Node-sparing modified short-course Radiotherapy Combined with CAPOX and Tislelizumab for locally Advanced MSS of Middle and low rectal Cancer (mRCAT): an open-label, single-arm, prospective, multicentre clinical trial.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is a standard treatment for locally advanced rectal cancer. Mismatch repair-deficient locally advanced rectal cancer (LARC) was highly sensitive to PD-1 blockade. However, most rectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) subtypes for which PD-1 blockade is ineffective. Radiation can trigger the activation of CD8 + T cells, further enhancing the responses of MSS/pMMR rectal cancer to PD-1 blockade. Radioimmunotherapy offers a promising therapeutic modality for rectal cancer. Progenitor T exhausted cells are abundant in tumour-draining lymph nodes and play an important role in immunotherapy. Conventional irradiation fields include the mesorectum and regional lymph nodes, which might cause considerable damage to T lymphocytes and radiation-induced fibrosis, ultimately leading to a poor response to immunotherapy and rectal fibrosis. This study investigated whether node-sparing modified short-course irradiation combined with chemotherapy and PD-1 blockade could be effective in patients with MSS/ pMMR LARC. METHODS: This was a open-label, single-arm, multicentre, prospective phase II trial. 32 LARC patients with MSS/pMMR will receive node-sparing modified short-course radiotherapy (the irradiated planned target volume only included the primary tumour bed but not the tumour-draining lymph nodes, 25 Gy/5f, 5 Gy/f) followed by CAPOX and tislelizumab. CAPOX and tislelizumab will be started two days after the completion of radiotherapy: oxaliplatin 130 mg/m2 intravenous infusion, day 1; capecitabine 1000 mg/m2 oral administration, days 1-14; and tislelizumab 200 mg, intravenous infusion, day 1. There will be four 21-day cycles. TME will be performed at weeks 14-15. We will collect blood, tumour, and lymphoid specimens; perform flow cytometry and in situ multiplexed immunofluorescence detection; and analyse the changes in various lymphocyte subsets. The primary endpoint is the rate of pathological complete response. The organ preservation rate, tumour regression grade, local recurrence rate, disease-free survival, overall survival, adverse effects, and quality of life will also be analysed. DISCUSSION: In our research, node-sparing modified radiotherapy combined with immunotherapy probably increased the responsiveness of immunotherapy for MSS/pMMR rectal cancer patients, reduced the occurrence of postoperative rectal fibrosis, and improved survival and quality of life. This is the first clinical trial to utilize a node-sparing radiation strategy combined with chemotherapy and PD-1 blockade in the neoadjuvant treatment of rectal cancer, which may result in a breakthrough in the treatment of MSS/pMMR rectal cancer. TRIAL REGISTRATION: This study was registered at www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05972655. Date of registration: 31 July 2023.

Inflammation index predicts radiation-induced lung injury and prognosis in lung tumors treated with stereotactic body radiation therapy.

PURPOSE: To investigate the effect of inflammation-based indexes in predicting radiation pneumonitis (RP) and prognosis in lung tumor patients treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: The data of one hundred and seventy-two patients with 272 lung lesions from November 2015 to December 2020 were retrospectively analyzed. Pretreatment hematological indexes including platelet count, neutrophil count, and lymphocyte count were collected before treatment. Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated. The receiver operating characteristic (ROC) curve was established to predict the RP and overall survival of patients, and the Youden index was calculated to determine the cutoff values of SII, NLR, and PLR before radiotherapy. RESULTS: Pretreatment SII, NLR, and PLR could predict RP in lung tumor patients treated with SBRT, the optimal cutoff values of SII, NLR, and PLR were 355.38, 2.04, and 141.09, respectively. Pretreatment PLR could predict survival and the optimal cutoff value of PLR was 166.83, patients with a PLR > 166.83 predict worse overall survival (OS) (P < 0.001). The 1-year and 2-year OS for patients with a PLR ≤ 166.83 were 96.3% and 82.4%, while for those with a PLR > 166.83 were 82.0% and 58.5%, respectively. CONCLUSION: In lung tumor patients treated with SBRT, pretreatment SII, NLR, and PLR can effectively predict RP and a higher PLR predicts poor OS. These inflammation-based indexes could serve as reliable and convenient predictors to guide treatment for physicians in clinical practice.

An Immune-Related Gene Signature for Predicting Neoadjuvant Chemoradiotherapy Efficacy in Rectal Carcinoma.

Background: Locally advanced rectal cancers (LARC) show a highly variable response to neoadjuvant chemoradiotherapy (nCRT), and the impact of the tumor immune response in this process is poorly understood. This study aimed to characterize the immune-related gene expression profiles (GEP), pathways, and cell types associated with response or resistance to neoadjuvant chemoradiotherapy. Methods: The transcriptomic and clinical data of Rectal carcinoma from the Gene Expression Omnibus database and Immune-related genes (IRGs) from ImmPort were downloaded to identify the differentially expressed immune-related genes (DEIRGs) between responder and non-responder to neoadjuvant chemoradiotherapy. Gene set enrichment analyses were performed to uncover significantly enriched GO terms and KEGG pathways. Immune cell infiltration was estimated from RNA-sequencing data using ImmuCellAI. Afterward, we constructed an immune-related gene-based predictive model (IRGPM) by Support Vector Machine and validated it in an external cohort. Result: A 15-gene signature (HLA-DPB1, HLA-DQA1, CXCL9, CXCL10, TAP2, INHBB, BMP2, CD74, IL33, CCL11, CXCL11, DEFB1, HLA-DPA1, CCN3, STAT1) was identified as DEIRGs and found to be significantly associated with nCRT outcomes. Gene set enrichment analyses indicated that the 15 genes play active roles in inflammation-related biological processes. In addition, ImmuCellAI revealed that CD4 naive T cells, Tex, Th1 were significantly up-regulated (p=0.035, p=0.02, p=0.0086, respectively), while Tfh were significantly down-regulated (p=0.015) in responder subgroup. Finally, a novel predictive model was developed by SVM based on DEIRGs with an AUC of 80% (internal validation) and 73.5% (external validation). Conclusion: Our team conducted a genomic study of the relationship between gene expression profile and response to nCRT in LARC. Our data suggested that the DEIRGs signature could help predict the efficacy of nCRT. And a DEIRGs-based SVM model was developed to monitor the outcomes of nCRT in LARC.

Prognostic value of CEA and CA19-9 in patients with local advanced rectal cancer receiving neoadjuvant chemoradiotherapy, radical surgery and postoperative chemotherapy.

BACKGROUND: We aim to investigate the prognostic factors and evaluate the role of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in local advanced rectal cancer (LARC) patients who received neoadjuvant chemoradiotherapy (neo-CRT), radical surgery and postoperative chemotherapy. METHODS: In total, 197 cases of LARC patients who underwent neo-CRT, total mesorectal excision (TME), and adjuvant chemotherapy were recruited. Serum levels of CEA and CA19-9 were detected both at baseline and after neo-chemoradiotherapy. Multivariate analysis was used to assess correlations between levels of CEA and CA19-9 and patients' prognosis (survival, recurrence, and metastasis). Rates of survival, distant metastasis (DM), and local recurrence (LR) were estimated using Kaplan-Meier survival analysis, the log-rank test, and Cox proportional hazards. RESULTS: The median follow-up time was 45.3 months, and a cohort of 197 patients was analyzed; 84 (42.6%) patients had elevated baseline CEA levels, 21 (10.7%) patients had elevated baseline CA19-9 levels, and 14 (7.1%) patients had both; 77.4% (65/84) patients with high CEA levels and 76.2% (16/21) with high CA19-9 levels returned to normal after neo-chemoradiotherapy. The Cox regression model suggested that elevated CEA was associated with an increased risk of disease-free survival (DFS) (HR: 2.058, 95% CI: 1.034-4.096, P=0.040) and DM (HR: 2.144, 95% CI: 1.058-4.346, P=0.034). Elevated CA19-9 was identified as an independent prognostic factor, with poorer overall survival (OS) (HR: 2.894, 95% CI: 1.196-7.006, P=0.018) and DFS (HR: 4.533, 95% CI: 2.067-9.940, P<0.001) and increased incidences of LR (HR: 6.139, 95% CI: 1.813-20.783, P=0.004) and DM (HR: 4.052, 95% CI: 1.892-8.678, P<0.001). Besides, combined CEA with CA19-9 was a stronger prognostic predictor. Patients with both high levels of CEA and CA19-9 had the poorest DFS (HR: 8.157, 95% CI: 3.232-20.591, P<0.001) and the highest risk of DM (HR: 8.790, 95% CI: 3.324-23.248, P<0.001). CONCLUSIONS: LARC patients with high levels of CEA or/and CA19-9 at initial treatment have a worse prognosis, even after neo-CRT, subsequent radical resection, and adjuvant chemotherapy. These findings suggest that this subset of patients requires more intensive treatment or additional treatment strategies.

Concurrent Chemoradiotherapy in Curatively Resected Gallbladder Carcinoma: A Propensity Score-Matched Analysis.

PURPOSE: To compare overall survival (OS) between patients receiving radical resection followed by concurrent chemoradiotherapy (S+CCRT) and patients receiving radical resection only (S) for advanced resectable gallbladder carcinoma (GBC). METHODS AND MATERIALS: Ninety-four GBC patients with stage pT2-4, N0-1, and M0 consented to inclusion in a clinical database from June 2003 to July 2013. Patients who received S+CCRT were matched by propensity score with those who received S through nearest-neighbor matching, with a caliper width of 0.2 to ensure similar baseline characteristics between each group. The effects of CCRT on OS and disease-free survival (DFS) were evaluated with Kaplan-Meier analysis. Cox proportional hazards regression was performed on the entire cohort. Adverse effects and oncologic outcomes were assessed. RESULTS: Seventy-eight patients with GBC (39 S+CCRT; 39 S) were matched according to propensity score; the 1-year, 3-year, and 5-year OS was 74.4%, 56.4%, and 42.4% for the S+CCRT group and 51.3%, 30.8%, and 17.9% for the S group. The median survival time was 27 months (interquartile range [IQR], 12-58 months) for the S+CCRT group versus 13 months (IQR, 5-30 months) for the S group (P=.004), with the 1-year and 3-year DFS being 59.0% versus 35.9% and 48.7% versus 13.5%, respectively, and the median DFS being 23 months (IQR, 8-57 months) versus 7 months (IQR, 4-23 months) (P=.004). CONCLUSIONS: The OS of matched patients with stage II-IVA GBC is significantly improved by CCRT. Radiation therapy combined with single-agent or dual-agent chemotherapy was feasible and well tolerated.

A feedback constraint optimization method for intensity-modulated radiation therapy of nasopharyngeal carcinoma.

Intensity-modulated radiation therapy (IMRT) is able to achieve good target conformance with a limited dose to organs at risk (OARs); however, IMRT increases the irradiation volume and monitor units (MUs) required. The present study aimed to evaluate the use of an IMRT plan with fewer segments and MUs, while maintaining quality in the treatment of nasopharyngeal carcinoma. In the present study, two types of IMRT plan were therefore compared: The direct machine parameter optimization (DMPO)-RT method and the feedback constraint DMPO-RT (fc_DMPO-RT) method, which utilizes compensative feedback constraint in DMPO-RT and maintains optimization. Plans for 23 patients were developed with identical dose prescriptions. Each plan involved synchronous delivery to various targets, with identical OAR constraints, by means of 7 coplanar fields. The average dose, maximum dose, dose-volume histograms of targets and the OAR, MUs of the plan, the number of segments, delivery time and accuracy were subsequently compared. The fc_DMPO-RT exhibited superior dose distribution in terms of the average, maximum and minimum doses to the gross tumor volume compared with that of DMPO-RT (t=62.7, 20.5 and 22.0, respectively; P<0.05). The fc_DMPO-RT also resulted in a smaller maximum dose to the spinal cord (t=7.3; P<0.05), as well as fewer MUs, fewer segments and decreased treatment times than that of the DMPO-RT (t=6.2, 393.4 and 244.3, respectively; P<0.05). The fc_DMPO-RT maintained plan quality with fewer segments and MUs, and the treatment time was significantly reduced, thereby resulting in reduced radiation leakage and an enhanced curative effect. Therefore, introducing feedback constraint into DMPO may result in improved IMRT planning. In nasopharyngeal carcinoma specifically, feedback constraint resulted in the improved protection of OARs in proximity of targets (such as the brainstem and parotid) due to sharp dose distribution and reduced MUs.

Effect of intensity modulated radiotherapy combined with s-1-based chemotherapy in locally advanced gastric cancer patients.

BACKGROUND: The optimal radiotherapy technique and combination with systemic therapy in locally advanced gastric cancer patients are far from being resolved despite the fact that radiochemotherapy is becoming more attractive in contemporary clinical practice. PATIENTS AND METHODS: 40 patients with locally advanced gastric cancer received intensity-modulated radiotherapy (IMRT) at a dosage of 45-50.4 Gy concurrent with chemotherapy using S-1 solely or with a combination of oxaliplatin. Surgery was recommended for those who were evaluated as resectable. Sequential chemotherapy with various regimens was adopted based on the efficacy and tolerance of radiochemotherapy. RESULTS: The overall response rate was 75% according to Response Evaluation Criteria in Solid Tumors and Japanese Gastric Cancer Association criteria. 24 finally underwent surgery, with 22 (91.7%) receiving an R0 resection (resection for cure or complete remission). The overall pathological response rate was 37.5% (9/24). Patients receiving an R0 resection had a higher 2-year overall survival rate (64.7 vs. 16.2%, p = 0.001) and local relapse-free survival rate (90.2 vs. 29.3%, p = 0.000), while there was no difference in distant metastasis-free survival rate (66.1 and 48.1% p = 0.231). Hematological and gastrointestinal toxicities of grade 1 or grade 2 were relatively common. CONCLUSION: The high rate of R0 resections and low rate of locoregional recurrence suggest that IMRT combined with S-1-based chemotherapy is an effective treatment for locally advanced gastric cancer patients.

HDAC inhibitors reverse acquired radio resistance of KYSE-150R esophageal carcinoma cells by modulating Bmi-1 expression.

Tumors treated with fractionated doses of ionizing radiation (IR) often acquire radioresistance. Although histone deacetylase inhibitors (HDIs) have been demonstrated to sensitize intrinsic radioresistant cancer cell lines to IR, little is known on the impact of HDIs on the effects of IR in acquired radioresistant cancer cells. This study evaluates the mechanisms by which HDIs sensitize acquired radioresistant esophageal squamous cell carcinoma cells to IR. The HDIs trichostatin A and sodium butyrate were tested for the irability to sensitize acquired radioresistant KYSE-150R and radiosensitive KYSE-150 parental cells to IR. Although the HDIs induced similar levels of cytotoxicity in the KYSE-150 and the KYSE-150R cells, HDIs increased the: (i) radiosensitivity, (ii) IR-induced ROS generation, and (iii) IR-induced G2/M arrest and apoptosis of KYSE-150R cells compared with those of KYSE-150 cells. These changes were accompanied by increased p21 expression and decreased mitochondrial membrane potential. When combined with IR, HDIs inhibited Bmi-1 expression in KYSE-150R cells and their ability to repair DNA damage. The results demonstrate the potential utility of HDIs in augmenting the efficacy of fractionated radiotherapy.

Prognostic impact of vascular endothelial growth factor-A expression in resected gallbladder carcinoma.

The purpose of this study was to evaluate the value of vascular endothelial growth factor-A (VEGF-A) expression and other confirmed prognostic factors in predicting clinical outcomes after the resection of gallbladder carcinoma (GBC). Between January 1999 and January 2006, a total of 84 consecutive and non-selected patients who underwent resection for GBC were retrospectively reviewed. Of the 84 patients studied, 45 cases (53.6%) exhibited high expression of VEGF-A and were placed into the high expression group. The 14 cases (16.7%) that showed no VEGF expression and the 25 cases (29.7%) that had lower VEGF-A levels were pooled into the low expression group (46.4%). There was a relationship between VEGF-A status and pM stage (P = 0.027) as well as histologic differentiation (P < 0.001). In univariate analysis by log-rank test, ECOG performance status, CA 19-9, pN stage, pM stage, histologic differentiation, and VEGF-A expression were significant prognostic factors (P = 0.015, 0.001, 0.020, <0.001, 0.040, and <0.001, respectively). Multivariate analysis revealed that pN status and VEGF-A expression maintained independent prognostic influence on overall survival (P < 0.001 and P = 0.013, respectively). VEGF-A expression has a positive correlation with pM stage and histologic differentiation. pN status and VEGF-A expression were independent prognostic factors of overall survival in patients with resected GBC.

Adjuvant radiotherapy for gallbladder cancer: a dosimetric comparison of conformal radiotherapy and intensity-modulated radiotherapy.

AIM: To assess the efficacy and toxicity of conformal radiotherapy (CRT) and compare with intensity-modulated radiotherapy (IMRT) in the treatment of gallbladder cancer. METHODS: Between November 2003 and January 2010, 20 patients with gallbladder cancer were treated with CRT with or without chemotherapy after surgical resection. Preliminary survival data were collected and examined using both Kaplan-Meier and actuarial analysis. Demographic and treatment parameters were collected. All patients were planned to receive 46-56 Gy in 1.8 or 2.0 Gy per fraction. CRT planning was compared with IMRT. RESULTS: The most common reported acute toxicities requiring medication (Radiation Therapy Oncology Group, Radiation Therapy Oncology Group Grade 2) were nausea (10/20 patients) and diarrhea (3/20). There were no treatment-related deaths. Compared with CRT planning, IMRT significantly reduced the volume of right kidney receiving > 20 Gy and the volume of liver receiving > 30 Gy. IMRT has a negligible impact on the volume of left kidney receiving > 20 Gy. The 95% of prescribed dose for a planning tumor volume using either 3D CRT or IMRT planning were 84.0% ± 6.7%, 82.9% ± 6.1%, respectively (P > 0.05). CONCLUSION: IMRT achieves similar excellent target coverage as compared with CRT planning, while reducing the mean liver dose and volume above threshold dose. IMRT offers better sparing of the right kidney compared with CRT planning, with a significantly lower mean dose and volume above threshold dose.