Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells.

BACKGROUND: Immune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting. METHODS: We utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release. RESULTS: In ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models. CONCLUSIONS: APG-1387 has the potential to turn "cold tumors" into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).

Endostar acts as a pneumonitis protectant in patients with locally advanced non-small cell lung cancer receiving concurrent chemoradiotherapy.

BACKGROUND: CCRT is presently the standard treatment for LA-NSCLC. RP is one of the main obstacles to the completion of thoracic radiation therapy, resulting in limited survival benefits in NSCLC patients. This research aims to explore the role of Endostar in the occurrence of grade≥2 RP and clinical curative effect in LA-NSCLC patients. METHODS: This study retrospectively analyzed 122 patients with stage III NSCLC who received CCRT from December 2008 to December 2017, or Endostar intravenous drip concurrently with chemoradiotherapy (Endostar + CCRT group). Standard toxicity of the pneumonitis endpoint was also collected by CTCAE V5.0. We further summarized other available studies on the role of Endostar in the prognosis of NSCLC patients and the incidence of RP. RESULTS: There were 76 cases in the CCRT group and 46 cases in the CCRT+ Endostar group. In the CCRT+ Endostar group, the occurrence of grade ≥2 RP in patients with V20Gy ≥25% was significantly higher than that in patients with V20Gy < 25% (p = 0.001). In the cohorts with V20Gy < 25%, 0 cases of 29 patients treated with Endostar developed grade ≥2 RP was lower than in the CCRT group (p = 0.026). The re-analysis of data from other available studies indicated that Endostar plus CCRT could be more efficient and safely in the occurrence of grade≥2 RP with LA-NSCLC. CONCLUSIONS: When receiving CCRT for LA-NSCLC patients, simultaneous combination of Endostar is recommended to enhance clinical benefit and reduce pulmonary toxicity.

The critical components for effective adaptive radiotherapy in patients with unresectable non-small-cell lung cancer: who, when and how.

Adaptive radiotherapy (ART) is a new radiotherapy technology based on image-guided radiation therapy technology, used to avoid radiation overexposure to residual tumors and the surrounding normal tissues. Tumors undergoing the same radiation doses and modes can occur unequal shrinkage due to the variation of response times to radiation doses in different patients. To perform ART effectively, eligible patients with a high probability of benefits from ART need to be identified. Confirming the precise timetable for ART in every patient is another urgent problem to be resolved. Moreover, the outcomes of ART are different depending on the various image guidance used. This review discusses 'who, when and how' as the three key factors involved in the most effective implementation for the management of ART.

Adaptive radiotherapy (ART) is an image-guided radiotherapy technology used to treat tumors. This article explores who can gain more benefits from ART, when is the optimal time to conduct ART and how to better implement ART. Non-small-cell lung cancer patients with large tumor lesions and high radiosensitivity are the most suitable people for ART. The period of 30­50 Gy and 15­25 fractions of radiotherapy may be the most appropriate time for ART. All imaging guidances have their advantages and disadvantages. Although ART has more benefits, ART is not universally used in the clinic because of the associated labor, economic burden and need for equipment updating. This paper helps guide and popularize the application of the ART strategy in the clinic within economic benefits and feasibility.

Comparison of Immune Microenvironment Between Colon and Liver Metastatic Tissue in Colon Cancer Patients with Liver Metastasis.

BACKGROUND: Liver metastasis is an indicator of unfavorable responses to immunotherapy in colorectal cancer patients. However, the difference of immune microenvironment between primary tumors and liver metastases has not been well understood. PATIENTS AND METHODS: Fifty-four colon cancer with liver metastasis patients who received resection of both primary and metastasis lesions have been analyzed. The immune score is based on the density of infiltrating immune cells (CD3+ cell, CD8+ cell, CD11b+ cell, CD11c+ cell, and CD33+ cell) in the center and margin of the tumor. The expression of immune markers between the primary tumor and hepatic metastases was analyzed using Wilcoxon's signed rank test. RESULTS: All the five markers had higher expression in tumor margins than center tumor in both primary tumor and hepatic metastases lesions. The expression of CD11c and CD11b had no difference between metastatic lesions and primary tumor. In tumor margins, except CD11b, all the other 4 markers expressed significantly higher in hepatic metastases than in primary tumor. Intra-tumor, CD3 had higher expression in primary tumor than in hepatic metastases, while CD33 had higher expression in hepatic metastases than in primary tumor. CD8+ CD3+ cells of the total CD8+ cell population in primary tumor was significantly higher than in hepatic metastases (36.42% vs. 24.88%, p = 0.0069). CONCLUSIONS: The immune microenvironment between primary tumor and hepatic metastasis is different. More immunosuppressing cells in liver may partially explain why immunotherapy in colon cancer is less effective with liver metastatic disease.

Increased CDKL3 expression predicts poor prognosis and enhances malignant phenotypes in esophageal squamous cell carcinoma.

BACKGROUND: Cyclin-dependent kinase-like 3 (CDKL3) is a putative protein serine kinase and plays an important role in the regulation of cell growth and/or differentiation. However, studies on the function of CDKL3 in esophageal squamous cell carcinoma (ESCC) is limited. In our study, we explored the role and prognosis of CDKL3 in ESCC and underlying mechanism. MATERIALS AND METHODS: The expression of CDKL3 was investigated by quantitative reverse transcription polymerase chain reaction and immunohistochemical staining. CDKL3 expression was downregulated by the RNAi-mediated knockdown. The functions of CDKL3 on cell growth were assessed by Celigo image cytometry, MTT assay, cell-cycle analysis, Annexin V assay, and caspase-3/7 activity analysis. The effect of CDKL3 on cellular invasive was investigated by the Transwell assay. Pathscan Stress Signaling Antibody Array was used to study the underlying mechanism. Additionally, the association between the survival and CDKL3 expression in ESCC were evaluated based on the TCGA data. RESULTS: CDKL3 was highly expressed in ESCC tissues and cell lines. TE-1 cells transfected with CDKL3-shRNA-lentivirus significantly decreased CDKL3 expression and resulted in inhibiting cell proliferation, inducing the S-phase cell-cycle arrest, attenuating cellular invasive and increasing cell apoptosis. The expression of pERK1/2, p-Akt, p-Smad2, p-p38 mitogen-activated protein kinase, cleaved caspase-7, and phospho-Chk1 were significantly decreased by CDKL3 knockdown. In addition, high expression of CDKL3 was associated with shorter overall survival. CONCLUSION: Our findings suggest that higher expression of CDKL3 is correlated with poor prognosis in patients with ESCC and play a vital role in the malignant phenotype of ESCC cell lines, which indicating that CDKL3 may be as a new therapeutic target in ESCC.

Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma.

BACKGROUND: Nuclear factor E2-related factor 2 (Nrf2 or NFE2L2) is abundantly expressed in cancer cells and relates to proliferation, invasion, and chemoresistance. Our early observations also found that expression of Nrf2 was up-regulated in kinds of cancer including human hepatocellular carcinoma (HCC) cells. But there are limited reports about the expression, significance, function of Nrf2 in HCC. METHODS: First, Nrf2 expression was analyzed in HCC cell lines and tumor samples. Then, the relationship of Nrf2 with clinicopathological factors and survival were analyzed. Further, the effect of Nrf2 on cell proliferation, apoptosis, and metastasis was examined in vitro by modulating expression of Nrf2 through specific shRNA or expression plasmid. Last, the potential mechanisms were also investigated. RESULTS: Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Univariate and multivariate analyses indicated that high Nrf2 expression might be a poor prognostic factor. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. Moreover, there are positive correlation between Nrf2 expression and that of Bcl-xL and MMP-9. CONCLUSION: Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma partly through regulating expression of Bcl-xL and MMP-9.

Cardiac substructures dosimetric predicts cardiac toxicity and prognosis in esophageal squamous cell cancer treated by radiotherapy.

PURPOSE: To look into the relationship between cardiac substructures (CS) dosimetric parameters and cardiac events (CE) or overall survival (OS) in patients undergoing radiation therapy (RT) for esophageal squamous cell carcinoma (ESCC). METHODS AND MATERIALS: A retrospective study included 350 patients with ESCC receiving definitive chemoradiotherapy or radiotherapy (d-CRT/d-RT) or neoadjuvant chemoradiotherapy (NCRT) from March 2013 to May 2022. Our study examined the adverse cardiac events of any grade or G3+, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Competing risk analysis and Cox regression analysis were used to assess the relationship between CS doses and CEs or OS. RESULTS: 201 (57.4 %) patients received any grade CEs over a median follow-up time of 22.50 months (IQR, 12.40-45.60), and 24 (6.86 %) patients suffered G3+ CEs. On landmark analysis, patients with any grade CEs had significantly lower OS (P = 0.003). Multivariable analysis revealed that any grade CEs were predicted by the dose of CSs in all populations. In addition, for G3+ cardiac events, arrhythmic and small probability of cardiac events, LAD V20 ((HR: 1.02, 95 % CI: 1.00-1.03, P = 0.012; HR: 1.01, 95 % CI: 1.00-1.02, P = 0.005; HR; 1.01, 95 % CI: 1.00-1.02, P = 0.012) was also an independent predictive factor. LAD V50 (HR: 1.07, 95 % CI: 1.03-1.10, P <0.001) predicted pericardium effusion events. Moreover, the multivariable analysis revealed that OS was predicted by LAD V30 (HR: 1.03; 95 % CI, 1.01-1.05, P = 0.015). CONCLUSIONS: In the population of ESCC patients receiving RT, we showed that the CS factors had a substantial predictive value for the various types and grades of CEs. The elevated radiation dose of LAD was a significant contributor to a higher rate of cardiac events and a worse prognosis.

CDKL3 shapes immunosuppressive tumor microenvironment and initiates autophagy in esophageal cancer.

Background: CDKL3 has been associated with the prognosis of several tumors. However, the potential role of CDKL3 in immunotherapy and the tumor microenvironment (TME) in esophageal carcinoma (ESCA) remains unclear. Methods: In this study, Cox regression analysis was used to assess the predictive value of CDKL3 for ESCA outcomes. We systematically correlated CDKL3 with immunological features in the TME. The role of CDKL3 in predicting the efficacy of immunotherapy was also analyzed. Correlation analysis, Cox analysis and LASSO Cox regression were used to construct the CDKL3-related autophagy (CrA) risk score model. The relationship between CDKL3 expression and postoperative pathological complete response (pCR) rate in esophageal squamous cell carcinoma (ESCC) patients undergoing neoadjuvant chemoradiotherapy (nCRT) was evaluated using Immunohistochemical staining (IHC). The relationship between CDKL3 expression and autophagy induction was confirmed by immunofluorescence staining and western blot, and the effect of CDKL3 expression on macrophage polarization was verified by flow cytometry. Results: High expression of CDKL3 was found in ESCA and was associated with poor prognosis in ESCA. Moreover, CDKL3 expression was negatively correlated with tumor-infiltrating immune cells (TIICs), the integrality of the cancer immunity cycles, and anti-tumor signatures, while CDKL3 expression was positively correlated with suppressive TME-related chemokines and receptors, immune hyperprogressive genes, and suppressive immune checkpoint, resulting in immunosuppressive TME formation in ESCA. An analysis of immunotherapy cohorts of the ESCA and pan-cancer showed a better response to immunotherapy in tumor patients with lower CDKL3 levels. The CrA risk score model was constructed and validated to accurately predict the prognosis of ESCA. Notably, the CrA risk score of ESCA patients was significantly positively correlated with M2 macrophages. Furthermore, knockdown CDKL3 in KYSE150 cells could inhibit autophagy induction and M2 macrophage polarization. And, radiation could downregulate CDKL3 expression and autophagy induction, while ESCC patients with high CDKL3 expression had a significantly lower response rate after nCRT than those with low CDKL3 expression. Conclusion: CDKL3 may play an important role in anti-tumor immunity by regulating autophagy to promote the formation of immunosuppressive TME, thus playing a critical role in the prognosis of ESCA.

CT-based different regions of interest radiomics analysis for acute radiation pneumonitis in patients with locally advanced NSCLC after chemoradiotherapy.

Purpose: To establish a radiomics model using radiomics features from different region of interests (ROI) based on dosimetry-related regions in enhanced computed tomography (CT) simulated images to predict radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC). Methods: Our retrospective study was conducted based on a cohort of 236 NSCLC patients (59 of them with RP≥2) who were treated in 2 institutions and divided into the primary cohort (n = 182,46 of them with RP≥2) and external validation cohort (n = 54,13 of them with RP≥2). Radiomic features extracted from three ROIs were defined as the whole lung (WL), the dose volume histogram (DVH) of the lung V20 (V20_Lung) and the DVH of the V30 of lung minus the planning target volume (PTV) (V30 Lung-PTV). A total of 107 radiomics features were extracted from each ROIs. The U test, correlation coefficient and least absolute shrinkage and selection operator (LASSO) were performed for features selection. Six models based on different classification algorithms were developed to select the best radiomics model (R model).In addition, we built a dosimetry model then combined it with the best R model to create a mixed model (R+D model) The receiver operating characteristic (ROC) curve was delineated to assess the predictive efficacy of the models. Decision curve analysis could benefit from the model proposals through the assessment of clinical utility. Results: Among the three ROIs, the best R model constructed from the LightGBM algorithm demonstrated the strongest discriminative ability in the ROI of V30 Lung-PTV. The corresponding area under the curve (AUC) value was 0.930 (95 % confidence interval (CI): 0.829-0.941). The D model, R model and R+D model achieved AUC values of 0.798 (95 %CI: 0.732-0.865), 0.930 (95 %CI: 0.829-0.941) and 0.940 (95 %CI: 0.906-0.974) in primary cohort, and in external validation cohort, the AUC values were 0.793 (95 %CI:0.637-0.949), 0.887 (95 %CI:0.810-0.993), 0.951 (95CI%:0.891-1.000). Decision curve demonstrate that R+D model could benefit for patients through the assessment of clinical utility. Conclusion: The radiomics model was able to predict the acute RP more effectively in comparison with the traditional dosimetry model. Especially the radiomics model based on the V30 Lung-PTV region was able to achieve a higher accuracy when compared to the other regions.

Current state, challenges, and future perspective of adaptive radiotherapy: A narrative review of nasopharyngeal carcinoma.

Patients with nasopharyngeal carcinoma often experience weight loss and tumor regression during the course of radiotherapy that lasts for up to 6-7 weeks. Adaptive radiotherapy is a systematic feedback control approach based on image-guided technology that adjusts these changes and optimizes the radiotherapy plans according to new imaging findings during treatment. There is growing evidence that adaptive radiotherapy can reduce side effects, improve the quality of life, and enhance disease control. However, the routine application of adaptive radiotherapy for nasopharyngeal remains relatively limited. This review discusses the necessity, clinical benefits, and limitations of adaptive radiotherapy, and presents the current state, challenges, and future perspective of adaptive radiotherapy strategies for nasopharyngeal carcinoma.

The paradoxical role of Nrf2 in tumor biology.

Nrf2 is used as a cell protector by mediating many downstream genes which express phase II detoxifying and antioxidant enzymes. Recently, large numbers of experiments have shown Nrf2 and its downstream genes are found to be overexpressed in many human tumors. Numerous evidences unveil that Nrf2 protects the normal cells while promoting the malignant tumor's progression. The paradoxical role of Nrf2 has not been clearly elucidated before. Here, we review the suppressor or oncogene roles of Nrf2 in different stages of specific tumors with respect to the newest studies. Further, we suspect that the hypoxic microenvironment around the tumors is the main crux which determines the role of Nrf2 in the tumor initiation, invasion, and metastasis. In the initiation of tumors, Nrf2 or Keap1 genes get mutations under the oxidative stress; as a result, the tumor cells obtain the advantage to growth. At the later stages, the hypoxic microenvironment around the malignant tumors has a profound influence on the character of Nrf2. Under the hypoxic microenvironment, expression of certain downstream genes of Nrf2 involved in angiogenesis are obviously elevated; other transcription factors derived from hypoxic microenvironment interact with Nrf2 and in that way promote or inhibit the invasion and metastasis.

Role of cancer-related inflammation in esophageal cancer.

Esophageal cancer (EC) is the ninth most common malignancy with a poor prognosis. It is clear that improvements need to be made to reveal the exact molecular mechanisms of EC. Cancer-related inflammation (CRI) recently has been proposed as a major physiological hallmark of malignancy and has important value in diagnosis, treatment, and prognosis. But the role of CRI in EC has remained unclear. In this review, we focus primarily on the function of key mediators of CRI in EC, including transcription factors, chemokines, cytokines, reactive oxygen species, COX-2, and specific microRNAs. Through a comprehensive analysis, we try to reveal the interaction between CRI and EC, providing novel preventive, diagnostic, and therapeutic strategies to reduce the health burden of EC.

The noncytotoxic dose of sorafenib sensitizes Bel-7402/5-FU cells to 5-FU by down-regulating 5-FU-induced Nrf2 expression.

BACKGROUND: Acquired resistance to 5-fluorouracil (5-FU) is a serious therapeutic obstacle in advanced hepatocellular carcinoma (HCC) patients. AIM: To investigate whether nuclear factor erythroid 2-related factor 2 (Nrf2) was associated with drug resistance in 5-FU resistant Bel-7402 (Bel-7402/5-FU) cells, and if sorafenib, an oral multikinase inhibitor targeting the tumor and vasculature, could reverse drug resistance in Bel-7402/5-FU cells at the noncytotoxic dosage. METHODS: We used MTT to detect the resistance reversal activity of sorafenib, compared Nrf2 expression in various conditions by western blot and qRT-PCR, and analyzed subcellular localization of Nrf2 by immunofluorescence. RESULTS: The endogenous expression of Nrf2 in Bel-7402/5-FU cells was similar to that observed in Bel-7402 cells. However, Nrf2 expression levels were increased by 5-FU treatment in Bel-7402/5-FU cells higher than that in Bel-7402 cells, which is to highlight the Nrf2 contribution to the enhanced resistance of Bel-7402/5-FU cells to 5-FU. Moreover, intracellular Nrf2 protein level was significantly down-regulated by Nrf2-shRNA in Bel-7402/5-FU cells, resulting in partial reversal of 5-FU resistance. Sorafenib down-regulated the increased expression of Nrf2 induced by 5-FU treatment and partly reversed 5-FU resistance in Bel-7402/5-FU cells. CONCLUSIONS: These results suggested that more sensitive cell defense mediated by Nrf2 was associated with drug resistance of Bel-7402/5-FU cells. Sorafenib reversed drug resistance, and its reversal mechanism might be due to the suppression of Nrf2 expression induced by 5-FU, indicating the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs in HCC patients.

Prognostic significance of XIAP and NF-κB expression in esophageal carcinoma with postoperative radiotherapy.

BACKGROUND: X-chromosome-linked IAP (XIAP) and nuclear factor-κB (NF-κB) are frequently overexpressed and correlate closely with chemoradiotherapy resistance and poor prognosis in many cancers. However, the significance of XIAP and NF-κB expression in radiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma (ESCC) are still unknown. The aim of this study was to examine XIAP and NF-κB status in ESCC patients undergoing postoperative radiotherapy after radical surgery, and to evaluate their clinical significance. METHODS: A total of 78 ESCC patients treated with postoperative radiotherapy after radical surgery were enrolled in this study. We immunohistochemically investigated the expression of XIAP and NF-κB in tissues from enrolled patients with specific antibodies. Then, the correlations among XIAP, NF-κB expression, clinicopathological features and its prognostic relevance in ESCC were analyzed. RESULTS: The increased expression of XIAP and NF-κB in ESCC tissues were clearly correlated with the tumor differentiation and p-TNM stage. Significant positive correlations were found between the expression status of XIAP and NF-κB (r = 0.779, P = 0.000). Overexpression of XIAP and NF-κB and metastasis were significantly associated with shorter overall survival times in univariate analysis (P < 0.05). Multivariate analysis also confirmed that XIAP expression was an independent prognostic factor (P = 0.005). CONCLUSIONS: XIAP and NF-κB are intensively expressed in ESCC. The level of XIAP is positively correlated to progression and prognosis of ESCC.

Preventive effect of ulinastatin on postoperative complications, immunosuppression, and recurrence in esophagectomy patients.

BACKGROUND: To evaluate the potential efficacy of preventive effect of ulinastatin in esophagectomy patients. METHODS: Eighty patients with esophageal cancer were preoperatively allocated at random into two equal groups. Ulinastatin was administered to the treatment group (U) whereas the control group (C) received a placebo. The arterial oxygen tension and carbon dioxide tension were measured and the respiratory index (RI) was calculated. Plasma levels of circulating T lymphocyte subsets and interleukin 6 (IL-6) were measured and clinical courses of patients in the two groups were compared. RESULTS: RI in the U group was significantly lower than that in the C group. The rate of postoperative complications and the duration of ICU stay were significantly lower in the U group. Ulinastatin significantly increased the rate of CD3+ and CD4+ cells, and ratio of CD4+/CD8+, but decreased the rate of CD8+ cells and release of IL-6 compared to the C group on postoperative days 1 and 3. Patients within the C group showed worse recurrence free survival. Multivariate analysis revealed that ulinastatin administration significantly decreased the incidence of recurrence. CONCLUSIONS: Ulinastatin had a preventive effect on postoperative complications and immunosuppression in esophagectomy patients, thereby prolongingrecurrence free survival.

Immunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies.

The high primary resistance incidence and unavoidable secondary resistance are the major clinical obstacle to lasting long-term benefits in Non-small-cell lung cancer (NSCLC) patients treated with immunotherapy. The mechanisms of immunotherapy resistance in NSCLC are complex, mainly involving tumor cells and tumor microenvironment (TME) infiltrating immune cells, including TAMs, B cells, NK cells, and T cells. The selection of clinical strategies for NSCLC progression after immunotherapy resistance should depend on the progressive mode. The progression pattern of NSCLC patients after immunotherapy resistance can be divided into oligo-progression and systemic/multiple progression, which should be considered for further treatment selection. In the future, it needs to explore how to optimize the combined therapy and explore strategies to reprogram infiltrating immune cells under various genetic backgrounds of tumor cells and timely reshape TME during antitumor treatments.

CT-based radiomics nomogram may predict who can benefit from adaptive radiotherapy in patients with local advanced-NSCLC patients.

BACKGROUND: Although adaptive radiotherapy (ART) has many advantages, ART is not universal in the clinical appliance due to the consumption of a lot of labor, and economic burden. It is necessary to explore a CT stimulation-based radiomics model for screening who can get more benefits from ART in locally advanced non-small cell lung cancer (NSCLC) patients. METHOD: 183 cases of NSCLC patients receiving concurrent chemoradiotherapy with an adaptive approach were enrolled as a primary cohort, while 28 cases from another hospital served as an independent external validation cohort. Tumor regression assessment was conducted based on GTV reduction (Criteria A) or according to RECIST Version 1.1(Criteria B). The radiomics features were extracted by the "PyRadiomics" package and further screened by the LASSO method. Then, logistic regression was used to establish the model. Bootstrap and external validation were applied to verify the stability of the model. The receiver operating characteristic (ROC) curve was delineated to assess the predictive efficacy of the radiomics model. Dose-volume histograms were quantitatively compared between the initial and composite ART plans. Clinical endpoints included overall survival (OS) and progression-free survival (PFS). RESULT: There were no significant differences in clinical features between tumor regression-resistant (RR) and tumor regression-sensitivity (RS) groups. The AUC values of the Criteria A model and Criteria B model were 0.767 and 0.771, respectively. Bootstrapping validation and external validation confirmed the stability of models. In all patients, there was a significant benefit of ART in the lung, heart, cord, and esophagus compared to non-ART, particularly in RS patients. Furthermore, PFS and OS from ART were significantly longer in RS as defined by Criterion B than in RR patients with the same ART application. CONCLUSION: CT-based radiomics can screen out the patients who can gain more benefits from ART, which contribute to guiding and popularizing the application of ART strategy in the clinic within economic benefits and feasibility.

Cuproptosis and Immune-Related Gene Signature Predicts Immunotherapy Response and Prognosis in Lung Adenocarcinoma.

Cuproptosis and associated immune-related genes (IRG) have been implicated in tumorigenesis and tumor progression. However, their effects on lung adenocarcinoma (LUAD) have not been elucidated. Therefore, we investigated the impact of cuproptosis-associated IRGs on the immunotherapy response and prognosis of LUAD using a bioinformatical approach and in vitro experiments analyzing clinical samples. Using the cuproptosis-associated IRG signature, we classified LUAD into two subtypes, cluster 1 and cluster 2, and identified three key cuproptosis-associated IRGs, NRAS, TRAV38-2DV8, and SORT1. These three genes were employed to establish a risk model and nomogram, and to classify the LUAD cohort into low- and high-risk subgroups. Biofunctional annotation revealed that cluster 2, remarkably downregulating epigenetic, stemness, and proliferation pathways activity, had a higher overall survival (OS) and immunoinfiltration abundance compared to cluster 1. Real-time quantitative PCR (RT-qPCR) validated the differential expression of these three genes in both subgroups. scRNA-seq demonstrated elevated expression of NRAS and SORT1 in macrophages. Immunity and oncogenic and stromal activation pathways were dramatically enriched in the low-risk subgroup, and patients in this subgroup responded better to immunotherapy. Our data suggest that the cuproptosis-associated IRG signature can be used to effectively predict the immunotherapy response and prognosis in LUAD. Our work provides enlightenment for immunotherapy response assessment, prognosis prediction, and the development of potential prognostic biomarkers for LUAD patients.

The effects of nrf2 on tumor angiogenesis: a review of the possible mechanisms of action.

To date, preclinical and clinical data have shown that various cancer patients benefit from antiangiogenic therapy because of the important role of angiogenesis in the tumor development process. NF-E2-related factor 2 (Nrf2) is recognized as a key transcription factor of genes coding for various antioxidant and cytoprotective enzymes, and Nrf2 plays important roles during tumor progression. Recent studies have begun to explore the role of Nrf2 in tumor angiogenesis, which may be to promote the advancement of tumor antiangiogenic therapy. This article reviews the Nrf2-related pathways involved in tumor angiogenesis and summarizes the possible mechanisms of Nrf2 action as a pro-angiogenic factor in tumor progression.