Conclusions: The rising incidence and global mortality from PDAC underscore the significance of identifying approaches to optimise the management of BRPC and LAPC. This review emphasises the importance of neoadjuvant therapy, both current and novel with surgical resection, which may warrant further investigation in future clinical trials. However, it is important to acknowledge the clinical heterogeneity of current data, which may introduce bias. Nevertheless, these findings can help to inform guidelines on the management of BRPC and LAPC. Full article