Age-related differences in progression patterns, follow-up strategies, and postoperative outcomes in locally advanced rectal cancer: insights from a large-scale validated study.

Background: Locally advanced rectal cancer (LARC) presents significant treatment challenges, particularly as patient age may influence disease progression and treatment response. Understanding the differences in progression patterns and treatment outcomes between older patient (OP) and non-older patient (NOP) is essential for tailoring effective management strategies. Objectives: We aimed to explore the differences of progression pattern, postoperative treatment, and survival outcome between OP and NOP groups in LARC. Design/Methods: The random survival forest model was used to determine the probability of time-to-event occurrence every 3 months. Patients in the NOP and OP group were both categorized into three risk groups based on progression-free survival nomogram scores. We employed inverse probability of treatment weighting (IPTW) analysis and the Surveillance, Epidemiology, and End Results (SEER) database to verify our findings. Results: Our results revealed that Groups 1, 2, and 3 experienced peaks in progression within the first 24 months in NOP group. As for OP group, Group 4 reached a progression peak at the 18th month, Group 5 at the 12th month, and Group 6 at the 9th month. In NOP group, high-risk patients who underwent postoperative chemotherapy had significantly improved overall survival compared to those who did not. Additionally, postoperative chemotherapy did not significantly improve prognosis for patients in low-, moderate-, or high-risk groups of OP group. Finally, the validation results of IPTW analysis and SEER database showed compliance with our findings. Conclusion: For NOP group, we recommended close follow-up during the first 2 years. As for OP group, it was suggested to conduct close follow-up at the 18th, 12th, and 9th month for low-, moderate-, and high-risk groups, respectively. Furthermore, postoperative chemotherapy can provide survival benefits for patients in high-risk group of NOP group. However, OP group patients should be informed that the potential benefits of postoperative chemotherapy may be minimal.

Comprehensive analysis of the prognostic value of pre-treatment nutritional indicators in elderly rectal cancer patients.

Nutritional status assessment has been deemed essential in treating elderly cancer patients. This study aims to investigate and compare the prognostic value and clinical utility of pre-treatment nutritional indicators in elderly rectal cancer (RC) patients. We retrospectively collected data from 361 elderly rectal cancer patients. The optimal cut-off values for pre-treatment nutritional indicators were calculated using ROC curve analysis. Univariate and multivariate Cox analyses were conducted to identify independent prognostic nutritional indicators. The predictive performance and clinical utility of these independent nutritional indicators was evaluated using time-dependent ROC. Multivariate analyses showed that body mass index (BMI), prognostic nutritional index (PNI), geriatric nutrition risk index (GNRI), and platelet-albumin ratio (PAR) independently predicted overall survival and progression-free survival in elderly RC patients (all p < 0.05), except for advanced lung cancer inflammation index (ALI). According to the nomogram model, the pre-treatment nutritional prognosis score was calculated and the patients were risk stratified. The KM curve showed that the survival of the high-risk group was significantly worse than that of the low-moderate risk group. Time-dependent ROC indicated that novel nutritional prognostic indicator (NNPI) had the best predictive ability compared with the independent prognostic nutritional indicator. Subgroup analysis also showed that NNPI had prognostic value across different clinical factors and had significant clinical utility. In elderly RC patients, BMI, PNI, GNRI, PAR, and NNPI serve as objective assessment tools for nutrition-related mortality risk. Identifying elderly patients at higher nutritional risk can guide early clinical nutritional interventions and improve patient outcomes.

Deciphering colorectal cancer radioresistance and immune microrenvironment: unraveling the role of EIF5A through single-cell RNA sequencing and machine learning.

Background: Radiotherapy (RT) is a critical component of treatment for locally advanced rectal cancer (LARC), though patient response varies significantly. The variability in treatment outcomes is partly due to the resistance conferred by cancer stem cells (CSCs) and tumor immune microenvironment (TiME). This study investigates the role of EIF5A in radiotherapy response and its impact on the CSCs and TiME. Methods: Predictive models for preoperative radiotherapy (preRT) response were developed using machine learning, identifying EIF5A as a key gene associated with radioresistance. EIF5A expression was analyzed via bulk RNA-seq and single-cell RNA-seq (scRNA-seq). Functional assays and in vivo experiments validated EIF5A's role in radioresistance and TiME modulation. Results: EIF5A was significantly upregulated in radioresistant colorectal cancer (CRC) tissues. EIF5A knockdown in CRC cell lines reduced cell viability, migration, and invasion after radiation, and increased radiation-induced apoptosis. Mechanistically, EIF5A promoted cancer stem cell (CSC) characteristics through the Hedgehog signaling pathway. Analysis of the TiME revealed that the radiation-resistant group had an immune-desert phenotype, characterized by low immune cell infiltration. In vivo experiments showed that EIF5A knockdown led to increased infiltration of CD8+ T cells and M1 macrophages, and decreased M2 macrophages and Tregs following radiation therapy, thereby enhancing the radiotherapy response. Conclusion: EIF5A contributes to CRC radioresistance by promoting CSC traits via the Hedgehog pathway and modulating the TiME to an immune-suppressive state. Targeting EIF5A could enhance radiation sensitivity and improve immune responses, offering a potential therapeutic strategy to optimize radiotherapy outcomes in CRC patients.

A large population-based and validated study on the follow-up management and supportive strategy of locally advanced rectal cancer patients.

OBJECTIVE: Our objective was to evaluate the predictive factors and metastatic time for liver and lung metastasis in locally advanced rectal cancer (RC) patients. METHODS: Univariate and multivariate analysis were performed to identify risk factors and prognostic factors for liver metastasis and lung metastasis in RC. Survival probabilities were calculated using the Kaplan-Meier model and compared using the log-rank test between groups. The probability of time-to-event occurrence was calculated using the random survival forest model. Finally, the SEER database was used to verify our findings. RESULTS: Our results indicated that pathological T stage and pathological N stage were independent predictive factors for liver metastasis. Furthermore, CEA level, pathological T stage, and tumor deposit were independent predictive factors for lung metastasis. Based on the results of a multivariate Cox analysis, we categorized patients with liver and lung metastasis into three groups based on their scores. The results revealed that patients with higher scores had a higher probability of experiencing metastasis. For liver metastasis, Groups 1, 2, and 3 all exhibited higher occurrence rates within the first 24 months. However, for lung metastasis, Group 4 showed the highest occurrence rate at the 12th month, while Groups 5 and 6 exhibited the highest occurrence rates at the 15th month. CONCLUSIONS: In summary, we developed predictive models to determine the likelihood of liver and lung metastasis in RC patients. It is crucial to implement a more intensive surveillance program for patients with unfavorable risk profiles in order to facilitate early detection of metastasis.

Analysis of risk characteristics for early progression and late progression in locally advanced rectal cancer patients: a large population-based and validated study.

BACKGROUND AND OBJECTIVE: The current study aimed to explore the factors influencing early progression (EP) and late progression (LP) in locally advanced rectal cancer (LARC) patients. METHODS: The patients were classified into EP and LP groups using one year as a cutoff. The random survival forest model was utilized to calculate the probability of time-to-progression. Besides, inverse probability of treatment weighting (IPTW) analysis and the Surveillance, Epidemiology, and End Results (SEER) were conducted to validate our results. RESULTS: Our study revealed that PNI, CEA level, and pathological stage were independent prognostic factors for PFS both in EP group and LP group. For EP group patients, Group 1 had the highest probability of progression at the 9th month of follow-up, while Group 2 exhibited the highest probability at the 6th month. Group 3, on the other hand, showed two peaks of progression at the 4th and 8th months of follow-up. As for LP group patients, Groups 4, 5, and 6 all exhibited peaks of progression between the 18th and 24th months of follow-up. Furthermore, our results suggested that PNI was also an independent prognostic factor affecting OS in both EP group and LP group. Finally, the analysis of IPTW and SEER database further confirmed our findings. CONCLUSIONS: Our results indicated a significant correlation between immune and nutritional status with PFS and OS in both EP and LP groups. These insights can aid healthcare professionals in effectively identifying and evaluating patients' nutritional status, enabling them to develop tailored nutrition plans and interventions.

Prediction of liver metastasis and recommended optimal follow-up nursing in rectal cancer.

We aimed to analyze and investigate the clinical factors that influence the occurrence of liver metastasis in locally advanced rectal cancer patients, with an attempt to assist patients in devising the optimal imaging-based follow-up nursing. Between June 2011 and May 2021, patients with rectal cancer at our hospital were retrospectively analyzed. A random survival forest model was developed to predict the probability of liver metastasis and provide a practical risk-based approach to surveillance. The results indicated that age, perineural invasion, and tumor deposit were significant factors associated with the liver metastasis and survival. The liver metastasis risk of the low-risk group was higher at 6-21 months, with a peak occurrence time in the 15th month. The liver metastasis risk of the high-risk group was higher at 0-24 months, with a peak occurrence time in the 8th month. In general, our clinical model could predict liver metastasis in rectal cancer patients. It provides a visualization tool that can aid physicians and nurses in making clinical decisions, by detecting the probability of liver metastasis.

STING Agonist-Loaded Nanoparticles Promotes Positive Regulation of Type I Interferon-Dependent Radioimmunotherapy in Rectal Cancer.

Hypoxia-associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X-ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon-dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and αPD-1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC.

Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation.

BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. METHODS: Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. RESULTS: We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8+ T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. CONCLUSIONS: Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice.

A large-scale study integrating nutritional indicators and clinicopathological parameters to evaluate prognosis, follow-up, and postoperative chemotherapy decisions in rectal cancer patients.

OBJECTIVE: The aim of this study was to evaluate the role of nutritional indicators and clinicopathological parameters in predicting the progression and prognosis for pathological stage II-III rectal cancer (RC) patients without neoadjuvant radiotherapy. In addition, we sought to explore the high-risk population who may require postoperative chemotherapy. METHODS: A total of 894 consecutive RC patients were enrolled in this study. Univariate and multivariate Cox analysis were performed to identify the independent risk factors for PFS and OS. The nomogram and calibration curves were conducted according to multivariable analysis result. Kaplan-Meier survival curves and log-rank tests were performed for different groups. Finally, random survival forest (RSF) model was developed to predict the probability of progression. RESULTS: Our results revealed that CEA level, pathological stage, tumor deposit, and PNI were independently associated with PFS in RC patients. Similarly, the results indicated that CEA level, pathological stage, tumor deposit, PNI, and NRI were independently associated with OS. RSF model revealed that group 1 had the highest risk of progression at the 12th month of follow-up, group 2 had the highest risk of progression at the 15th month of follow-up, while group 3 had the highest risk of progression at the 9th month of follow-up. Besides, subgroup analysis suggested that the high-risk group needs postoperative adjuvant chemotherapy, while patients in the low- and moderate-risk groups may not need postoperative adjuvant chemotherapy. Finally, we validated our results with the SEER database. CONCLUSIONS: In conclusion, we demonstrated that preoperative nutritional indicator and clinicopathological parameters could act as auxiliary prognostication tools for RC patients without neoadjuvant radiotherapy. We also established follow-up strategies for different groups of patients. Collectively, incorporating nutritional assessment into risk stratification for RC resection is crucial and should be an integral part of preoperative planning.

A positive feedback loop between ID3 and PPARγ via DNA damage repair regulates the efficacy of radiotherapy for rectal cancer.

OBJECTIVE: To study the effect of inhibitor of differentiation 3 (ID3) on radiotherapy in patients with rectal cancer and to explore its primary mechanism. METHODS: Cell proliferation and clonogenic assays were used to study the relationship between ID3 and radiosensitivity. Co-immunoprecipitation and immunofluorescence were performed to analyze the possible mechanism of ID3 in the radiosensitivity of colorectal cancer. At the same time, a xenograft tumor model of HCT116 cells in nude mice was established to study the effect of irradiation on the tumorigenesis of ID3 knockdown colorectal cancer cells in vivo. Immunohistochemistry was performed to analyze the relationship between ID3 expression and the efficacy of radiotherapy in 46 patients with rectal cancer. RESULTS: Proliferation and clonogenic assays revealed that the radiosensitivity of colorectal cancer cells decreased with ID3 depletion through p53-independent pathway. With the decrease in ID3 expression, MDC1 was downregulated. Furthermore, the expression of ID3, MDC1, and γH2AX increased and formed foci after irradiation. ID3 interacted with PPARγ and form a positive feedback loop to enhance the effect of ID3 on the radiosensitivity of colorectal cancer. Irradiation tests in nude mice also confirmed that HCT116 cells with ID3 knockdown were more affected by irradiation. Immunohistochemical study showed that rectal cancer patients with low expression of ID3 had better radiotherapy efficacy. CONCLUSIONS: ID3 and PPARγ influence the radiosensitivity of colorectal cancer cells by interacting with MDC1 to form a positive feedback loop that promotes DNA damage repair. Patients with low expression of ID3 who received neoadjuvant chemoradiotherapy can obtain a better curative effect.

Comprehensive analysis of transient receptor potential channels-related signature for prognosis, tumor immune microenvironment, and treatment response of colorectal cancer.

Background: Transient receptor potential channels (TRPC) play critical regulatory functions in cancer occurrence and progression. However, knowledge on its role in colorectal cancer (CRC) is limited. In addition, neoadjuvant treatment and immune checkpoint inhibitors (ICIs) have increasing roles in CRC management, but not all patients benefit from them. In this study, a TRPC related signature (TRPCRS) was constructed for prognosis, tumor immune microenvironment (TIME), and treatment response of CRC. Methods: Data on CRC gene expression and clinical features were retrospectively collected from TCGA and GEO databases. Twenty-eight TRPC regulators (TRPCR) were retrieved using gene set enrichment analysis. Different TRPCR expression patterns were identified using non-negative matrix factorization for consensus clustering, and a TRPCRS was established using LASSO. The potential value of TRPCRS was assessed using functional enrichment analysis, tumor immune analysis, tumor somatic mutation analysis, and response to preoperative chemoradiotherapy or ICIs. Moreover, an external validation was conducted using rectal cancer samples that received preoperative chemoradiotherapy at Fujian Cancer Hospital (FJCH) via qRT-PCR. Results: Among 834 CRC samples in the TCGA and meta-GEO cohorts, two TRPCR expression patterns were identified, which were associated with various immune infiltrations. In addition, 266 intersected genes from 5564 differentially expressed genes (DEGs) between two TRPC subtypes, 4605 DEGs between tumor tissue and adjacent non-tumor tissue (all FDR< 0.05, adjusted P< 0.001), and 1329 prognostic related genes (P< 0.05) were identified to establish the TRPCRS, which was confirmed in the TCGA cohort, two cohorts from GEO, and one qRT-PCR cohort from FJCH. According to the current signature, the high-TRPC score group had higher expressions of PD-1, PD-L1, and CTLA4, lower TIDE score, and improved response to anti-PD-1 treatment with better predictive ability. Compared to the high-TRPC score group, the low-TRPC score group comprised an immunosuppressive phenotype with increased infiltration of neutrophils and activated MAPK signaling pathway, but was more sensitive to preoperative chemoradiotherapy and associated with improved prognosis. Conclusions: The current TRPCRS predicted the prognosis of CRC, evaluated the TIME in CRC, and anticipated the response to immune therapy and neoadjuvant treatment.

Role of a lipid metabolism-related lncRNA signature in risk stratification and immune microenvironment for colon cancer.

BACKGROUND: Energy metabolism disorder, especially lipid metabolism disorder, is an important biological characteristic of colon cancer. This research sought to examine the association between lipid metabolism-related long non-coding RNAs (lncRNAs) and prognoses among colon cancer patients. METHODS: The transcriptome profile and clinical data of patients with colon cancer were retrieved from The Cancer Genome Atlas database. Using consensus clustering, cases were divided into two clusters and Kaplan-Meier analysis was executed to analyze differences in their prognoses. The gene set enrichment analysis (GSEA) was used to discover biological processes and signaling pathways. A lipid metabolism-related lncRNA prognostic model (lipid metabolism-LncRM) was created utilizing the least absolute shrinkage and selection operator (LASSO) regression. The tumor microenvironment was evaluated on the basis of the composition of immune and stromal cells. RESULTS: The patients in Cluster 2 were found to have a better prognosis and higher expression of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) relative to Cluster 1. The results of GSEA showed the enrichment of energy metabolism pathways in Cluster 2. LASSO regression was used to identify the five LncRNAs that were shown to be most substantially linked to patient prognosis. These were NSMCE1-DT, LINC02084, MYOSLID, LINC02428, and MRPS9-AS1. Receiver operating characteristic (ROC) curves and survival analysis illustrated that the lipid metabolism-LncRM had a significant prognostic value. Further analysis showed that high- and low-risk groups were significantly different in terms of clinical characteristics and immune cells infiltration. CONCLUSIONS: Lipid metabolism-related lncRNAs could predict the prognoses and tumor microenvironment of colon cancer and might be important biomarkers relevant to immunotherapy.

Postoperative locoregional recurrence pattern and treatment management of stage pT4 sigmoid colon cancer: a retrospective cohort study.

BACKGROUND: This study aimed to explore the pattern of locoregional recurrence after surgery in patients with non-metastatic stage pT4 sigmoid colon cancer and the role of adjuvant radiotherapy on survival. METHODS: We retrospectively analyzed data from 208 patients who underwent surgery in our hospital. The patients were randomly divided into training and validation groups at a 1:1 ratio. Patients at high risk for locoregional recurrence were screened using Cox regression analysis. Based on the data of 2,886 patients in the Surveillance, Epidemiology, and End Results (SEER) database, the effect of adjuvant radiotherapy on overall survival (OS) and cancer-specific survival (CSS) was evaluated by Kaplan-Meier curves. RESULTS: Of the 208 patients, 57 (27.4%) presented with locoregional recurrences (14 anastomotic and 43 abdominal or pelvic lymph node recurrences). Multivariate analysis showed that serum CEA, differentiation, lymph node dissection number, and N stage were independent predictors of locoregional recurrence-free survival (all p < 0.05). A risk-stratification model was constructed, and a total score of ≥ 6.5 points was considered the high-risk group for locoregional recurrence. Both the training and validation sets presented that the model had a good predictive ability (area under the curve = 0.828 and 0.724, respectively). Analysis of SEER data revealed that adjuvant radiotherapy significantly prolonged OS and CSS in the high-risk population (all p < 0.05, vs. no radiotherapy). CONCLUSIONS: Patients with a total risk score of 6.5 or more had a high likelihood of locoregional recurrence, and perhaps adjuvant radiotherapy could improve their survival.

Identifying the long-term survival beneficiary of preoperative radiotherapy for rectal cancer in the TME era.

This study was to verify the long-term survival efficacy of preoperative radiotherapy (preRT) for locally advanced rectal cancer (LARC) patients and identify potential long-term survival beneficiary. Using the Surveillance, Epidemiology, and End Results (SEER) database, 7582 LARC patients were eligible for this study between 2011 and 2015 including 6066 received preRT and 1516 received surgery alone. Initial results showed that preRT prolonged the median overall survival (OS) of LARC patients (HR 0.86, 95% CI 0.75-0.98, P < 0.05), and subgroup analysis revealed that patients with age > 65 years, stage III, T3, T4, N2, tumor size > 5 cm, tumor deposits, and lymph nodes dissection (LND) ≥ 12 would benefit more from preRT (all P < 0.05). A prognostic predicting nomogram was constructed using the independent risk factors of OS identified by multivariate Cox analysis (all P < 0.05), which exhibited better prediction of OS than the 8th American Joint Cancer Committee staging system on colorectal cancer. According to the current nomogram, patients in the high-risk subgroup had a shorter median OS than low-risk subgroup (HR 2.62, 95% CI 2.25-3.04, P < 0.001), and preRT could benefit more high-risk patients rather than low-risk patients. Hence, we concluded that preRT might bring long-term survival benefits to LARC patients, especially those with high risk.

An Unfolded Protein Response-Related mRNA Signature Predicting the Survival and Therapeutic Effect of Hepatocellular Carcinoma.

BACKGROUND: Tumorigenesis, metastasis, and treatment response of hepatocellular carcinoma (HCC) are regulated by unfolded protein responses (UPR) signaling pathways, including IRE1a, PERK, and ATF6, but little is known about UPR related genes with HCC prognosis and therapeutic indicators. OBJECTIVE: We aimed to identify a UPR related prognostic signature (UPRRPS) for HCC and explore the potential effect of the current signature on the existing molecular targeted agents and immune checkpoint inhibitors (ICIs). METHODS: We used The Cancer Genome Atlas (TCGA) database to screen candidate UPR genes (UPRGs), which are expressed differentially between hepatocellular carcinoma and normal liver tissue and associated with prognosis. A gene risk score for overall survival prediction was established using the least absolute shrinkage and selection operator (LASSO) regression analysis, which was validated using data from the International Cancer Genome Consortium (ICGC) database and evaluated by the C-index. Then immune and molecular characteristics stratified by the current UPRRPS were analyzed, and the corresponding drug sensitivity was conducted. RESULTS: Initially, 42 UPRGs from the TCGA database were screened as differentially expressed genes, which were also associated with HCC prognosis. Using the LASSO regression analysis, nine UPRGs (EXTL3, PPP2R5B, ZBTB17, EIF2S2, EIF2S3, HDGF, SRPRB, EXTL2, and TPP1) were used to develop a UPRRPS to predict the OS of HCC patients in the TCGA set with the Cindex of 0.763. The current UPRRPS was also well-validated in the ICGC set with the C-index of 0.700. Multivariate Cox regression analyses also confirmed that the risk score was an independent risk factor for HCC in both the TCGA and ICGC sets (both P<0.05). Functional analyses showed that low-risk score was associated with increased natural killer cells, T helpers, tumor immune dysfunction and exclusion score, microsatellite instability expression, and more benefit from ICIs; the high-risk score was associated with increased active dendritic cells, Tregs, T-cell exclusion score, and less benefit from ICIs. Gene set enrichment analyses showed that the signaling pathways of VEGF, MAPK, and mTOR were enriched in high UPRRPS, and the drug sensitivities of the corresponding inhibitors were all significantly higher in the high UPRRPS subgroup (all P<0.001). CONCLUSION: With the current findings, UPRRPS was a promising biomarker for predicting the prognosis of HCC patients. UPRRPS might also be taken as a potential indicator to guide the management of immune checkpoint inhibitors and molecular targeted agents.

Prognostic Nomogram for Rectal Cancer Patients With Tumor Deposits.

AIM: Tumor deposits (TDs) are an aggressive hallmark of rectal cancer, but their prognostic value has not been addressed in current staging systems. This study aimed to construct and validate a prognostic nomogram for rectal cancer patients with TDs. METHODS: A total of 1,388 stage III-IV rectal cancer patients who underwent radical surgical resection from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed to identify the clinical value of TDs. TD-positive rectal cancer patients in the SEER database were used as the training set to construct a prognostic model, which was validated by Fujian Cancer Hospital. Three models were constructed to predict the prognosis of rectal cancer patients with TDs, including the least absolute shrinkage and selection operator regression (LASSO, model 1), backward stepwise regression (BSR, model 2), and LASSO followed by BSR (model 3). A nomogram was established among the three models. RESULTS: In the entire cohort, TD was also identified as an independent risk factor for overall survival (OS), even after adjusting for baseline factors, stage, other risk factors, treatments, and all the included variables in this study (all P < 0.05). Among patients with TDs, model 3 exhibited a higher C-index and area under the curves (AUCs) at 3, 4, and 5 years compared with the American Joint Committee on Cancer staging system both in the training and validation sets (all P < 0.05). The nomogram obtained from model 3 showed good consistency based on the calibration curves and excellent clinical applicability by the decision curve analysis curves. In addition, patients were divided into two subgroups with apparently different OS according to the current nomogram (both P < 0.05), and only patients in the high-risk subgroup were found to benefit from postoperative radiotherapy (P < 0.05). CONCLUSION: We identified a novel nomogram that could not only predict the prognosis of rectal cancer patients with TDs but also provide reliable evidence for clinical decision-making.

The Correlation Between Survival Benefit of Preoperative Radiotherapy and Pretreatment Carcinoembryonic Antigen Level in Locally Advanced Rectal Cancer.

BACKGROUND: Preoperative radiotherapy followed by radical surgery is the standard treatment for locally advanced rectal cancer; however, its long-term survival benefit remains controversial. This study aimed to determine the relationship between pretreatment carcinoembryonic antigen (CEA) levels and the long-term prognosis of preoperative radiotherapy in locally advanced rectal cancer (LARC) patients. METHODS: Data of LARC patients who underwent surgery between 2011 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database, and patients were accordingly divided into surgery (S) group and radiotherapy followed by surgery (RT+S) group. The primary outcomes were cancer-specific survival (CSS) and cancer-specific mortality (CSM). CSS was evaluated using Kaplan-Meier analysis, while CSM was evaluated using a competitive risk model. Subgroup analysis was also conducted, which was stratified by pretreatment CEA levels. RESULTS: A total of 2,760 patients were eligible for this study, including 350 (12.7%) patients in the S group and 2,410 (87.3%) in the RT+S group. There were no significant differences in the CSS and CSM rates at 1, 3, and 4 years between the S and RT+S groups before and after PSM (all p > 0.05). Pretreatment CEA levels were independently associated with CSS and CSM after adjusting for age, sex, stage, pathological factors, and treatment factors (all p < 0.05). Subgroup analysis showed that preoperative radiotherapy would benefit patients with elevated CEA in terms of CSS and CSM (both p < 0.05) but not those patients with normal CEA (both p > 0.05). Further analysis showed that preoperative radiotherapy was an independent protective factor for CSS and CSM in patients with elevated CEA levels (both p < 0.05). CONCLUSIONS: Pretreatment CEA level may be considered a potential biomarker to screen LACR patients who would benefit from preoperative radiotherapy in terms of long-term prognosis.

Identification of Aging-Related Genes Associated With Clinical and Prognostic Features of Hepatocellular Carcinoma.

Background: Aging is a well-studied concept, but no studies have comprehensively analyzed the association between aging-related genes (AGs) and hepatocellular carcinoma (HCC) prognosis. Methods: Gene candidates were selected from differentially expressed genes and prognostic genes in The Cancer Genome Atlas (TCGA) database. A gene risk score for overall survival prediction was established using the least absolute shrinkage and selection operator (LASSO) regression analysis, and this was validated using data from the International Cancer Genome Consortium (ICGC) database. Functional analysis was conducted using gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis, and immune microenvironment and tumor stemness analyses. Results: Initially, 72 AGs from the TCGA database were screened as differentially expressed between normal and tumor tissues and as genes associated with HCC prognosis. Then, seven AGs (POLA1, CDK1, SOCS2, HDAC1, MAPT, RAE1, and EEF1E1) were identified using the LASSO regression analysis. The seven AGs were used to develop a risk score in the training set, and the risk was validated to have a significant prognostic value in the ICGC set (p < 0.05). Patients with high risk scores had lower tumor differentiation, higher stage, and worse prognosis (all p < 0.05). Multivariate Cox regression analyses also confirmed that the risk score was an independent prognostic factor for HCC in both the TCGA and ICGC sets (all p < 0.05). Further analysis showed that a high risk score was correlated with the downregulation of metabolism and tumor immunity. Conclusion: The risk score predicts HCC prognosis and could thus be used as a biomarker not only for predicting HCC prognosis but also for deciding on treatment.

Prognostic analysis and beneficiary identification of adjuvant external beam radiotherapy for stage pT4b sigmoid colon cancer.

The clinical efficacy of adjuvant radiotherapy in sigmoid colon cancer remains questioned. To evaluate the clinical efficacy of adjuvant external beam radiotherapy (EBRT) for patients with pathologic stage T4b sigmoid colon cancer. Patients with stage pT4b sigmoid colon cancer receiving adjuvant EBRT or not followed by surgery between 2004 and 2016 were extracted from the Surveillance, Epidemiology, and End Results database. Analysis of overall survival (OS) was performed using Kaplan-Meier curves and prognostic factors were identified using Cox proportional hazards regression models with 95% confidence intervals within the entire cohort. A risk-stratification system was then developed based on the ß regression coefficient. Among 2073 patients, 284 (13.7%) underwent adjuvant EBRT. The median OS in the group receiving adjuvant EBRT was significantly longer than that in the non-radiotherapy group (p < 0.001). Age, serum carcinoembryonic antigen (CEA) level, perineural invasion, lymph node dissection (LND) number, and adjuvant EBRT were independent factors associated with OS. A risk-stratification system was generated, which showed that low-risk patients had a higher 5-year survival rate than high-risk patients (75.6% vs. 42.3%, p < 0.001). Adjuvant EBRT significantly prolonged the 5-year survival rate of high-risk patients (62.6% vs. 38.3%, p = 0.009) but showed no survival benefit among low-risk patients (87.7% vs. 73.2%, p = 0.100). Our risk-stratification model comprising age, serum CEA, perineural invasion, and LND number predicted the outcomes of patients with stage pT4b sigmoid colon cancer based on which subgroup of high-risk patients should receive adjuvant EBRT.

Meta-analysis of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND AND PURPOSE: With the advent of more intensive chemotherapy regimens, neoadjuvant chemoradiotherapy (NACRT) for patients with locally advanced rectal cancer (LARC) has always been questioned due to its inevitable radiation toxicity. Hence, we conducted a meta-analysis to compare the clinical efficacy of neoadjuvant chemotherapy (NAC) and NACRT. MATERIALS AND METHODS: Eligible studies were searched using PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science up to 31 July 2020, comparing the clinical efficacy of NAC versus NACRT for LARC. Short- and long-term outcomes were determined using the odds ratio (OR) with 95% confidence interval (CI). RESULTS: Six studies with 12,812 patients were eligible for this meta-analysis, including 677 patients in the NAC group and 12,135 patients in the NACRT group. There were no significant differences between the two groups in terms of pathological complete response rate (OR=0.62, 95%CI=0.27~1.41), N down-staging rate (OR=1.20, 95%CI=0.25~5.79), R0 resection rate (OR=1.24, 95%CI=0.78~1.98), and local relapse rate (OR=1.12, 95%CI=0.58~2.14). The pooled OR for the total response rate and T down-staging were in favor of NACRT (OR=0.41, 95%CI=0.22~0.76 versus OR=0.67 95%CI=0.52~0.87). However, the pooled OR for the sphincter preservation rate favored NAC compared with NACRT (OR=1.87, 95%CI=1.24~2.81). Moreover, NAC was found to be superior to NACRT in terms of distant metastasis (14.3% vs. 20.4%), but the difference was not significant (OR=0.84, 95%CI=0.31~2.27). CONCLUSION: We concluded that NAC was superior to NACRT in terms of the sphincter preservation rate, and non-inferior to NACRT in terms of pCR, N down-staging, R0 resection, local relapse, and distant metastasis. However, the conclusion warrants further validation.