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Safety and efficacy of neoadjuvant radiotherapy and immunotherapy in the treatment of esophageal squamous cell carcinoma

ABSTRACT: Background: Immunotherapy has been employed in the neoadjuvant treatment of locally advanced esophageal squamous cell carcinoma. To assess the feasibility of neoadjuvant radiotherapy combined with immunotherapy (NRIT), this study compares the efficacy and effectiveness of neoadjuvant chemoradiotherapy combined with immunotherapy (NICRT) and NRIT, while also exploring the underlying mechanisms of NRIT. Methods:This study retrospectively analyzed a cohort of 64 patients diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant therapy followed by esophagectomy between January 2019 and September 2023. Of these, 26 patients received neoadjuvant radiotherapy and immunotherapy (NRIT), while 38 patients were treated with neoadjuvant chemoradiotherapy (NICRT). The final analysis included pathological complete response (pCR), major pathological response (MPR), tumor regression grade (TRG), the rate of positive lymph node pCR, toxicity, surgical outcomes, postoperative complications, disease-free survival (DFS), and overall survival (OS). Additionally, paraffin-embedded tissue sections obtained before and after neoadjuvant NRIT were subjected to whole-exome sequencing, transcriptome sequencing, and immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) analysis. Results: There was no significant difference in the rates of MPR and PCR (28.95% vs 30.77%, P=0.873), TRG classification (P=0.338), surgical outcomes, or postoperative complications (P=0.148), as well as overall survival (OS) and disease-free survival (DFS) between the NICRT and NRIT groups. However, a notable difference was observed in grade 3 or higher adverse events during treatment, with the NICRT group experiencing a higher incidence (34.21% vs 7.69%, P = 0.017) and severe hematological toxicity (23.68% vs 0.00%, P = 0.008). In the NRIT group, patients with high CPS scores demonstrated improved pathological responses. Pre-treatment genomic analyses indicated no differences in tumor mutation burden (TMB), somatic mutations, and copy number variations between MPR and non-MPR patients post-surgery. Transcriptome analysis revealed a significant number of differentially expressed genes in patients before and after treatment, closely associated with key pathways related to immunity. Following treatment, MPR patients exhibited a marked upregulation of the type I interferon response and the MHC class I antigen presentation pathway. Additionally, the number of B cells and monocytes increased, while non-MPR patients showed a significant downregulation of dendritic cells (DCs) after treatment, alongside the activation of various immune cells, including CD8 naïve cells, NK cells, and B cells. Conclusion: There was no significant difference between the NRIT group and the NICRT group regarding pathological response, surgical outcomes, postoperative complications, and survival analysis; furthermore, NRIT demonstrated a better safety profile compared to NICRT during treatment. Additionally, the mechanism of action of NRIT has been elucidated through a comprehensive analysis of genomic, transcriptomic, immunohistochemical, and other methods in conjunction with clinical results, thereby establishing NRIT as a neoadjuvant treatment that is both effective and safe.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289185 | GEO | 2026/02/07

REPOSITORIES: GEO

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Project description:Objective: Neoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer (NSCLC), yet its real-world implementation is often challenged by surgical delays, cancellations, immune-related fibrosis, and increased postoperative complications. Smokers with NSCLC, despite being at higher risk for postoperative complications, have enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could inform treatment strategies. Methods: Single-cell RNA sequencing was performed on 61 lung samples from non-smokers, smokers, and patients with chronic obstructive pulmonary disease (COPD), as well as 8 invasive lung adenocarcinomas, to define smoking-related immune signatures. Using RNA sequencing data from 102 resected NSCLC and 24 NSCLC patients treated with neoadjuvant chemoimmunotherapy, we conducted in silico deconvolution to evaluate associations between cellular composition and clinical outcomes. Results: Among 140 lung cellular phenotypes, two natural killer (NK) cell subsets were strongly associated with smoking and COPD severity. “Stress-responsive NK (NKSR)” cells exhibited immature features and cytokine-responsive signatures. “Exhausted NK (NKExh)” cells showed mature features and elevated multiple immune checkpoint expression (PDCD1, TIGIT, and LAG3). Abundant intratumoral NKSR cells were associated with significantly improved survival after surgery, particularly in current smokers. Conversely, tumors with low NKSR and high NKExh cell profiles were associated with better responses to neoadjuvant chemoimmunotherapy. Conclusions: Tumor-infiltrating NK cell phenotyping may aid in therapeutic stratification in smokers with NSCLC. NKSR cell preservation predicts favorable outcomes with upfront surgery, while NKExh cell enrichment indicates greater benefit from neoadjuvant chemoimmunotherapy. These profiles may help optimize treatment by balancing therapeutic benefit and risk.

Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific M-bM-^@M-^\signatureM-bM-^@M-^] associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (M-OM-^G2=11M-bM-^@M-"793; p= 0M-bM-^@M-"001) and TS expression (M-OM-^G2=10M-bM-^@M-"589; p= 0M-bM-^@M-"001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer. Experiments were performed on purified RNA from preoperatory biopsies of 38 patients with histological diagnosis of rectal adenocarcinoma invading through the intestinal wall and/or with pelvic lymph node involvement as evaluated by endorectal ultrasonography (uT3-T4 and/or uN+). Patients were treated with neoadjuvant chemo-radiotherapy (capecitabine + oxaliplatin in combination with 45 Gy of pelvic conformal radiotherapy). Patients have been divided in the following two groups: group A those who had obtained a pathologic complete response M-bM-^@M-^S TRG 1, including the patient without detectable disease who refused surgery, group B any pathologic response other than complete.

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Safety and efficacy of neoadjuvant radiotherapy and immunotherapy in the treatment of esophageal squamous cell carcinoma

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