Search Results (564)

Lymph node evaluation is a central determinant of oncologic quality in the surgical management of non-small-cell lung cancer (NSCLC). Accurate assessment of hilar and mediastinal lymph nodes underpins pathologic staging, informs postoperative treatment decisions, and remains essential for prognostic stratification and assessment of resection completeness. Although international guidelines provide clear recommendations, real-world data consistently demonstrate substantial variability in lymph node staging practices, with inadequate evaluation frequently observed across institutions and surgical settings. Insufficient nodal assessment, manifested as the omission of mediastinal staging, limited station sampling, or low lymph node yield, is associated with reduced nodal upstaging, inappropriate omission of adjuvant therapy, higher recurrence rates, and inferior long-term survival. Contemporary guidance from major societies, including the National Comprehensive Cancer Network, European Society of Thoracic Surgeons, International Association for the Study of Lung Cancer, and the Commission on Cancer, has increasingly converged on a station-based definition of adequacy, emphasizing systematic evaluation of both N1 and N2 nodal stations rather than reliance on absolute node counts alone. In parallel, preoperative mediastinal staging algorithms have evolved toward routine use of endobronchial and esophageal ultrasound as first-line invasive modalities, reserving surgical mediastinoscopy for selected high-risk or inconclusive cases. Evidence from randomized trials, population-level databases, and meta-analyses indicates that thorough nodal assessment improves staging accuracy and survival, while recent data support the selective use of lobe-specific or tailored lymphadenectomy in carefully staged, low-risk early disease. Finally, emerging quality improvement interventions, including standardized specimen handling, operative checklists, and multidisciplinary feedback mechanisms, have demonstrated measurable improvements in guideline adherence and patient outcomes. This narrative review integrates contemporary evidence and guideline recommendations to outline a practical framework for implementing reliable, high-quality lymph node staging in modern lung cancer surgery. Full article

Management of resectable esophageal cancer has evolved into a multidisciplinary paradigm centered on multimodality therapy. Historically, induction chemoradiotherapy followed by surgery, as established by the CROSS trial, became the standard of care for locally advanced disease due to improvements in R0 resection rates and overall survival. More recently, the ESOPEC trial reexamined this paradigm in esophageal adenocarcinoma, demonstrating superior survival and improved systemic disease control with perioperative chemotherapy using the FLOT regimen compared with chemoradiotherapy. In parallel, the MATTERHORN trial further advanced perioperative treatment by showing improved event-free survival with the addition of the immune checkpoint inhibitor durvalumab to FLOT chemotherapy. Alongside these systemic therapy advances, surgical management has transitioned toward minimally invasive and robotic-assisted esophagectomy, offering equivalent oncologic outcomes with reduced perioperative morbidity. This review summarizes the evolving evidence from pivotal clinical trials, highlights ongoing studies integrating immunotherapy, and discusses emerging strategies such as adoptive cell transfer which currently is under investigation for metastatic recurrence, but in the future may provide additional treatment options for resectable esophageal cancer. Full article

Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), remains a highly lethal disease because of its late diagnosis, significant biological heterogeneity, and frequent resistance to therapy. Growing evidence indicates that microRNAs (miRNAs) are key posttranscriptional regulators involved in tumor initiation, progression, metastasis, and response to treatment. This review provides a comprehensive and updated overview of miRNA dysregulation in both ESCC and EAC, with a specific focus on its emerging clinical relevance in early detection, prognostic assessment, and prediction of therapeutic response. Multiple tissue-based and circulating miRNA signatures, some capable of distinguishing between Barrett’s esophagus (BE), dysplasia, and EAC, demonstrate promising diagnostic performance. In parallel, several miRNAs, including miR-21, miR-23a, miR-455-3p, and miR-196b, have been consistently associated with chemoresistance and radioresistance. Moreover, distinct miRNA expression patterns are correlated with tumor aggressiveness, metastatic potential, and the risk of recurrence, supporting their integration with conventional histopathological and molecular parameters for improved patient stratification. Overall, miRNAs represent a powerful class of biomarkers and potential therapeutic targets in EC, with increasing translational relevance in precision oncology. Full article

The gut microbiome has emerged as a key regulator of human health, influencing not only metabolism and immunity but also the development and treatment of cancer. Mounting evidence suggests that microbial dysbiosis contributes to oncogenesis by driving chronic inflammation, producing genotoxic metabolites, altering bile acid metabolism, and disrupting epithelial barrier integrity. At the same time, the gut microbiome significantly modulates the host response to oncotherapies including chemotherapy, radiotherapy, and especially immunotherapy, where microbial diversity and specific taxa determine treatment efficacy and toxicity. This review synthesizes current evidence on the role of the gut microbiome in both oncogenesis and oncotherapies, focusing on thirteen cancers with the strongest and most clinically relevant microbiome associations, colorectal cancer, gastric cancer, hepatocellular carcinoma, gallbladder cancer, esophageal cancer, pancreatic cancer, oral squamous cell carcinoma, cervical cancer, prostate cancer, breast cancer, lung cancer, brain cancer, and melanoma. These cancers were selected based on robust mechanistic data linking microbial alterations to tumor initiation, progression, and therapy modulation, as well as their global health burden and translational potential. In addition, we have provided mechanistic insights or clinical correlations between the microbiome and cancer outcomes. Across cancers, common microbial mechanisms included pro-inflammatory signaling (e.g., NF-κB and STAT3 pathways), DNA damage from bacterial toxins (e.g., colibactin, nitrosating species), and metabolite-driven tumor promotion (e.g., secondary bile acids, trimethylamine N-oxide). Conversely, beneficial commensals such as Faecalibacterium prausnitzii and Akkermansia muciniphila supported antitumor immunity and improved responses to immune checkpoint inhibitors. In conclusion, the gut microbiome functions as both a driver of malignancy and a modifiable determinant of therapeutic success. Integrating microbiome profiling and modulation strategies such as dietary interventions, probiotics, and fecal microbiota transplantation into oncology practice may pave the way for personalized and more effective cancer care. Full article

Neurotrophic tyrosine receptor kinase (NTRK) fusions function as oncogenes and have been targeted by TRK inhibitors with excellent clinical outcomes. The international expert consensus recommends immunohistochemical (IHC) screening for TRK protein followed by next generation sequencing (NGS) to measure expression of NTRK fusions for tumors with low NTRK fusion expression. To confirm the clinical utility of this recommendation in esophageal and gastric cancers, total TRK protein expression was measured by IHC using anti-pan-TRK antibody in 254 esophageal squamous cell carcinoma (ESCC) and 401 gastric adenocarcinoma (GA) samples. Subsequently, DNA-based NGS and fluorescence in situ hybridization (FISH) were performed for tumors expressing TRK to measure NTRK fusion expression. Further, expression of NTRK fusions was evaluated in esophageal and gastric cancers using public databases. IHC staining revealed TRK was expressed in 10 out of 254 ESCC and 0 out of 401 GC cases. NGS and FISH analyses were performed for 10 TRK positive ESCC cases, identifying that none of these cases harbored NTRK fusions. In silico analyses further confirmed that NTRK fusions are rarely present in esophageal and gastric cancers. IHC screening for TRK protein is recommended to detect NTRK fusions, but this method may include many false-positives cases based on the sequencing analysis. Full article

Cryotherapy involves flash freezing of tissue and removing unwanted tissue. Mechanism of injury is causing cell membrane rupture by rapid multiple freeze–thaw cycles, while reserving tissue architecture and the collagen matrix. This promotes favorable wound healing. In recent years, it has gained increasing attention as a treatment option for upper gastrointestinal diseases (Barrett’s Esophagus and early cancer). Currently, two FDA-approved delivery methods are available in the GI tract: Cryoballoon and spray cryotherapy, which will be discussed. In this review, we also propose to examine the expanding role of cryotherapy in gastrointestinal practice, drawing from both clinical studies and illustrative vignettes. In addition, we will highlight its established role in eradicating Barrett’s with low and high-grade dysplasia and compare its outcomes and safety profile with radiofrequency ablation (RFA). We will also discuss the application and safety of spray cryotherapy in the palliation of malignant esophageal strictures when compared with Esophageal stent placement. Cryotherapy may have immunological potential, and it may shrink both primary and metastatic diseases. Ongoing research in this field of Cryo-immunology will be highlighted. Beyond esophageal neoplasia, cryotherapy is increasingly utilized in other upper gastrointestinal precancerous conditions. Through this synthesis, our goal is to provide a timely and comprehensive overview of advancements in cryotherapy and its potential to reshape novel therapeutic approaches in upper gastrointestinal cancers. Finally, we highlight the evolution of a novel platform using nitrous oxide delivered by a handheld device, a contact balloon, and a small replaceable cartridge. This approach may make delivery of cryogen application favorable and a first-line approach in the management of Barrett’s esophagus and early cancer. In addition, Cryoballoon therapy for dysphagia palliation for malignant esophageal strictures may become a preferred approach as more data evolves. Full article

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis due to aggressive invasion and therapy resistance. Cancer-associated fibroblasts (CAFs) are key stromal components that promote tumor progression; however, their specific roles in ESCC remain unclear. Using a direct co-culture model of ESCC cell lines (TE-9, -10, and -15) and mesenchymal stem cells (MSCs) to generate CAF-like cells, we identified biglycan (BGN) as a significantly upregulated gene in CAF-like cells via cDNA microarray analysis. Public single-cell RNA sequencing data also demonstrated elevated BGN expression in CAF clusters. We confirmed that CAF-like cells exhibited elevated BGN expression and secretion at both the mRNA and protein levels. Recombinant human BGN enhanced ESCC cell proliferation and migration by activating Erk and NF-κB signaling pathways, effects abrogated by TLR4 blockade. Furthermore, BGN promoted CAF marker expression in MSCs, M2-like macrophage polarization, and enhanced proliferation and migration abilities in both cell types. Immunohistochemical analysis of 66 ESCC tissues revealed that high stromal BGN expression correlated with greater tumor invasion, lymphatic invasion, and shorter disease-free survival. These findings indicate that CAF-derived BGN promotes ESCC progression via TLR4-mediated signaling and modulates stromal cell behavior, highlighting its potential as a prognostic biomarker and therapeutic target. Full article

Background/Objectives: Esophageal cancer (EC) remains highly lethal. The standard management of locally advanced disease includes neoadjuvant chemoradiotherapy (nCRT) followed by surgery. However, the role of esophagectomy in patients achieving clinical complete response (cCR) after nCRT remains uncertain. Methods: We conducted a retrospective study at the Davidoff Cancer Center, Rabin Medical Center (2013–2023). Patients with thoracic EC (adenocarcinoma and squamous cell carcinoma) stage cT2–4a, N+, M0 who received nCRT (cisplatin/5-FU or CROSS regimen with 41.4–50.4 Gy) were included. Patients with cCR, defined by negative biopsies, endoscopic ultrasound, and PET-CT, were managed with surgery or surveillance. Survival was analyzed using Kaplan–Meier and Cox regression. Results: Of 252 patients treated with nCRT, 118 achieved cCR. Seventy underwent surgery, with 47% (33 patients) achieving pathological complete response (pCR), and 48 were managed with surveillance. Five-year overall survival (OS) was 48% with surveillance and 49% with surgery; disease-free survival (DFS) was 36% vs. 43%. No significant differences were observed in OS (HR = 0.75, 95% CI 0.47–1.26) or DFS (HR = 0.88, 95% CI 0.55–1.41). In patients ≤70 years, surgery conferred an OS and DFS benefit (HR = 0.44, p = 0.03). No benefit was observed in patients >70 years, where outcomes trended against surgery. On multivariable analysis, older age (p = 0.005) and female sex (p = 0.007) were independent predictors of OS. Conclusions: In younger patients (≤70 years), surgery yielded significant survival benefit, supporting its role as the preferred treatment. In patients >70 years, surveillance produced comparable or superior outcomes, suggesting deferral of surgery may avoid morbidity without compromising survival. Age-specific tailoring of management is essential. Full article

Esophageal cancer (EC) is one of the most aggressive cancers of the digestive system, with two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Over four decades, the frequencies of EAC and Barrett’s esophagus (BE), the known precursor lesion for EAC, have sharply increased in North America and Europe. This is mainly due to lifestyle and risk factors such as gastroesophageal reflux disease (GERD), obesity, and smoking. BE development to EAC involves numerous molecular modifications, including genetic and epigenetic alterations. Epigenetic changes, such as aberrant DNA methylation, play a critical role in the pathogenesis and progression of BE. This review discusses how non-genetic risk factors contribute to DNA methylation changes driving the transformation from BE to EAC, providing insights into the potential of developing methylation-based biomarkers for early diagnosis, risk stratification, and therapeutic intervention. Full article

Esophageal cancer (EC) is a highly aggressive gastrointestinal malignancy, with a notable increase in incidence over recent decades, representing a significant global health burden. The main histological subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with the former being closely associated with gastroesophageal reflux disease, Barrett’s esophagus, and obesity, and its incidence continues to increase in Western populations. The rising incidence of EC, combined with poor survival rates, underscores the need for new therapeutic approaches. A deeper understanding of the molecular basis of this prevalent malignancy may open new avenues for optimal therapeutic strategies, with immunotherapy now central in several clinical trials. Understanding the interplay between the tumor microenvironment (TME) and disease progression is pivotal for managing this malignancy, which remains highly challenging. This review highlights the role of the TME in EAC progression and drug resistance, and recent therapeutic advances. Full article

Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological subtype of esophageal cancer worldwide, typically manifesting as an endoluminal mass with overt mucosal involvement. Exceptionally, however, ESCC may present with an intramural growth pattern beneath an apparently intact mucosal surface, a presentation that is exceedingly rare and prone to misdiagnosis. In such cases, repeated endoscopic biopsies are frequently non-diagnostic, thereby delaying appropriate management. Endoscopic ultrasound (EUS) has emerged as the cornerstone for detecting and characterizing intramural lesions, enabling assessment of tumor infiltration depth and nodal status, while complementary imaging with CT and PET contributes to accurate staging. To date, only a handful of intramural ESCC cases have been described, and their clinical, endoscopic, and radiological features remain poorly delineated. This review appraises the existing literature on primary intramural ESCC with intact mucosa, with the dual aims of summarizing the diagnostic challenges and highlighting the value of a multimodal approach to avoid unnecessary surgical interventions. Furthermore, we report an additional case from our experience, which underscores the critical role of EUS and integrated imaging in achieving timely and accurate diagnosis of this unusual entity. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and show notable success in some cancer types such as non-small cell lung cancer, melanoma and colorectal cancers, while they demonstrate relatively low response rate in others, such as esophageal cancers. Due to the heterogeneous nature of the tumor microenvironment and patient-to-patient variability, there remains a need to improve ICI response rates. Combining ICIs with therapies that can overcome resistance is a promising strategy. Compared to de novo drug development, drug repurposing offers a faster and more cost-effective approach to identifying such combination candidates. A variety of computational drug repurposing tools leverage genomics and/or transcriptomic data. As single-cell RNA sequencing (scRNA-seq) technology becomes available, it enables precise targeting of cancer-driving cellular components. In this review, we highlight current computational drug repurposing tools utilizing scRNA-seq data and demonstrate the application of two such tools, scDrug and scDrugPrio, on an esophageal squamous cell carcinoma dataset to identify potential drug candidates for combination with ICI therapy to enhance treatment response. scDrug focuses on predicting tumor cell-specific cytotoxicity, while scDrugPrio prioritizes drugs by reversing gene signatures associated with ICI non-responsiveness across diverse tumor microenvironment cell types. Together, this review underscores the importance of a multi-faceted approach in computational drug repurposing and highlights its potential for identifying drugs that enhance ICI treatment. Future work can expand the application of these strategies to multi-omics and spatial transcriptomics datasets, as well as personalized patient samples, to further refine drug repurposing involving ICI therapy. Full article

Background/Objectives: Treatment planning for stage III non–small cell lung cancer (NSCLC) presents dosimetric challenges due to the proximity of critical structures. RapidPlan (RP), a knowledge-based planning (KBP) system, offers the potential for improved plan consistency and organ-at-risk (OAR) sparing. The objective of this study was to compare dosimetric and clinical outcomes of RP-generated plans versus manually optimized plans in patients with stage III NSCLC undergoing IMRT or VMAT. Methods: In this retrospective analysis, 50 patients treated with concurrent chemoradiation for stage III NSCLC at Hadassah Medical Center (2015–2021) were analyzed. RP plans were generated using a lung-specific model in the Eclipse treatment planning system and compared with the original clinical manual plans. Dosimetric parameters for target volumes and OARs were evaluated, and subgroup analyses were performed by technique (IMRT vs. VMAT). Toxicity and survival outcomes were analyzed, and Normal Tissue Complication Probability (NTCP) modeling was conducted. Results: RP significantly reduced mean heart dose (Δ = −2.54 Gy, p < 0.001), spinal cord maximum dose (Δ = −4.08 Gy, p < 0.001), and esophageal mean dose (Δ = −3.89 Gy, p < 0.001) compared with manual plans. Lung doses were slightly higher in RP plans (V20 Δ = +2.12%, p < 0.001). VMAT-RP plans demonstrated greater cardiac and esophageal sparing than VMAT-manual plans. RP yielded significant NTCP reductions for the heart (0.34% → 0.20%) and esophagus (16.6% → 11.5%), but no improvement for lung or spinal cord. Lung toxicity ≥ grade 2 was associated with reduced overall survival (16.2 vs. 51.8 months, p < 0.001). Conclusions: RapidPlan-based knowledge-based planning enhances OAR sparing while maintaining target coverage in locally advanced NSCLC. Slight increases in lung dose highlight the need for ongoing model refinement. An association between lung toxicity and reduced survival was observed, underscoring the impact of treatment-related morbidity on outcomes. Full article

Background: Esophageal squamous cell carcinoma (ESCC) typically occurs in older individuals. The etiology and clinical characteristics of ESCC in relatively younger patients under 60 years of age remain unclear. Understanding whether age affects tumor behavior or prognosis is important for improving patient management. This study aimed to analyze the characteristics of ESCC diagnosed before the age of 60. Methods: We retrospectively reviewed the medical records of ESCC patients diagnosed between December 2008 and May 2025. A total of 516 patients were divided into two groups based on whether they were aged 60 or above. Medical history, clinical features, and outcomes were compared between the two groups. Results: There were 100 patients under 60 years and 416 patients aged 60 and above. The median ages were 55 (range 41–59) and 72 (range 60–95), respectively. Younger patients had a significantly stronger association with heavy drinking (72.0% vs. 39.2%, p < 0.001) and smoking (76.0% vs. 55.0%, p < 0.001). There was a trend toward more advanced disease (Stage IV: 26.0% vs. 18.5%, p = 0.094) and metastatic presentation (18.0% vs. 13.9%, p = 0.305) in the under-60 group. Despite being younger with better performance status and fewer comorbidities, their overall survival did not differ from that of older patients (HR 0.92; 95% CI, 0.67–1.26; p = 0.593). Conclusions: Patients diagnosed with ESCC under the age of 60 showed a stronger association with heavy alcohol consumption and smoking and more frequent presentation with advanced-stage disease compared with older patients. Younger age did not confer a better prognosis, highlighting the importance of early detection and timely intervention regardless of patient age. Full article

Esophageal squamous cell carcinoma (ESCC) remains a major global health challenge due to its aggressive nature and frequent late-stage diagnosis. Accurate locoregional staging is critical for guiding appropriate therapy, and endoscopic ultrasound (EUS) has emerged as the preferred modality for assessing tumor depth and regional lymph node involvement. In this narrative review, we provide a comprehensive overview of the role of EUS in the management of ESCC, from initial staging to post-treatment assessment. We discuss its strengths and limitations, particularly in differentiating early-stage disease and in restaging after neoadjuvant therapy. The importance of a multimodal approach—integrating EUS with computed tomography (CT), positron emission tomography (PET), and histologic sampling—is emphasized to improve diagnostic precision. We also explore emerging techniques, such as contrast-enhanced EUS, elastography, and novel therapeutic strategies including immune checkpoint inhibitors and endoscopic mucosal resurfacing. While EUS remains a cornerstone in the management of ESCC, ongoing innovation and integration with personalized medicine are expected to further enhance its clinical impact. Full article