Background Whether preoperative anemia is independently associated with short-term postoperative outcomes in colorectal cancer (CRC) remains controversial. This study investigated the association between preoperative anemia and 30-day postoperative complications (PO30C) and evaluated how different anemia diagnostic criteria influence this association. Methods In this retrospective cohort study, patients who underwent radical CRC surgery from January 2018 to January 2021 were consecutively enrolled. Firth’s regression was used for univariate and multivariable analysis to evaluate the impact of preoperative anemia on short-term outcomes after CRC surgery. Dose-response analysis assessed the relationship between anemia severity and PO30C. Sensitivity analysis compared the association under WHO and China’s anemia criteria, and misclassification analysis characterized criteria-related differences. Population-based examination of the misclassification mechanism was performed using China Health and Retirement Longitudinal Study (CHARLS) data. Internal validation used 10-fold cross-validation and bootstrap resampling. Results Among 231 patients, 108 (46.8%) had preoperative anemia and 29 (12.6%) developed PO30C. Multivariable analysis showed that preoperative anemia (OR = 2.39, 95% CI: 1.04–5.81, P = 0.039) and male sex (OR = 3.11, 95% CI: 1.23–9.24, P = 0.015) were independently associated with PO30C. A significant dose-response relationship was observed across anemia severity groups (P-trend = 0.005), with moderate-to-severe anemia independently associated with PO30C (OR = 2.88, 95% CI: 1.04–8.03, P = 0.042). The association was significant under China criteria (P = 0.039) but not under WHO criteria (P = 0.075). Misclassification analysis revealed that WHO criteria reclassified 33 borderline patients as anemic, whose PO30C rate (9.1%) resembled the normal group (6.7%) rather than the anemia group (18.5%), thereby attenuating the association. CHARLS data corroborated this misclassification mechanism. The model showed moderate discrimination (optimism-corrected C-index = 0.704). Conclusion Preoperative anemia was independently associated with PO30C under the China criteria, whereas WHO criteria attenuated this association through misclassification of low-risk borderline patients. Population-appropriate diagnostic criteria are important for perioperative risk estimation and may explain conflicting findings in the existing literature.
Background Bladder cancer (BC) is a common malignancy, and chronic kidney disease (CKD) is an increasingly prevalent comorbidity that may adversely affect oncological outcomes. However, the prognostic impact of CKD in patients with BC remains unclear. We investigated the association between CKD and postoperative outcomes in patients with BC. Methods This study was registered in PROSPERO (CRD420261417895). A systematic search of PubMed, Web of Science, Embase, and Cochrane Library was conducted from database inception up to June 8, 2026. The investigation concentrated on two primary keywords: BC and CKD. Stata SE 18 and R 4.5 were used for data analysis. Results Seven studies involving 2756 patients were included in this meta-analysis. CKD was significantly associated with increased risks of progression (OR = 2.23, 95% CI: 1.34-3.73, P < 0.05), recurrence (OR = 1.82, 95% CI: 1.53-2.18, P < 0.05), and poorer cancer-specific survival (CSS) (OR = 3.39, 95% CI: 1.45-7.94, P < 0.05). Conversely, no significant association was observed between CKD and overall survival (OR = 1.32, 95% CI: 0.65-2.69, P = 0.45). Conclusions CKD correlated with unfavorable postoperative outcomes in patients with BC, particularly progression, recurrence, and CSS. These findings suggest that CKD may represent a clinically relevant prognostic factor that could aid risk stratification and postoperative surveillance. Further prospective studies are warranted to validate these findings.
Gastric cancer continues to be a major contributor to global cancer morbidity and mortality. Although the Correa cascade is widely used as a model for gastric carcinogenesis, the molecular mechanisms driving the transition from chronic atrophic gastritis to invasive cancer have not been comprehensively integrated into a unified molecular framework. This review aims to synthesize current knowledge of the molecular events associated with each stage of the Correa cascade and to evaluate the clinical relevance of established and emerging biomarkers for risk stratification, early diagnosis, and personalized surveillance. This review summarizes the principal molecular mechanisms involved in the progression from chronic gastritis through chronic atrophic gastritis, intestinal metaplasia, dysplasia, and ultimately gastric cancer. These mechanisms include inflammatory cytokine networks, epigenetic modifications, genomic instability, disruption of signaling pathways, clonal evolution, and remodeling of the tumor microenvironment. Particular emphasis is placed on contemporary tissue and circulating biomarkers, their diagnostic and prognostic significance, and the application of advanced technologies including multi-omics analysis, spatial transcriptomics, single-cell sequencing, and liquid biopsy. The available evidence supports a conceptual model of gastric carcinogenesis as a continuous molecular evolutionary process in which chronic inflammation initiates progressive epigenetic and genetic alterations that promote clonal selection and malignant transformation. Integrating molecular biomarkers with conventional morphological assessment may improve risk stratification, facilitate earlier detection of disease progression, and support the implementation of personalized strategies for gastric cancer prevention, surveillance, and treatment.
Background The clinical significance of CXC ligand 12 (CXCL12) expression at the invasive front of pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study examined the expression of stromal CXCL12 using RNAscope for direct visualization of RNA localization and compared expression profiles with clinicopathological findings. Methods This retrospective investigation analyzed CXCL12 expression in 66 PDAC tissue samples, specifically where the cancer had infiltrated the peripancreatic fatty tissue, using RNAscope. RNA expression was quantified and categorized into high and low groups for evaluating associations with clinicopathological data. Single-cell RNA sequencing (scRNA-seq) was employed to elucidate cellular expression patterns of CXCL12 and its receptor, C-X-C motif chemokine receptor 4 (CXCR4) . Results CXCL12-positive staining was found in 88% of samples, with expression predominantly in the stroma rather than in tumor cells. Venous invasion was significantly less in the high CXCL12 expression group (P = 0.019). We observed no significant difference in overall survival between the high and low CXCL12 expression groups (P = 0.233), although relapse-free survival showed a trend toward being longer in the high CXCL12 expression group (P = 0.0673). scRNA-seq revealed that CXCL12 was predominantly produced by fibroblasts and endothelial cells, while its CXCR4 receptor was expressed mainly on T cells, B cells, and myeloid cells. Conclusion RNAscope findings revealed that stromal CXCL12 expression was associated with reduced PDAC progression and may represent a marker of favorable prognosis. Further studies are needed to confirm its role and prognostic value.
Background The 9th edition of the AJCC/UICC TNM staging system (TNM-9) has introduced key updates for nasopharyngeal carcinoma (NPC) compared with TNM-8. However, there is limited data on the metabolic basis and performance of TNM-9 evaluated using 18 F-FDG PET/CT. We aimed to investigate the association between PET/CT metabolic parameters and TNM-8 and TNM-9 staging systems, and evaluate the metabolic homogeneity across TNM-9 substages. Methods This single-center, retrospective cross-sectional study enrolled 822 NPC patients who underwent pre-treatment 18 F-FDG PET/CT. Uptake, volumetric, glucose-normalized, and body composition-normalized metabolic parameters of the primary tumor (T) and the most metabolically active lymph node (LN) were compared across the TNM-8 and TNM-9 staging systems, and comparisons were also performed between the substages in the TNM-9 system. Multicollinearity diagnosis using the Variance Inflation Factor (VIF) and ordinal logistic regression were performed to identify independent stage-related parameters. Results Baseline age, fasting blood glucose and 18 F-FDG dose were comparable across stages (all P>0.05), while weight differed significantly in both staging systems (both P<0.001). All metabolic parameters differed significantly among stages in both systems (all P<0.001). TNM-9 showed more coherent metabolic distributions compared with TNM-8, whereas TNM-8 exhibited distinct metabolic overlap between certain stages. Metabolic homogeneity was observed in volumetric parameters between TNM-9 stage Ia and Ib, and in all parameters between stage IVa and IVb. T/LN metabolic tumor volume (TMTV/LNMTV) and T/LN lean body mass-normalized maximum standardized uptake value (TSULmax/LNSULmax) were independent predictors in both systems, with a slightly higher McFadden R 2 for TNM-9 (0.16 vs. 0.13). Conclusions PET/CT metabolic parameters provide supportive evidence for the biological basis and clinical utility of TNM-9 in NPC. TNM-9 demonstrated superior metabolic homogeneity and slightly better model fit compared with TNM-8. TMTV, TSULmax, LNMTV, and LNSULmax can serve as promising complementary biomarkers for NPC staging.
Background The 9th edition of the AJCC/UICC TNM staging system (TNM-9) has introduced key updates for nasopharyngeal carcinoma (NPC) compared with TNM-8. However, there is limited data on the metabolic basis and performance of TNM-9 evaluated using 18 F-FDG PET/CT. We aimed to investigate the association between PET/CT metabolic parameters and TNM-8 and TNM-9 staging systems, and evaluate the metabolic homogeneity across TNM-9 substages. Methods This single-center, retrospective cross-sectional study enrolled 822 NPC patients who underwent pre-treatment 18 F-FDG PET/CT. Uptake, volumetric, glucose-normalized, and body composition-normalized metabolic parameters of the primary tumor (T) and the most metabolically active lymph node (LN) were compared across the TNM-8 and TNM-9 staging systems, and comparisons were also performed between the substages in the TNM-9 system. Multicollinearity diagnosis using the Variance Inflation Factor (VIF) and ordinal logistic regression were performed to identify independent stage-related parameters. Results Baseline age, fasting blood glucose and 18 F-FDG dose were comparable across stages (all P>0.05), while weight differed significantly in both staging systems (both P<0.001). All metabolic parameters differed significantly among stages in both systems (all P<0.001). TNM-9 showed more coherent metabolic distributions compared with TNM-8, whereas TNM-8 exhibited distinct metabolic overlap between certain stages. Metabolic homogeneity was observed in volumetric parameters between TNM-9 stage Ia and Ib, and in all parameters between stage IVa and IVb. T/LN metabolic tumor volume (TMTV/LNMTV) and T/LN lean body mass-normalized maximum standardized uptake value (TSULmax/LNSULmax) were independent predictors in both systems, with a slightly higher McFadden R 2 for TNM-9 (0.16 vs. 0.13). Conclusions PET/CT metabolic parameters provide supportive evidence for the biological basis and clinical utility of TNM-9 in NPC. TNM-9 demonstrated superior metabolic homogeneity and slightly better model fit compared with TNM-8. TMTV, TSULmax, LNMTV, and LNSULmax can serve as promising complementary biomarkers for NPC staging.
Background Local excision (LE) has emerged as an organ-preserving option for patients with early rectal cancer, but high-risk pathological features significantly increase the risk of local recurrence. When completion total mesorectal excision (TME) is refused or medically unfeasible, combining radiotherapy, chemotherapy, and immunotherapy offers an adjuvant organ-preservation strategy in microsatellite-stable (MSS) rectal cancer. Objectives The TORCH-LE trial aims to evaluate the efficacy and safety of combining radiotherapy, chemotherapy, and immunotherapy as an adjuvant organ-preservation strategy for patients with high-risk pathological features after local excision (LE) who refuse or are unfit for completion TME. Design This is a prospective, multi-center, single-arm, hypothesis-generating phase II trial. Methods and Analysis A total of 60 patients with MSS early rectal cancer who have high-risk features following LE will be enrolled. All participants will receive short-course radiotherapy (SCRT; 25 Gy in 5 fractions), followed by four cycles of capecitabine and oxaliplatin (CapeOx) plus the PD-1 inhibitor toripalimab. The primary endpoint is the 3-year local recurrence-free survival (LRFS) rate, with an expected benchmark of 95% (target two-sided 95% CI: 85.6%–98.9%). Secondary endpoints include 3-year disease-free survival (DFS) rate, overall survival (OS) rate, treatment-related adverse events, and quality of life. Follow-up will include regular imaging and endoscopic surveillance. Discussion The TORCH-LE trial explores a novel adjuvant treatment strategy for early rectal cancer patients with high-risk features who are not eligible for or decline completion TME. By combining SCRT, chemotherapy, and immunotherapy, the study seeks to reduce recurrence risk while preserving rectal function. Given the single-arm design, findings should be considered exploratory and hypothesis-generating. The findings may support a more personalized organ-preserving approach and provide a rationale for future randomized trials.
Background Breast cancer is the leading cause of cancer-related mortality among women. Laminin subunit alpha 3 (LAMA3), a constituent of the extracellular matrix, is associated with tumor progression. However, its clinical relevance and function remain inadequately understood. Methods We conducted a systematic evaluation of LAMA3 expression in breast cancer by assessing plasma, cell lines, and tissues using mass spectrometry, qRT-PCR, Western blotting, and immunohistochemistry (IHC). The colocalization of LAMA3 with tumor and stromal markers was detected by immunofluorescence. Tumor and stromal regions were digitally segmented using QuPath software to compute compartment-specific histochemical scores. The correlation of LAMA3 with clinical characteristics was evaluated using Chi-square and nonparametric statistical tests. The impact of LAMA3 expression on survival was analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. Bioinformatics analyses were performed to investigate potential underlying mechanisms. Results Plasma LAMA3 protein levels were elevated in patients, but its mRNA and protein levels were reduced in breast cancer cell lines and tissues. Analysis on TIMER 2.0 database showed LAMA3 was positively related to cancer-associated fibroblasts and epithelial cells infiltration in breast cancer tissues. Multiplex immunofluorescence revealed LAMA3 colocalized with cancer-associated fibroblasts and tumor epithelial cells. Although LAMA3 protein levels were reduced in breast cancer tissues, high stromal—but not tumor—LAMA3 expression was significantly associated with advanced histological grade, TNM stage, molecular subtype, recurrence, and poorer survival outcomes. Multivariate analysis indicated stromal LAMA3 as an independent prognostic factor for survival in breast cancer, with enhanced predictive power when combined with lymph node metastasis. Bioinformatic analyses suggested that LAMA3 protein was correlated with epithelial-mesenchymal transition and extracellular matrix-receptor interaction pathways in breast cancer. Conclusions Stromal LAMA3, expressed in the tumor microenvironment, is a new potential prognostic biomarker for breast cancer, emphasizing the significance of spatial context in biomarker discovery and suggesting its use in risk stratification.
Background Malignant pleural mesothelioma (MPM) originates from pleural mesothelial cells and represents a highly aggressive malignancy. Characterized by a prolonged latency period, poor survival prognosis, and non-specific clinical manifestations, MPM poses significant diagnostic and therapeutic challenges. BRCA-1-associated protein 1 (BAP1) is a nuclear deubiquitinating enzyme involved in chromatin regulation, homologous recombination, and programmed cell death. Although multiple studies have suggested that BAP1 loss or mutation holds prognostic significance in malignant pleural mesothelioma, this remains a matter of debate. Methods A meta-analysis was conducted using data from the Web of Science, PubMed, Embase, Cochrane, and CNKI up to October 21, 2025. We included studies involving patients with malignant pleural mesothelioma that assessed the prognostic significance of BAP1. These studies reported hazard ratios (HR) and 95% confidence intervals (CI) for median overall survival (mOS) and median progression-free survival (mPFS). Results A total of 14 articles meeting the inclusion criteria were identified, encompassing 1,835 patients. We conducted both univariate and multivariate analyses of mOS, revealing that BAP1 deletion or mutation consistently correlated with improved prognosis, with hazard ratios of 0.51 (95% CI, 0.45–0.58, P < 0.0001) and 0.62 (95% CI, 0.54–0.71, P < 0.0001), respectively. The values were statistically significant (P < 0.0001). Furthermore, analyses of mPFS continued to demonstrate that BAP1 deletion or mutation consistently correlated with improved prognosis (U: HR = 0.62, 95% CI = 0.39–0.99, P = 0.04; M: HR = 0.79, 95% CI = 0.51–1.24, P = 0.31), though this did not reach statistical significance. Sensitivity analyses confirmed the robustness of these findings, with minimal heterogeneity between studies. Conclusion BAP1 serves as a potential prognostic marker for MPM, with its deletion or mutation indicating a favourable prognosis for patients. However, whether it provides valuable insights for various treatment strategies, including immunotherapy, requires further clinical investigation to determine.
Background Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, with incidence rates in Lebanon among the highest in the Middle East and North Africa (MENA) region. Despite this, data on CRC epidemiology, tumor characteristics, and treatment outcomes in MENA populations remain limited. This study aimed to investigate these factors, with the goal of supporting early detection, guiding clinical decision-making, and informing personalized treatment strategies. Methods This retrospective cross-sectional study included patients diagnosed with CRC between 2019 and 2023 at the American University of Beirut Medical Center. Clinical data were retrieved from electronic health records and histopathological reports. Overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) were assessed using Kaplan-Meier survival analysis and multivariable Cox regression models. Results A total of 349 patients (mean age 61 years) were included. Most tumors were low-grade adenocarcinomas (88.1%; n=306/347), and 73.3% (n=243/331) of patients presented with advanced-stage disease (Stages III/IV). Among patients with available MMR testing (n=181/349), 5.5% (n=10/181) were mismatch repair-deficient (dMMR) by immunohistochemistry. Molecular testing revealed KRAS mutations in 42.9% (n=70/163 tested) and BRAF mutations in 7.0% (n=9/128 tested). Smoking (HR = 2.58, p = 0.007) and age ≥65 years (HR = 1.98, p = 0.050) were associated with reduced OS. Patients with inflammatory bowel disease had a significantly increased risk of progression (HR = 9.39, p = 0.032). Left-sided tumors were associated with improved OS (HR = 0.42, p = 0.018). Conclusions This study identifies key risk factors, including tumor location, age, IBD, and smoking, influencing survival outcomes in Lebanese patients with CRC. Findings support implementation of risk-adapted screening strategies and population-specific therapeutic approaches in Middle Eastern settings.
Background Glioblastoma (GB), or grade IV astrocytoma, is the most prevalent primary tumor of the central nervous system (CNS). This systematic review aimed to investigate the efficacy and tolerability of virotherapy treatment for recurrent and progressive glioblastoma patients. We also examined recent progress in preclinical and clinical trials, and future perspectives. Methods We developed a search strategy using Medical Subject Headings (MeSH) terms and keywords. Inclusion criteria were English language published and ongoing clinical trials that involved patients undergoing virotherapy for glioblastoma. We searched through PubMed, Embase, Ovid, Scopus, Cochrane databases and https://Clinicaltrials.gov from inception until May 9 th , 2025. Two independent reviewers screened records, extracted data, and assessed risk of bias (ROB2). No meta-analysis was performed due to heterogeneity. PROSPERO CRD420250636791. Results Of 975 records screened, 43 studies (24 published, 19 ongoing) enrolled 462 virotherapy patients. Most common adverse events: headache (n=145), fatigue (n=83) and fever (n=78). Risk of bias was moderate to serious in most studies. Conclusion We encountered several limitations, including high heterogeneity, reporting inconsistencies, and small sample sizes. Most patients experienced disease stabilization. However, objective response and complete remission occurred infrequently. A small proportion of patients achieved long-term survival, suggesting that virotherapy could be effective in specific subgroups. While oncolytic virus therapy is generally tolerated, neurotoxicity remains the most significant risk. Adverse effects were mostly Grade 1–2. Some trials (notably with HSV-1 or NDV) had severe events. Symptoms were often transient and manageable but need closely monitoring. However, the observed heterogeneity, limited data standardisation, and lack of randomized controlled trials, besides tumor heterogeneity, antiviral immunity and immunosuppressive microenvironment, necessitate further research to identify predictive biomarkers and optimize therapeutic protocols. We also suggest further trials on novel delivery methods, such as the nanoparticles, to enhance blood-brain barrier (BBB) penetration.
Background:Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases. Circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers for cancer detection. In this exploratory study, we investigated the diagnostic and prognostic value of four circulating miRNAs (miR-107, miR-199-3p, miR-485-5p, and miR-574-5p) in NSCLC, three of which have not previously been examined in this context. Methods:Serum samples from 58 NSCLC patients and 20 healthy controls were analyzed. Relative expression levels of the target miRNAs were quantified by quantitative RT-PCR. Differences between groups were evaluated with the Mann-Whitney U test, and the diagnostic performance of each miRNA was assessed by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate regression analyses were performed to identify factors associated with survival. Results:Three of the four miRNAs showed significantly different expression between NSCLC patients and healthy controls: miR-107, miR-199, and miR-485 were all expressed at significantly lower levels in patients (p < 0.001, p < 0.001, and p = 0.002, respectively), whereas miR-574 levels did not differ between groups (p = 0.370). ROC analysis confirmed significant discriminatory power for all four miRNAs (p < 0.001), with miR-107 yielding the highest area under the curve (AUC = 0.952). In multivariate analysis, ECOG performance status and miR-199 emerged as covariates significantly associated with survival. Conclusion:These exploratory findings indicate that circulating miR-107, miR-199, and miR-485 have strong discriminative potential in NSCLC. Larger validation studies are needed to confirm their utility as non-invasive biomarkers.
Background Diabetes mellitus (DM) is a common comorbidity in patients undergoing neurosurgical procedures and has been associated with adverse surgical outcomes. However, the extent to which DM, particularly the presence of chronic diabetic complications, affects perioperative outcomes and healthcare utilization in patients undergoing craniotomy for brain tumors remains unclear. Clarifying this relationship is essential for perioperative risk stratification and optimization. Methods We conducted a retrospective cohort study using the National Inpatient Sample (NIS) database, identifying adults (≥18 years) who underwent craniotomy for brain tumors between 2016 and 2022. Patients were stratified into three groups: non-DM, DM without chronic complications, and DM with chronic complications. Outcomes included in-hospital mortality, postoperative complications, length of stay (LOS), discharge disposition, and hospitalization costs. Results A total of 49,100 patients were included, of whom 8,822 (18.1%) had DM. Overall, DM patients experienced higher rates of postoperative complications, longer LOS, increased non-routine discharge, and greater hospitalization costs compared with non-DM patients. Notably, patients with DM without chronic complications had outcomes comparable to those of non-DM patients. In contrast, DM patients with chronic complications demonstrated significantly higher risks of adverse outcomes across all measured endpoints. Conclusions DM alone does not significantly worsen outcomes after craniotomy for brain tumors. However, the presence of chronic diabetic complications is strongly associated with increased perioperative morbidity, mortality, prolonged hospitalization, and higher healthcare costs. These findings underscore the importance of incorporating diabetic complication status into preoperative evaluation and targeted perioperative management strategies.
Background Augmented reality navigation (ARN) has been increasingly applied in laparoscopic liver surgery to improve anatomical orientation and surgical precision. However, its clinical value compared with conventional anatomical liver resection (ALR) and non-anatomical liver resection (NALR) remains unclear. Method This retrospective single-center study included 96 patients with hepatocellular carcinoma who underwent laparoscopic hepatectomy from January 2019 to December 2021. Patients were divided into three groups: ARN-assisted laparoscopic nonanatomic hepatectomy (Group A, n=28), laparoscopic anatomical hepatectomy without navigation (Group B, n=35), and laparoscopic nonanatomic hepatectomy without navigation (Group C, n=33). Baseline demographic, clinical, tumor, and segmental distributions were comparable among groups. Postoperative outcomes, postoperative complications, and 36-month follow-up data were analyzed. Result Preoperative characteristics did not significantly differ among the three groups. Operative time was significantly shorter in Group A than in Group B ( p =0.003) and Group C ( p =0.039). Median intraoperative blood loss in Group A was 125ml, which was 175ml less than in Group B ( p =0.048) and 75 ml less than in Group C ( p =0.049). On postoperative day 7, median α-fetoprotein was lower ( p= 0.049) in group A (4.26 iu/ml) than in group C (5.82 iu/ml). 3-Year overall survival did not significantly differ among three groups. 3-Year tumor-free survival rates were 60.7% in group A, 62.9% in group B, and 36.3% in group C, with Group A and B showing significantly better tumor-free survival than group C ( p ( A v s . C ) = 0.041; p ( B v s . C ) = 0.024). Postoperative complication rates were similar across groups. Conclusion In this cohort, ARN-assisted laparoscopic nonanatomic hepatectomy was associated with reduced operative time and blood loss and demonstrated short-term oncological outcomes similar to anatomical hepatectomy. These findings suggest that ARN may enhance the effectiveness of non-anatomical hepatectomy; however, confirmation in larger prospective studies is required.
Background The incidence of papillary thyroid cancer (PTC) has risen sharply over the past several decades. Early identification of high-risk PTC is crucial to mitigate the societal burden associated with its overdiagnosis. ER-phagy, a selective form of autophagy targeting the endoplasmic reticulum, is categorized into macro-ER-phagy and micro-ER-phagy. To date, the role of ER-phagy receptors and their impact on risk stratification and progression in thyroid cancer remain unclear. Methods This study employed an integrative approach combining bioinformatics analysis with wet-lab molecular biology experiments. Transcriptomic and clinical data from TCGA were processed using Xiantaoxueshu, GSCA, TIMER, and TISIDB platforms to assess differential expression, survival, ROC characteristics, and KEGG/GO enrichment, as well as immune infiltration. In vitro, shRNAs targeting RTN3, SEC62, or ATL3 were transfected into TPC-1 and CAL-62 cells to silence gene expression, validated by RT-qPCR and Western Blot. Cell proliferation, migration, and invasion were assessed by CCK-8, EdU, colony formation, wound healing, and Transwell assays. All experiments were performed in at least three independent replicates, and the resulting data were subjected to statistical analysis. Data were analyzed using SPSS 18.0 and GraphPad Prism 9.3.0. Quantitative results are presented as mean ± SEM. Independent-samples t-tests, univariate/multivariate Cox regression and LASSO Cox regression were used; P < 0.05 was considered significant. Results Comprehensive analysis of all ER-phagy receptors using public databases revealed that several receptors significantly impact the diagnosis and prognosis of thyroid cancer. We also characterized the mutation and methylation pattern of these receptors. Furthermore, these genes were also closely associated with immune infiltration in thyroid cancer. Of note, RTN3, SEC62 and ATL3 appeared to have distinct importance in thyroid cancer. All three genes were downregulated and their reduced expression was significantly related to poor survival in thyroid cancer. Receiver Operating Characteristic (ROC) curve analysis demonstrated that these markers hold substantial promise for thyroid cancer diagnosis, particularly RTN3 and SEC62. Immune-related analysis indicated a strong correlation with immune infiltration, implying a potential role in modulating the immune landscape of thyroid cancer. Functional assays demonstrated that knockdown of RTN3, SEC62, and ATL3 promoted proliferation and metastasis of thyroid cancer cells in vitro. Western blot analysis indicated that this process is likely mediated by the Epithelial-Mesenchymal Transition (EMT). Conclusion In summary, our findings indicate that ER-phagy represents a promising avenue for thyroid cancer diagnosis. Specifically, RTN3, SEC62, and ATL3 were found to suppress the proliferation and metastasis of thyroid cancer cells, underscoring their pivotal roles in disease progression.
Background MRI-detected circumferential resection margin (CRM) involvement, extramural venous invasion (EMVI), and tumor deposits (TDs) are established high-risk features associated with poor prognosis in rectal cancer. These features may help identify patients who are more likely to benefit from neoadjuvant therapy (NAT). However, the prognostic significance of changes in these MRI high-risk features after NAT remains unclear. The objective of this study was to determine whether baseline MRI high-risk features can identify patients likely to benefit from NAT and whether their changes after NAT predict treatment response and prognosis in rectal cancer. Methods This retrospective single-center cohort study included patients who underwent curative resection for rectal adenocarcinoma and received neoadjuvant therapy (NAT) at Sun Yat-sen University, Sixth Affiliated Hospital, between 2017 and 2019. Patients with MRI-detected CRM involvement, EMVI, or TDs were classified as MRI high-risk. Those who showed a shift from MRI high-risk to MRI low-risk—defined by the absence of CRM involvement, EMVI, or TDs—on post-treatment scans were considered good responders. The survival outcomes of good responders were then compared to those of poor responders, who remained persistently MRI high-risk. Additional analyses were performed within the baseline MRI high-risk subgroup to determine which MRI high-risk features were most strongly associated with prognosis. Results The study included 302 patients in total. Of these, 146 (48.3%) were classified as MRI high-risk and 156 (51.7%) as MRI low-risk based on pre-treatment imaging. The high-risk group had significantly worse outcomes: three-year disease-free survival (DFS) was 54.8% compared with 93.6% in the low-risk group (p < 0.001), three-year overall survival (OS) was 76% versus 98.1% (p < 0.001), and the rate of local recurrence (LR) at three years was 10.9% compared to 1.3% (p = 0.002). Among the 146 patients initially identified as MRI high-risk, those who converted to low-risk status after treatment showed improved outcomes, with a three-year DFS of 82.9%, OS of 94.3%, and LR rate of 2.9%. Within the baseline MRI high-risk subgroup, baseline mrEMVI and mrTD, as well as post-treatment ymrMRF, ymrEMVI, and ymrTD, were associated with worse DFS. Conclusions Baseline MRI high-risk features and their persistence after NAT were associated with poor prognosis in rectal cancer. MRI risk conversion after NAT may help identify a subgroup of initially high-risk patients with more favorable outcomes.
Background: Dacomitinib has demonstrated superior efficacy compared with first-generation tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) exon 21-mutated non-small-cell lung cancer (NSCLC). However, the standard 45 mg dose often leads to a high incidence of grade 3 and 4 toxicities, limiting its clinical application. This study aimed to evaluate the preliminary efficacy and safety of a proactive low-dose dacomitinib strategy as first-line treatment. Methods: This retrospective cohort study analyzed data from 31 patients with EGFR exon 21-mutated advanced NSCLC consecutively enrolled between August 2019 and April 2023, who initiated dacomitinib at 15 or 30 mg/d. A comparative cohort of 35 patients receiving first-generation EGFR-TKIs was also included. Initial dose selection was based on clinical judgment regarding patient age, comorbidities, and performance status. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline. Results: The objective response rate (ORR) in the low-dose dacomitinib group was 67.7%, higher than that observed in the first-generation EGFR-TKI group ( P = .009). Subgroup analysis showed ORRs of 75% and 60% in the 15 mg and 30 mg cohorts, respectively ( P = .389). The median progression-free survival (PFS) in the low-dose dacomitinib group was 14.2 months (95% confidence interval [CI] = 12.4-15.9 months). Compared with first-generation EGFR-TKIs, low-dose dacomitinib was associated with significantly prolonged PFS (HR = 0.43, 95% CI = 0.25-0.72; P = .001). No significant difference in PFS was observed between the 15 mg and 30 mg groups (HR = 0.81, 95% CI = 0.37-1.76; P = .594). While grade 1 and 2 toxicities were common, the 15 mg group exhibited a significantly lower incidence of grade 3 and 4 rash compared with the 30 mg group (0% vs 33.3%). Conclusions: Initial low-dose dacomitinib demonstrated promising efficacy with an improved safety profile in patients with EGFR exon 21-mutated NSCLC. These findings support the feasibility of a dose-optimization strategy, although further prospective studies are warranted.
Background: Osteosarcoma (OS) is a malignant tumor originating in the bones, predominantly affecting children and adolescents, characterized by high aggressiveness and poor prognosis. Identifying new prognostic biomarkers is crucial for improving the diagnosis and treatment of OS. Methods: In this study, we collected gene expression data from 88 OS samples from the UCSC Xena platform and normal tissue expression data from 396 Genotype-Tissue Expression (GTEx) samples. Prognosis-related genes were first screened by univariate Cox regression and then further selected using the Least Absolute Shrinkage and Selection Operator (LASSO) regression. Based on these candidate genes, non-negative matrix factorization (NMF) was used for molecular subtype identification, and the Kaplan-Meier analysis was applied to compare survival among subtypes. Tumor microenvironment and immune cell infiltration analyses were performed to characterize differences between risk groups. In addition, the expression patterns of key genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR), hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence. Results: Pyrroline-5-carboxylate reductase 1 (PYCR1) was consistently upregulated in OS and was associated with poor prognosis. In contrast, glycogen phosphorylase, muscle-associated (PYGM) showed analysis-level-dependent expression patterns: it was downregulated at the bulk transcriptomic and tumor cell levels compared with normal controls, whereas within the OS cohort, relatively higher PYGM expression was observed in the high-risk group. Tumor microenvironment and immune cell infiltration analyses revealed significant immune differences between high- and low-risk groups. Histological and protein-level assays further confirmed the presence and cellular localization of PYCR1 and PYGM in OS tissues. Conclusion: This study systematically identified and validated PYCR1 and PYGM as potential prognostic biomarkers for OS using integrated statistical and machine learning approaches. The PYCR1 showed a consistently tumor-promoting expression pattern, whereas PYGM demonstrated context-dependent expression changes across bulk tissue, risk-stratified tumor samples, and tumor cell lines, highlighting the biological complexity of metabolic biomarkers in OS.
Background: Gastric cancer remains one of the most common malignancies and a leading cause of cancer-related mortality worldwide. Human epidermal growth factor receptor 2 (HER2) status is a key biomarker influencing both prognosis and treatment selection. While HER2-positive patients benefit from trastuzumab, outcomes for HER2-low and HER2-zero groups remain less clearly defined. Methods: In this retrospective cohort study, we reviewed 507 patients diagnosed with metastatic gastric adenocarcinoma between 2015 and 2023. Patients were classified as HER2-zero (n = 134), HER2-low (n = 303), or HER2-positive (n = 70) based on immunohistochemistry and in situ hybridization results. Clinicopathologic features, treatment strategies, and survival outcomes were analyzed. Kaplan-Meier methods estimated progression-free survival (PFS) and overall survival (OS), whereas Cox regression identified independent prognostic factors. Results: The HER2-positive group achieved a median PFS of 9.0 months and OS of 20.0 months, superior to HER2-zero patients (PFS: 6.1; OS: 14.5; P < .001). HER2-low patients demonstrated intermediate outcomes (PFS: 6.7; OS: 16.6 months). Group distribution was HER2-zero 26.4%, HER2-low 59.8%, and HER2-positive 13.8%. All HER2-positive patients received trastuzumab-based therapy. Multivariate analysis confirmed HER2-positive status as an independent predictive factor for both progression (hazard ratio [HR] = 0.65) and mortality (HR = 0.62). Conclusions: HER2 status is a strong predictive determinant in metastatic gastric cancer. Trastuzumab provided significant real-world benefit for HER2-positive patients, validating the impact of targeted therapy. Notably, HER2-low patients had better outcomes than HER2-zero, supporting the recognition of HER2-low as a distinct subgroup with potential eligibility for future HER2-directed treatments.
