Search Results (1,082)

Chemotherapy remains a cornerstone in the treatment of esophageal cancer (EC), yet chemoresistance remains a critical challenge, leading to poor outcomes and limited therapeutic success. Mitochondrial DNA (mtDNA) has emerged as a pivotal player in mediating these responses, influencing cellular metabolism, oxidative stress regulation, and apoptotic pathways. This review provides a comprehensive overview of the mechanisms by which mtDNA alterations, including mutations and copy number variations, drive chemoresistance in EC. Specific focus is given to the role of mtDNA in metabolic reprogramming, including its contribution to the Warburg effect and lipid metabolism, as well as its impact on epithelial–mesenchymal transition (EMT) and mitochondrial bioenergetics. Recent advances in targeting mitochondrial pathways through novel therapeutic agents, such as metformin and mitoquinone, and innovative approaches like CRISPR/Cas9 gene editing, are also discussed. These interventions highlight the potential for overcoming chemoresistance and improving patient outcomes. By integrating mitochondrial diagnostics with personalized treatment strategies, we propose a roadmap for future research that bridges basic mitochondrial biology with translational applications in oncology. The insights offered in this review emphasize the critical need for continued exploration of mtDNA-targeted therapies to address the unmet needs in EC management and other diseases associated with mitochondria. Full article

Cancer is a systemic disease rather than a localized pathology and is characterized by widespread effects, including whole-body exhaustion and chronic inflammation. A thorough understanding of cancer pathophysiology requires a systemic approach that accounts for the complex interactions between cancer cells and host tissues. To explore these dynamics, we employed a comprehensive metabolomic analysis of plasma samples from patients with either esophageal or head and neck squamous cell carcinoma (SCC). Plasma samples from 149 patients were metabolically profiled and correlated with clinical data. Among the metabolites identified, lysophosphatidylcholine (LPC) emerged as the sole biomarker strongly correlated with prognosis. A significant reduction in plasma LPC levels was linked to poorer overall survival. Plasma LPC levels demonstrated minimal correlation with patient-specific factors, such as tumor size and general condition, but showed significant association with the response to immune checkpoint inhibitor therapy. Proteomic and cytokine analyses revealed that low plasma LPC levels reflected systemic chronic inflammation, characterized by high levels of inflammatory proteins, the cytokines interleukin-6 and tumor necrosis factor-α, and coagulation-related proteins. These findings indicate that plasma LPC levels may be used as reliable biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in patients with SCC. Full article

Gastrointestinal (GI) malignancies are diverse and particularly challenging in terms of current immunotherapy but hold great opportunity for impact given that they constitute the highest cancer incidence and mortality rates worldwide. Traditional treatment options for solid GI malignancies include surgical intervention, chemotherapy, radiation, or a combination of these treatments. Emerging modalities within immunotherapy are anticipated to extend the results with conventional therapy by stimulating the patient’s own intrinsic potential for tumor-specific immunologic rejection. Combination regimens of chemotherapy and tumor-infiltrating lymphocyte (TIL) therapy in advanced colorectal cancer and pancreatic cancer, autologous monocyte therapy in advanced gastric cancer, and CAR-T therapy trained against GI-selective tumor antigens such as carcinoembryonic antigen are currently being studied. Clinical trials are underway to study the combination of various chemotherapeutic agents along with immunotherapy in the management of cholangiocarcinoma, hepatocellular carcinoma, and esophageal cancer. Alternative therapies are needed based on the tumor immune microenvironment, which can lead to a personalized approach to treatment. In this review, we discuss the current status of various modalities of immunotherapy in common GI malignancies, along with their mechanisms of immune activation and cancer suppression. We will also discuss the use of immunotherapy in less common solid GI malignancies and touch on recent advancements and clinical trials. Full article

Early prediction of lymph node metastasis (LNM) following neoadjuvant therapy (NAT) is crucial for timely treatment optimization in esophageal squamous cell carcinoma (ESCC). This study developed and validated a computed tomography-based radiomic model for predicting pathologically confirmed LNM status at the time of surgery in ESCC patients after NAT. A total of 469 ESCC patients from Sun Yat-sen University Cancer Center were retrospectively enrolled and randomized into a training cohort (n = 328) and a test cohort (n = 141). Three signatures were constructed: the tumor-habitat-based signature (Habitat_Rad), derived from radiomic features of three tumor subregions identified via K-means clustering; the multiple instance learning-based signature (MIL_Rad), combining features from 2.5D deep learning models; and the clinicoradiological signature (Clinic), developed through multivariate logistic regression. A combined radiomic nomogram integrating these signatures outperformed the individual models, achieving areas under the curve (AUCs) of 0.929 (95% CI, 0.901–0.957) and 0.852 (95% CI, 0.778–0.925) in the training and test cohorts, respectively. The decision curve analysis confirmed a high net clinical benefit, highlighting the nomogram’s potential for accurate LNM prediction after NAT and guiding individualized therapy. Full article

Sub-Saharan Africa is experiencing the highest mortality rates for several cancer types. While cancer research globally has entered the genomic era and advanced the deployment of precision oncology, Africa has largely been excluded and has received few benefits from tumour profiling. Through a thorough literature review, we identified only five whole cancer genome databases that include patients from Sub-Saharan Africa, covering four cancer types (breast, esophageal, prostate, and Burkitt lymphoma). Irrespective of cancer type, these studies report higher tumour genome instability, including African-specific cancer drivers and mutational signatures, suggesting unique contributory mechanisms at play. Reviewing bioinformatic tools applied to African databases, we carefully select a workflow suitable for large-scale African resources, which incorporates cohort-level data and a scalable design for time and computational efficiency. Using African genomic data, we demonstrate the scalability achieved by high-level parallelism through physical data or genomic interval chunking strategies. Furthermore, we provide a rationale for improving current workflows for African data, including the adoption of more genomic techniques and the prioritisation of African-derived datasets for diverse applications. Together, these enhancements and genomic scaling strategies serve as practical computational guidance, lowering technical barriers for future large-scale African-inclusive research and ultimately helping to reduce the disparity gap in cancer mortality rates across Sub-Saharan Africa. Full article

Background: Proximal gastrectomy (PG) with double tract reconstruction (DTR) offers organ preservation for early gastric cancers, leading to reduced vitamin B12 deficiency, less weight loss, and improved quality of life. The JCOG1401 study confirmed excellent long-term outcomes for PG in stage I gastric cancer. However, in locally advanced proximal gastric cancer (LAPGC), preserving the gastric body and lymph node station 4d may compromise margin clearance and adequate lymphadenectomy. Methods: We propose a modified PG that removes the distal esophagus, gastroesophageal junction (GEJ), cardia, fundus, and gastric body, preserving only the antrum and performing DTR. Lymphadenectomy is also adapted, removing stations 1, 2, 3a, 4sa, 4sb, 4d, 7, 8, 9, 10 (spleen preserving), 11, and lower mediastinal nodes (stations 19, 20, and 110), while preserving stations 3b, 5, and 6. Indications for this procedure include GEJ (Siewert type II and III) and proximal gastric cancers with ≤2 cm distal esophageal involvement and ≤5 cm gastric involvement. Results: In our initial experience with 14 patients, we achieved R0 resection in all patients, adequate lymph node harvest (median 24 nodes, IQR 18–38), and no locoregional recurrences at a median follow-up of 18 months. We also found favorable postoperative weight loss, reflux, and anemia in the PG cohort. Conclusion: While larger studies and long-term data are still needed, our early results suggest that modified PG—despite sparing only the antrum—retains the key benefits of PG over total gastrectomy, including better weight maintenance and improved hemoglobin levels, while maintaining oncologic outcomes for LAPGC. Full article

Background and Clinical Significance: Inherited thrombocytopenia (IT) is a heterogeneous group of disorders caused by mutations in over 45 genes. Among these, ANKRD26-related thrombocytopenia (ANKRD26-RT) accounts for a notable subset and is associated with variable bleeding tendencies and an increased risk of myeloid malignancies. However, the extent of this oncogenic risk appears to vary between specific gene variants. Understanding the genotype–phenotype relationship is essential for patient counseling and management. This report presents a multigenerational family carrying the rare c.−118C > G variant in the 5′ untranslated region of ANKRD26, contributing to the discussion on variant-specific cancer predisposition. Case Presentation: Two sisters aged 57 and 60 presented with lifelong bleeding diathesis and moderate thrombocytopenia. Their symptoms included easy bruising, menorrhagia, and excessive postoperative bleeding. Genetic testing confirmed heterozygosity for the ANKRD26 c.−118C > G variant. Bone marrow analysis revealed abnormal megakaryopoiesis without evidence of dysplasia or somatic mutations. One sister underwent major surgery without complications when managed with prophylactic hemostatic therapy. Their family history included multiple female relatives with similar symptoms, although formal testing was limited. Notably, none of the affected individuals developed hematologic malignancy, and only one developed esophageal cancer, with no current evidence linking this variant to solid tumors. Conclusions: This case underscores the importance of distinguishing between ANKRD26 variants when assessing malignancy risk. While ANKRD26-RT is associated with myeloid neoplasms, the c.−118C > G variant may confer a lower oncogenic potential. Variant-specific risk stratification and genetic counseling are crucial for optimizing surveillance and avoiding unnecessary interventions in low-risk individuals. Full article

Background and Objectives: The COVID-19 pandemic disrupted cancer care, prompting adaptations to reduce patient exposure while preserving treatment efficacy. This retrospective observational study compared a weekly cisplatin and 5-fluorouracil (5-FU) regimen to the standard monthly regimen for neoadjuvant chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma. Materials and Methods: This single-center retrospective study included 91 patients, divided into two cohorts: weekly chemotherapy (n = 30) and standard chemotherapy (n = 61). Treatment assignment was based on hospital policy changes during the pandemic, with weekly outpatient chemotherapy implemented after November 2022 to conserve inpatient resources. All patients received radiotherapy at 50 Gy in 25 fractions. The weekly regimen consisted of cisplatin 20 mg/m² and 5-FU 800 mg/m², administered over 1–2 h weekly, while the standard regimen administered the same doses over four consecutive days on weeks 1 and 5. Primary endpoints were pathologic complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: The response rates were similar between groups (weekly: 86.7% vs. standard: 90.2%; p = 0.724). The weekly regimen group showed a higher pCR (40.0% vs. 26.2%; p = 0.181) and significantly lower recurrence (26.7% vs. 52.5%; p = 0.020). Mortality was also reduced in the weekly group (6.7% vs. 34.4%; p = 0.004), though the follow-up duration was shorter (10.6 vs. 22.8 months; p < 0.001). Conclusions: In this retrospective observational study, weekly cisplatin and 5-FU demonstrated comparable efficacy to the standard regimen, with potential advantages in reducing recurrence and mortality. This modified approach may be a viable alternative for maintaining oncologic outcomes while minimizing the burden on healthcare systems during pandemic conditions, although prospective validation is needed. Full article

Objectives: To investigate the real-world outcomes of a population-based gastric cancer (GC) screening program in Kawasaki City, a major urban area with a growing aging population and relatively high screening participation rates. Methods: Between December 2012 and 2021, a total of 337,842 citizens in Kawasaki City underwent population-based GC screening, leading to the detection of 1087 GC cases. Esophageal cancer (EC) has been recorded since 2016, with 236 cases detected. To evaluate the short- and long-term clinical outcomes of screening-detected GC and EC, we conducted a retrospective study using the electronic medical records of patients treated at our hospital, a high-volume institution for GC and EC treatment in the city. As a control group, we included 34 GC and EC cases diagnosed based on symptoms at our hospital in 2018. Results: Among the 1087 GC cases detected through population-based screening, 102 cases treated at our hospital were included in the analysis. Of them, 91 patients (89%) were diagnosed with early-stage GC. All screening-detected GC cases underwent either surgery (27 cases) or endoscopic submucosal dissection (75 cases). The five-year survival rates for GC were 90% in males and 86% in females. Eighteen EC cases were also included in the study. The five-year survival rate for screening-detected advanced GC was 70.0%, while for screening-detected EC, it was 100%. Both survival rates were significantly higher than those for symptom-diagnosed GC (30.0%) and EC (40.8%). Conclusions: The prognosis of GC and EC detected through population-based endoscopic screening is significantly better than that of cancers diagnosed based on symptoms. This underscores the effectiveness of endoscopic screening as a valuable tool for the early detection of upper gastrointestinal tract cancers. Full article

Background/Objectives: Adequate vitamin D levels are essential for various physiological functions, including cell growth, immune modulation, metabolic regulation, DNA repair, and overall health span. Despite its proven cost-effectiveness, widespread deficiency persists due to inadequate supplementation and limited sunlight exposure. Methods: This systematic review (SR) examines the relationship between vitamin D and the reduction of cancer risk and mortality, and the mechanisms involved in cancer prevention. This SR followed the PRISMA and PICOS guidelines and synthesized evidence from relevant studies. Results: Beyond genomic actions via calcitriol [1,25(OH)₂D]-receptor interactions, vitamin D exerts cancer-protective effects through mitigating inflammation, autocrine, paracrine, and membrane signaling. The findings reveal a strong inverse relationship between serum 25(OH)D levels and the incidence, metastasis, and mortality of several cancer types, including colon, gastric, rectal, breast, endometrial, bladder, esophageal, gallbladder, ovarian, pancreatic, renal, vulvar cancers, and both Hodgkin’s and non-Hodgkin’s lymphomas. While 25(OH)D levels of around 20 ng/mL suffice for musculoskeletal health, maintaining levels above 40 ng/mL (100 nmol/L: range, 40–80 ng/mL) significantly lowers cancer risks and mortality. Conclusions: While many observational studies support vitamin D’s protective role in incidents and deaths from cancer, some recent mega-RCTs have failed to demonstrate this. The latter is primarily due to critical study design flaws, like recruiting vitamin D sufficient subjects, inadequate dosing, short durations, and biased designs in nutrient supplementation studies. Consequently, conclusions from these cannot be relied upon. Well-designed, adequately powered clinical trials using appropriate methodologies, sufficient vitamin D₃ doses, and extended durations consistently demonstrate that proper supplementation significantly reduces cancer risk and markedly lowers cancer mortality. Full article

Introduction: Esophagectomy for esophageal cancer traditionally involves delayed postoperative oral feeding due to concerns about complications like anastomotic leakage. Enhanced Recovery After Surgery (ERAS) protocols favor early oral feeding (EOF), but its safety and benefits remain debated. This systematic review and meta-analysis compared EOF versus late oral feeding (LOF) after esophagectomy. Methods: We systematically searched PubMed, Scopus, Web of Science, EMBASE, and the Cochrane Library through March 2025 for primary studies comparing EOF (≤7 days post-op) with LOF (>7 days or delayed) in adult patients after esophagectomy. Outcomes included anastomotic leakage, pneumonia, other complications, gastrointestinal recovery, length of hospital stay (LOS), quality of life (QoL), and mortality. Results: Twenty-nine studies involving 3962 patients were included. There was no significant difference in the risk of anastomotic leakage between the two groups (RR: 1.03, 95% CI: 0.80–1.33, p = 0.82, I² = 0%). EOF was associated with a significantly shorter time to first flatus (Cohen’s d: −1.26, 95% CI: −1.93 to −0.58, p < 0.001) and first defecation (Cohen’s d: −0.87, 95% CI: −1.51 to −0.22, p = 0.01) and a shorter LOS (p = 0.01). No significant differences were found for other complications (acute respiratory distress syndrome [ARDS], chyle leak, conduit issues, ileus, sepsis, wound infection) or mortality rates (in-hospital, 30-day, 90-day, overall). QoL assessment suggested potential improvement in emotional function with EOF. Conclusions: EOF after esophagectomy appears safe, as it does not increase the risk of anastomotic leakage or other major complications compared to LOF. It is associated with faster gastrointestinal recovery and shorter hospital stays, supporting its use within ERAS protocols. Full article

Rare presentations are surprising and may disturb the day-to-day routine of a medical unit; however, they are expected (not as individual entities, but as a group of “uncommon causes”). While reviewing the literature in relation to three clinical cases of upper gastrointestinal bleeding (UGIB) encountered in our institution—gastric metastases of breast cancer (GMB), pyloric gland adenoma, and gastrointestinal stromal tumor (GIST)—we identified seven and 29 case reports for the first two entities, and over 100 publications addressing GIST. This prompted a shift in focus from novel reporting to diagnostic contextualization. We found it difficult to obtain an overview of the spectrum of UGIB etiologies, as most publications refer to a few individual entities or to a subgroup of rare causes. The narrative review we conducted arose from this particular research methodology. Based on a broad literature search, UGIB etiologies were organized in five categories (lesions of the mucosa, neoplasms, vascular causes, bleeding predisposition, and external sources of bleeding). In the management of patients with UGIB, the underlying etiology deviates from the classic peptic ulcer disease/esophageal varices dyad in approximately half of the cases. This underscores the need for heightened clinical vigilance, particularly in complex scenarios, where endoscopic findings, imaging results, and histopathological interpretations may be unexpected or prone to misinterpretation. As an illustration, we conducted two systematic reviews of case reports of bleeding GMB and PGA. Our findings support a proactive diagnostic and research mindset and advocate for improved awareness of uncommon UGIB etiologies. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can help to overcome immunotherapy resistance in ESCC, their severe side effects limit clinical application. This study aimed to explore new resistance mechanisms to immunotherapy in ESCC and identify novel molecular targets to overcome immunotherapy resistance. Methods: We employed immunohistochemistry staining to examine the p-FGFR1^Y654 in tumor samples obtained from 103 patients with ESCC, in addition to evaluating CD8+ T cell infiltration. In vitro expression, western blotting, CCK-8, 5-bromo-2′-deoxyuridine incorporation assays, and migration assays were used to confirm the impact of AZD4547 on p-FGFR1^Y654 expression and the proliferation and migration in ESCC cell lines. Through RNA sequencing analysis, databases such as the Cancer Genome Atlas (TCGA) and Gene Set Cancer Analysis (GSCA), and the reconstruction of transgenic mice using the humanized immune system, we validated the correlation between the expression of p-FGFR1^Y654 and CD8+ T cell infiltration. We also explored how p-FGFR1^Y654 recruits myeloid-derived suppressor cells (MDSCs) through the CXCL8–CXCR2 axis to suppress the therapeutic efficacy of immunotherapy in ESCC. Finally, the tumor-suppressive effects of AZD4547 combined with immunotherapy were confirmed in vivo in tumor-bearing mice with a humanized immune system. Results: We found that the inhibition of p-FGFR1^Y654 expression in ESCC can enhance CD8+ T cell infiltration by suppressing the CXCL8-–XCR2 recruitment of MDSCs. AZD4547, combined with immunotherapy, further promotes immunotherapeutic efficacy in ESCC. Conclusions: In conclusion, our study presents a promising model for combination therapy in ESCC immunotherapy. Full article

Background: The rapid advancement of radiomics and artificial intelligence (AI) technology has provided novel tools for the diagnosis of esophageal cancer. This study innovatively combines muscle imaging features with conventional esophageal imaging features to construct deep learning diagnostic models. Methods: This retrospective study included 1066 patients undergoing radical esophagectomy. Preoperative computed tomography (CT) images covering esophageal, stomach, and muscle (bilateral iliopsoas and erector spinae) regions were segmented automatically with manual adjustments. Diagnostic models were developed using deep learning (2D and 3D neural networks) and traditional machine learning (11 algorithms with PyRadiomics-derived features). Multimodal features underwent Principal Component Analysis (PCA) for dimension reduction and were fused for final analysis. Results: Comparative analysis of 1066 patients’ CT imaging revealed the muscle-based model outperformed the esophageal plus stomach model in predicting N2 staging (0.63 ± 0.11 vs. 0.52 ± 0.11, p = 0.03). Subsequently, multimodal fusion models were established for predicting pathological subtypes, T staging, and N staging. The logistic regression (LR) fusion model showed optimal performance in predicting pathological subtypes, achieving accuracy (ACC) of 0.919 in the training set and 0.884 in the validation set. For predicting T staging, the support vector machine (SVM) model demonstrated the highest accuracy, with training and validation accuracies of 0.909 and 0.907, respectively. The multilayer perceptron (MLP) fusion model achieved the best performance among all models tested for N staging prediction, although the accuracy remained moderate (ACC = 0.704 in the training set and 0.685 in the validation set), indicating potential for further optimization. Fusion models significantly outperformed single-modality models. Conclusions: Based on CT imaging data from 1066 patients, this study systematically constructed predictive models for pathological subtypes, T staging, and N staging of esophageal cancer. Comparative analysis of models using esophageal, esophageal plus stomach, and muscle modalities demonstrated that muscle imaging features contribute to diagnostic accuracy. Multimodal fusion models consistently showed superior performance. Full article

Aberrant activation of Wnt/β-catenin signaling, frequently caused by oncogenic mutations, plays a crucial role in the development, progression, and therapy resistance of gastric, esophageal, hepatic, pancreatic, and colorectal cancers. Concurrently, circular RNAs (circRNAs), produced by back-splicing of precursor mRNAs (pre-mRNAs), have emerged as critical modulators of this pathway. Accumulating evidence indicates that specific circRNAs regulate Wnt/β-catenin signaling by sponging microRNAs, interacting with RNA-binding proteins, modulating protein function, and altering the expression of pathway components. Some circRNAs are also subject to feedback regulation by Wnt signaling itself. Clinically, tumor-associated circRNAs are present in body fluids and correlate with disease stage, metastatic burden, and patient survival, underscoring their potential as early and minimally invasive biomarkers. Moreover, targeting oncogenic circRNAs has shown promise in preclinical models of Wnt-driven gastrointestinal malignancies. In this review, we summarize the current understanding of the interplay between circRNAs and Wnt/β-catenin signaling in gastric and esophageal cancers. We discuss the translational challenges and emerging opportunities for biomarker development and targeted therapy. Full article