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.

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.

Predicting the Efficacy of SBRT for Lung Cancer with 18F-FDG PET/CT Radiogenomics.

PURPOSE: to develop a radiogenomic model on the basis of 18F-FDG PET/CT radiomics and clinical-parameter EGFR for predicting PFS stratification in lung-cancer patients after SBRT treatment. METHODS: A total of 123 patients with lung cancer who had undergone 18F-FDG PET/CT examination before SBRT from September 2014 to December 2021 were retrospectively analyzed. All patients' PET/CT images were manually segmented, and the radiomic features were extracted. LASSO regression was used to select radiomic features. Logistic regression analysis was used to screen clinical features to establish the clinical EGFR model, and a radiogenomic model was constructed by combining radiomics and clinical EGFR. We used the receiver operating characteristic curve and calibration curve to assess the efficacy of the models. The decision curve and influence curve analysis were used to evaluate the clinical value of the models. The bootstrap method was used to validate the radiogenomic model, and the mean AUC was calculated to assess the model. RESULTS: A total of 2042 radiomics features were extracted. Five radiomic features were related to the PFS stratification of lung-cancer patients with SBRT. T-stage and overall stages (TNM) were independent factors for predicting PFS stratification. AUCs under the ROC curve of the radiomics, clinical EGFR, and radiogenomic models were 0.84, 0.67, and 0.86, respectively. The calibration curve shows that the predicted value of the radiogenomic model was in good agreement with the actual value. The decision and influence curve showed that the model had high clinical application values. After Bootstrap validation, the mean AUC of the radiogenomic model was 0.850(95%CI 0.849-0.851). CONCLUSIONS: The radiogenomic model based on 18F-FDG PET/CT radiomics and clinical EGFR has good application value in predicting the PFS stratification of lung-cancer patients after SBRT treatment.

Failure patterns of locoregional recurrence after reducing target volumes in patients with nasopharyngeal carcinoma receiving adaptive replanning during intensity-modulated radiotherapy: a single-center experience in China.

BACKGROUND: Previous researches have demonstrated that adaptive replanning during intensity-modulated radiation therapy (IMRT) could enhance the prognosis of patients with nasopharyngeal carcinoma (NPC). However, the delineation of replanning target volumes remains unclear. This study aimed to evaluate the feasibility of reducing target volumes through adaptive replanning during IMRT by analyzing long-term survival outcomes and failure patterns of locoregional recurrence in NPC. METHODS: This study enrolled consecutive NPC patients who received IMRT at our hospital between August 2011 and April 2018. Patients with initially diagnosed, histologically verified, non-metastatic nasopharyngeal cancer were eligible for participation in this study. The location and extent of locoregional recurrences were transferred to pretreatment planning computed tomography for dosimetry analysis. RESULTS: Among 274 patients, 100 (36.5%) received IMRT without replanning and 174 (63.5%) received IMRT with replanning. Five-year rates of locoregional recurrence-free survival (LRFS) were 90.1% (95%CI, 84.8% to 95.4%) and 80.8% (95%CI, 72.0% to 89.6%) for patients with and without replanning, P = 0.045. There were 17 locoregional recurrences in 15 patients among patients with replanning, of which 1 (5.9%) was out-field and 16 (94.1%) were in-field. Among patients without replanning, 19 patients developed locoregional recurrences, of which 1 (5.3%) was out-field, 2 (10.5%) were marginal, and 16 (84.2%) were in-field. CONCLUSIONS: In-field failure inside the high dose area was the most common locoregional recurrent pattern for non-metastatic NPC. Adapting the target volumes and modifying the radiation dose prescribed to the area of tumor reduction during IMRT was feasible and would not cause additional recurrence in the shrunken area.

The prognostic value of circulating lymphocyte counts and ABO blood group in lung cancer stereotactic body radiation therapy: a retrospective study.

Background: Clinically, there is a lack of simple and feasible indicators to predict the efficacy of stereotactic body radiation therapy (SBRT). Circulating lymphocyte counts (CLCs) is considered to be related to curative effect in conventional radiotherapy of lung cancer, and blood groups are also associated with the survival. In this study, we investigate the prognostic value of CLCs and ABO blood groups in lung cancer patients treated with SBRT. Methods: We retrospectively analyzed 191 patients who were treated with lung cancer SBRT in Taizhou Hospital of Zhejiang Province from September 2014 to December 2018. The medical record system of Taizhou Hospital was used to collect relevant clinical data, such as stage, CLC, ABO blood groups and other important clinical co-variates. The effects of SBRT were evaluated by patient reexamination image data and telephone follow-up. The RECIST 1.1 standard was used to evaluate the short-term efficacy in the first, third, and sixth months after SBRT. Progression-free survival (PFS) was defined as the time from the day of SBRT to disease progression or death from any cause. Overall survival (OS) was measured from the day of SBRT until the last follow-up or death. Survival curves and univariate, multivariate logistic-regression analyses were used to expound the prognostic factors for local control (LC), PFS, and OS of lung cancer SBRT patients. Results: Univariate and multivariate analysis results showed that post-SBRT CLCs were independent factors for the short-term efficacy 3 and 6 months after lung cancer SBRT [hazard ratio (HR) =0.249, P=0.037; HR =0.347, P=0.012]. Survival analyses showed that the PFS and OS of lung cancer SBRT patients with A blood type was significantly shorter than that in the other three non-A blood groups (PFS: 6.5 vs. 10 months, HR =1.535, P=0.020; OS: 24 vs. 41 months, HR =1.578, P=0.048). Moreover, the patients with high post-SBRT CLCs in the non-A blood group had the longest PFS and OS after lung cancer SBRT (HR =0.551, P=0.043). Conclusions: Lung cancer SBRT patients with high-post-SBRT CLCs and non-A blood groups seem to exhibits best curative effect, which represent a potential opportunity to improve the clinical management of these patients. The mechanisms of this association deserve further verification and investigation.

Long-term outcomes of replanning during intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma: An updated and expanded retrospective analysis.

BACKGROUND AND PURPOSE: Recent studies show that adaptive replanning for patients with nasopharyngeal carcinoma (NPC) during intensity-modulated radiation therapy (IMRT) improve the short-term local-regional recurrence-free survival (LRFS), and quality of life (QoL). We aimed to assess the long-term survival outcomes and QoL in patients with non-metastatic NPC who received IMRT with replanning compared to those who received IMRT without replanning. METHODS AND MATERIALS: We conducted an updated and expanded retrospective analysis from an existing prospective cohort for non-metastatic NPC patients undergoing IMRT in our institution. Non-metastatic NPC patients receiving IMRT from June 2007 to December 2015 were consecutively enrolled based on electronic medical record. Patients who were still alive were eligible for the QoL study. The survival outcomes and QoL were compared between patients with and without replanning. RESULTS: Among 290 patients, 147 (50.7%) received IMRT without replanning and 143 (49.3%) received IMRT with replanning. Replanning group had a higher 8-year LRFS rate (87.4% vs. 75.6%, P = 0.025). However, 8-year overall survival rate was not statistically significant. Patients with replanning compared to those who without replanning had significant improvements in social functioning (P = 0.016), insomnia (P = 0.048), dry mouth (P = 0.004), and sticky saliva (P = 0.005). Additionally, the score of the role functioning was marginally higher in patients treated with IMRT replanning (P = 0.063). CONCLUSION: This extended follow-up study demonstrates the long-term security and validity for adaptive radiotherapy in IMRT for non-metastatic NPC patients. We highly recommend that adaptive replanning should be routinely implemented for non-metastatic NPC patients.

Radiotherapy improves the outcomes of immunotherapy with Sintilimab in non-small-cell lung cancer: A real-world analysis.

Introduction: Radiotherapy may augment systemic antitumor responses to immunotherapy. We did a retrospective study to infer whether radiotherapy improves outcomes to immunotherapy in patients with stage III and IV non-small-cell lung cancer (NSCLC). Methods: This retrospective study conducted at Enze Medical Center enrolled 259 patients with histopathology confirmed NSCLC from December 2018 to December 31, 2021. All were treated with Sintilimab, some patients received radiotherapy at an appropriate time point. Radiation type includes conventional radiotherapy and stereotactic body radiotherapy. The progression-free survival (PFS), and overall survival (OS) were the primary endpoint. Results: A retrospective analysis was performed on 259 patients, of whom 140 had been treated with immunotherapy lonely and 119 had been remedied with immunotherapy plus radiotherapy. Baseline variables were well balanced between the two groups, including gender, age, smoking status, TNM staging, number of metastases, ECOG score, pathological type and lines of previous systemic therapy. The median PFS in the immunotherapy alone group was 5.00 months (95%CI 4.38-5.62) versus immunotherapy plus radiotherapy was 9.00 months (5.95-12.05; p<0.001). The median OS in the immunotherapy alone group was 16.00 months (12.59-19.42) versus immunotherapy plus radiotherapy was 30.00 months (20.75-39.25; p=0.027). PFS was finer in the radiotherapy plus immunotherapy group than the immunotherapy group alone in both stage III(P=0.0069) and Stage IV(P=0.006) patients. In the univariate analysis, radiotherapy, male, ECOG=0 and <2 lines of previous systemic therapy were connected with an observably better PFS (P<0.001; P=0.03; P=0.002;P=0.021). In a multivariate analysis, radiotherapy, ECOG=0 and <2 lines of previous systemic therapy were independent prognostic factors with a markedly better PFS (P<0.001; P=0.006;P=0.009). An univariate analysis, radiotherapy, male, stage III, non-metastasis, ECOG=0 and squamous carcinoma were associated with a significantly better OS (P=0.032, P=0.036,P=0.002,P<0.001,P=0.002,P=0.025). A multivariate analysis, non-metastasis was a standalone prognostic indicator with a significantly better OS (P=0.006). However, radiotherapy was a tendency indicator with a better OS (HR0.70 95% CI 0.47-1.06). There were also no obvious increases in adverse events in the combination group. Conclusions: Radiotherapy with addition of immunotherapy was observably linked to a better outcome in patients with III and IV staging NSCLC.

Reduced PHLPP Expression Leads to EGFR-TKI Resistance in Lung Cancer by Activating PI3K-AKT and MAPK-ERK Dual Signaling.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in advanced EGFR-mutation non-small cell lung cancer (NSCLC) but the magnitude of tumor regression varies, and drug resistance is unavoidable. The pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) levels are reduced or lost and acts as a tumor suppressor in many cancers. Here, we hypothesized that PHLPP is a key regulator of EGFR-TKI sensitivity and a potential treatment target for overcoming resistance to EGFR-TKI in lung cancer. METHODS: Cell proliferation and growth inhibition were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assay. PHLPP- knockdown stable cell lines were generated by lentivirus-mediated delivery of PHLPP shRNAs. The expression of PHLPP mRNA and protein levels was detected by real-time quantitative polymerase chain reaction (qPCR) and Western blotting. Immunohistochemical (IHC) staining was performed to detect the PHLPP expression in clinical patient tissue samples. A transcriptomic assay of genome-wide RNA expressions of PHLPP in NSCLC cell lines according to gefitinib sensitivity was obtained from Gene Expression Omnibus (GEO) database. Murine xenograft model was established to verify the function of PHLPP in gefitinib resistance in vivo. RESULTS: PHLPP highly expressed in gefitinib-sensitive NSCLC cell lines than gefitinib-resistant NSCLC cell lines. In gefitinib-acquired resistance cell line HCC827-GR, PHLPP expression even dramatically reduced. Knockdown of PHLPP in NSCLC cells decreased cell death induced by the EGFR-TKI, while overexpression PHLPP in gefitinib-resistance NSCLC cells can enhance or restore EGFR-TKIs sensitivity. Mechanism study indicated that PHLPP downregulation attenuates the effect of EGFR-TKI on the both AKT and ERK pathway, thereby decreasing the cell death sensitivity to EGFR inhibitors. In xenograft mice, knockdown of PHLPP decreased tumor response to gefitinib and advanced tumor cells re-growth after gefitinib treatment. In clinical, PHLPP expression were reduced in the post-relapse tumor compared to that of pre-treatment, and lower pre-treatment PHLPP levels were significantly correlated with shorter progression-free survival (PFS) in patients with EGFR-mutant lung adenocarcinoma whom treated with EGFR-TKI. CONCLUSIONS: Our data strongly demonstrated that loss of PHLPP function was a key factor of EGFR-TKI resistance in NSCLC. Downregulated PHLPP expression activated PI3K-AKT and MAPK-ERK pathway which strengthened cell survival to EGFR-TKI. Therefore, PHLPP expression level was not only a potential biomarker to predict EGFR-TKIs sensitivity but also as a therapeutic target in EGFR-TKIs therapy, enhancing PHLPP expression may be a valuable strategy for delaying or overcoming EGFR-TKIs drug resistance.

GBP1 Facilitates Indoleamine 2,3-Dioxygenase Extracellular Secretion to Promote the Malignant Progression of Lung Cancer.

IDO1-mediated immune escape can lead to the malignant progression of tumors. However, the precise mechanism of IDO1 remains unclear. This study showed that IDO1 can bind to GBP1 and increase the extracellular secretion of IDO1 with the assistance of GBP1, thereby promoting the malignant proliferation and metastasis of lung cancer. In vitro study showed that the high expression levels of IDO1 and GBP1 in lung cancer cells promoted cell invasion and migration. In vivo study revealed that knock-down of IDO1 and GBP1 inhibited tumor growth and metastasis. In addition, Astragaloside IV reduces the extracellular secretion of IDO1 by blocking the interaction of IDO1 and GBP1, thereby reducing T cell exhaustion and inhibiting tumor progression. These results suggest that blocking the extracellular secretion of IDO1 may prevent T cell exhaustion and thereby enhance the effect of PD-1 inhibitors on cancer treatment.