Phase II multicenter trial: first-line immunochemotherapy with or without radiotherapy in metastatic esophageal squamous cell cancer (SCR-ESCC-01).

This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24 months. In arm A, LDRT (2 Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50 Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).

Dose-escalation by hypofractionated simultaneous integrated boost IMRT in unresectable stage III non-small-cell lung cancer.

BACKGROUND: To explore the maximum tolerated dose (MTD) and evaluate the safety of dose escalation using hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) concurrent with chemotherapy for unresectable stage III non-small cell lung cancer (NSCLC). METHODS: Four escalating radiation dose levels were used. This study included 25 patients with previously untreated NSCLC who received six concurrent weekly chemotherapy cycles comprising cisplatin and docetaxel. Dose-limiting toxicity (DLT) was defined as any acute toxicity that interrupted radiotherapy for more than 1 week. MTD was defined as the highest dose level that didn't induce DLT or grade 5 toxicity in two patients. RESULTS: All 25 patients received the prescribed escalating radiation dose from the start dose up to LEVEL 4. Two patients experienced DLT at dose LEVEL 4. One patient died because of upper gastrointestinal hemorrhage within 6 months after radiotherapy, whereas another patient among the additional five patients died because of grade 5 radiation pneumonitis within 2 months after radiotherapy. Dose LEVEL 3 was defined as MTD. The 1- and 2-year local controls were 82.8 and 67.8%, respectively. The median progression-free survival was 15.4 months, whereas the median overall survival was 27.3 months. CONCLUSIONS: Dose escalation was safely achieved up to LEVEL 3 [the planning gross target volume (PTVG) 60.5 Gy/22 Fx, 2.75 Gy/Fx; the planning clinical target volume (PTVC) 49.5 Gy/22 Fx] using SIB-IMRT concurrently with chemotherapy for unresectable stage III NSCLC, and the acute toxicities were generally well tolerated. Further prospective studies on long-term outcomes and late toxicities are warranted. TRIAL REGISTRATION: Retrospective registration, ChiCTR1900027290 (08/11/2019).

Analyzing the Effect of Vitronectin on Cell Growth and Mesenchymal-Epithelial Transition of Pulmonary Fibroblast Cells.

PURPOSE: Vitronectin (VTN), a multifunctional glycoprotein, is involved in various biological and pathological processes. The purpose of this study was to explore the effect of VTN on mesenchymal-epithelial transition (MET) of pulmonary fibroblast cells. METHODS: Lentivirus encoding for VTN-specific shRNA was constructed and infected into the cultured fibroblast WI-38 cells. Real-time PCR and Western blot were applied to examine the expression of VTN in WI-38 cells. MTT assay was used to assess cell proliferation. Western blot was conducted to examine the expression of MET-related and apoptosis-related proteins. RESULTS: The knockdown of VTN significantly inhibited the growth of WI-38 cells compared to the control group. Meanwhile, knockdown of VTN remarkably increased the expression of Bax and Caspase 3 compared with the control group. Furthermore, knockdown of VTN significantly promoted the expression of E-cadherin in comparison to control group. CONCLUSIONS: Knockdown of VTN promoted the expression of apoptosis-related factors, meanwhile, facilitated the MET process of fibroblast cells by regulating the expression of relevant factors. In sum, VTN performed a potential regulator in cell growth and MET of pulmonary fibroblast cells, which can be considered as a potential target for diagnose and therapy of relevant diseases.

Identifying EGFR mutations in lung adenocarcinoma by noninvasive imaging using radiomics features and random forest modeling.

OBJECTIVES: The tyrosine kinase inhibitor (TKI)-sensitive mutations of the epidermal growth factor receptor (EGFR) gene is essential in the treatment of lung adenocarcinoma. To overcome the difficulty of EGFR gene test in situations where surgery and biopsy samples are too risky to obtain, we tried a noninvasive imaging method using radiomics features and random forest models. METHODS: Five hundred three lung adenocarcinoma patients who received surgery-based treatment were included in this study. The diagnosis and EGFR gene test were based on resections. TKI-sensitive mutations were found in 60.8% of the patients. CT scans before any invasive operation were gathered and analyzed to extract quantitative radiomics features and build random forest classifiers to identify EGFR mutants from wild types. Clinical features (sex and smoking history) were added to the image-based model. The model was trained on a set of 345 patients and validated on an independent test group (n = 158) using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. RESULTS: The performance of the random forest model with 94 radiomics features reached an AUC of 0.802. Its AUC was further improved to 0.828 by adding sex and smoking history. The sensitivity and specificity are 60.6% and 85.1% at the best diagnostic decision point. CONCLUSION: Our results showed that radiomics could not only reflect the genetic differences among tumors but also have diagnostic value and the potential to be a diagnostic tool. KEY POINTS: • Radiomics provides a potential noninvasive method for the prediction of EGFR mutation status. • In situations where surgeries and biopsy are not available, CT image-based radiomics models could help to make treatment decisions. • The accuracy, sensitivity, and specificity still need to be improved before the image-based EGFR identifier could be used in clinics.

Postoperative Radiotherapy for Resected Stage IIIA-N2 Non-small-cell Lung Cancer: A Population-Based Time-Trend Study.

INTRODUCTION: The value of postoperative radiotherapy (PORT) for resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial with few studies focusing on whether PORT always plays a part in clinical practice and generates benefits to patients across different time periods. We investigated this issue using the Surveillance, Epidemiology, and End Results Database (SEER) and assessed the temporal trends spanning 27 years. METHODS: Within SEER, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumonectomy and coded as receiving PORT or never receiving radiotherapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival analyses were performed and propensity score matching (PSM) was used in the potentially beneficial subgroup. RESULTS: 45.4% of 5568 eligible patients received PORT. The yearly PORT use rates varied largely from 27.8% to 74.4%. Overall survival (OS) was distinctly improved over the period. The application of PORT had a significant impact on survival only in period 1 and 3. In subgroup analysis, the OS benefit of PORT was significant in each period in patients with 50% or more lymph node ratio (LNR) both before (hazard ratios, and P values of 0.647, P = .002; 0.804, P = .008; 0.721, P < .001 for period 1, 2, 3, respectively) and after PSM (0.642, P = .006; 0.785, P = .004; 0.748, P = .003 for period 1, 2, 3, respectively). CONCLUSIONS: The benefits of PORT are lasting and stable throughout the years in patients with LNR of 50% or more. This might provide a clue on proper patient selection for PORT application.

The positive role of vitronectin in radiation induced lung toxicity: the in vitro and in vivo mechanism study.

BACKGROUND: Radiation-induced lung toxicity (RILT) is a severe complication of radiotherapy in patients with thoracic tumors. Through proteomics, we have previously identified vitronectin (VTN) as a potential biomarker for patients with lung toxicity of grade ≥ 2 radiation. Herein, we explored the molecular mechanism of VTN in the process of RILT. METHODS: In this study, lentivirus encoding for VTN and VTN-specific siRNA were constructed and transfected into the cultured fibroblasts and C57BL mice. Real-time PCR, western blot and ELISA were used to examine expression of collagens and several potential proteins involved in lung fibrosis. Hematoxylin-eosin and immunohistochemical staining were used to assess the fibrosis scores of lung tissue from mice received irradiation. RESULTS: The expression of VTN was up-regulated by irradiation. The change trend of collagens, TGF-ß expression and p-ERK, p-AKT, and p-JNK expression levels were positively related with VTN mRNA level. Furthermore, overexpression of VTN significantly increased the expression level of α-SMA, as well as the degree of lung fibrosis in mice at 8 and 12 weeks post-irradiation. By contrast, siRNA VTN induced opposite results both in vitro and in vivo. CONCLUSIONS: VTN played a positive role in the lung fibrosis of RILT, possibly through modulation of fibrosis regulatory pathways and up-regulating the expression levels of fibrosis-related genes. Taken together, all the results suggested that VTN had a novel therapeutic potential for the treatment of RILT.

The emerging outcome of postoperative radiotherapy for stage IIIA(N2) non-small cell lung cancer patients: based on the three-dimensional conformal radiotherapy technique and institutional standard clinical target volume.

BACKGROUND: The aim of this study was to evaluate the clinical efficacy of postoperative radiotherapy (PORT), administered using three-dimensional conformal radiotherapy (3D-CRT) and our institutional standard clinical target volume (CTV) delineation, for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC). METHODS: From 2005 to 2012, consecutive patients with pT1-3N2 NSCLC who were treated with PORT employing our institutional CTV delineation after complete surgery or who underwent complete resection in our hospital but without PORT were identified. We excluded patients who had received neoadjuvant chemotherapy or radiation therapy (RT). Kaplan-Meier estimates for locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were performed. In the OS estimation, patients who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) during follow-up were censored at the time of TKI initiation. RESULTS: Data from 70 patients in the PORT group and 287 in the non-PORT group were analysed. All 70 cases received 3D-CRT following our institutional CTV guideline, with a median total dose of 50.4 Gy at 1.8 Gy/fraction. At a median follow-up of 34.3 months for the PORT group and 31.2 months for the non-PORT group, PORT significantly improved local control (5-yr LRFS 91.9% for PORT vs 66.4% for non-PORT, P < 0.001) and OS (5-yr OS 57.5% for PORT vs 35.1% for non-PORT, P = 0.003), whereas no differences in DMFS were noted (P = 0.18). In multivariable analyses, PORT was independently associated with an improved LRFS (HR 0.2, P = 0.001) and OS (HR 0.4, P = 0.001). All patients completed the planned RT dose without interruption of RT due to treatment-related complications. CONCLUSIONS: Our data suggested that PORT administered using the 3D-CRT technique following our institutional CTV delineation guideline resulted in a promising outcome with favourable survival for completely resected IIIA(N2) NSCLC, after controlling for subsequent EGFR-TKI confounding in the OS analysis. Prospective trials are needed to further corroborate these results.

Full-dose pemetrexed plus cisplatin combined with concurrent thoracic radiotherapy for previously untreated advanced nonsquamous non-small cell lung cancer.

Compared with other platinum-based doublet chemotherapy, pemetrexed plus platinum is more effective and tolerable as the first-line treatment for nonsquamous non-small cell lung cancer (NSCLC). Thus, we examined the feasibility of using thoracic radiotherapy combined with concurrent full-dose pemetrexed as the first-line treatment for advanced nonsquamous NSCLC patients. From January 2009 to July 2012, 41 patients with stage IIIB or IV nonsquamous NSCLC were treated with full-dose pemetrexed plus cisplatin as the first-line chemotherapy combined with concurrent thoracic radiotherapy, with or without radiotherapy for metastases. The status of mutations in the epidermal growth factor receptor was unknown before the treatment, and no tyrosine-kinase inhibitor and cytotoxic drug maintenance therapy were administered to the patients after the chemotherapy. The median follow-up duration was 26.3 months (range, 5.8-57.5 months). Twenty-one patients had stage IIIB disease (19 with stage N3-IIIB). Of the 20 patients with stage IV disease, 16 had oligometastases (≤5) and four had polymetastases. The median number of chemotherapy cycles was 4. The median radiation dose was 60 Gy. Thirty-six patients received radical doses of radiotherapy. Toxicities were highly tolerated. The median progression-free survival was 12 months and the median overall survival was 32 months. The 1-, 2-, and 3-year overall survival rates were 87.5, 67.1, and 43.4%, respectively. As the first-line treatment for selected patients with advanced nonsquamous NSCLC, thoracic radiotherapy combined with concurrent full-dose pemetrexed plus cisplatin was safe and highly tolerable. In addition, the survival rate was encouraging. Prospective clinical trials are needed to verify the results.

Safety and efficacy of nimotuzumab in combination with radiotherapy for patients with squamous cell carcinoma of the esophagus.

BACKGROUND: We investigated nimotuzumab (h-R3), a humanized monoclonal antibody against epidermal growth factor receptor, when combined with irradiation or chemoradiation for squamous cell carcinoma (SCC) of the esophagus. The aim of this study was to evaluate its safety and efficacy. METHODS: We retrospectively analyzed 66 patients with esophageal SCC treated with a combination of h-R3 and radiation or chemoradiation between December 2008 and September 2011 at Fudan University Shanghai Cancer Center. Fifty-two of the 66 patients received h-R3 combined with chemoradiation and 14 received h-R3 plus radiation. The median total irradiation dose was 61 Gy given by conventional fractionation. The h-R3 weekly dosage was 100 mg (6/66), 200 mg (54/66), or 400 mg (6/66) given concurrently during the irradiation period. RESULTS: Patients tolerated the treatment well. Grade 3-4 adverse events and toxicities occurred in 50 % of the patients. h-R3-related toxicities manifested as Grade 1 skin rash in 1 case and Grade 2 infusion-related reaction in 2 cases. The median overall survival (OS) and progression-free survival (PFS) were 26.0 months and 16.7 months, respectively. OS, PFS and locoregional control (LC) at 2 years were 54, 37 and 80 %, respectively. CONCLUSIONS: h-R3 in combination with irradiation or chemoradiation was safe and tolerable, and yielded encouraging OS, PFS and LC.

AS-NeSt: A Novel 3D Deep Learning Model for Radiation Therapy Dose Distribution Prediction in Esophageal Cancer Treatment With Multiple Prescriptions.

PURPOSE: Implementing artificial intelligence technologies allows for the accurate prediction of radiation therapy dose distributions, enhancing treatment planning efficiency. However, esophageal cancers present unique challenges because of tumor complexity and diverse prescription types. Additionally, limited data availability hampers the effectiveness of existing artificial intelligence models. This study developed a deep learning model, trained on a diverse data set of esophageal cancer prescriptions, to improve dose prediction accuracy. METHODS AND MATERIALS: We retrospectively collected data from 530 patients with esophageal cancer, including single-target and simultaneous integrated boost prescriptions, for model building. The proposed Asymmetric ResNeSt (AS-NeSt) model features novel 3-dimensional (3D) ResNeSt blocks and an asymmetrical architecture. We constructed a loss function targeting global and local doses and validated the model's performance against existing alternatives. Model-assisted experiments were used to validate its clinical benefits. RESULTS: The AS-NeSt model maintained an absolute prediction error below 5% for each dosimetric metric. The average Dice similarity coefficient for isodose volumes was 0.93. The model achieved an average relative prediction error of 2.02%, statistically lower than Hierarchically Densely Connected U-net (4.17%), DoseNet (2.35%), and Densely Connected Network (3.65%). It also demonstrated significantly fewer parameters and shorter prediction times. Clinically, the AS-NeSt model raised physicians' ability to accurately preassess appropriate treatment methods before planning from 95.24% to 100%, reduced planning time by over 61% for junior dosimetrists and 52% for senior dosimetrists, and decreased both inter- and intra-dosimetrist discrepancies by more than 50%. CONCLUSIONS: The AS-NeSt model, developed with innovative 3D ResNeSt blocks and an asymmetrical encoder-decoder structure, has been validated using clinical esophageal cancer patient data. It accurately predicts 3D dose distributions for various prescriptions, including simultaneous integrated boost, showing potential to improve the management of esophageal cancer treatment in a clinical setting.

Telehealth With Comprehensive Live-Fed Real-World Data as a Patient Care Platform for Lung Cancer: Implementation and Evaluation Study.

BACKGROUND: Telehealth has emerged as a popular channel for providing outpatient services in many countries. However, the majority of telehealth systems focus on operational functions and offer only a sectional patient journey at most. Experiences with incorporating longitudinal real-world medical record data into telehealth are valuable but have not been widely shared. The feasibility and usability of such a telehealth platform, with comprehensive, real-world data via a live feed, for cancer patient care are yet to be studied. OBJECTIVE: The primary purpose of this study is to understand the feasibility and usability of cancer patient care using a telehealth platform with longitudinal, real-world data via a live feed as a supplement to hospital electronic medical record systems specifically from physician's perspective. METHODS: A telehealth platform was constructed and launched for both physicians and patients. Real-world data were collected and curated using a comprehensive data model. Physician activities on the platform were recorded as system logs and analyzed. In February 2023, a survey was conducted among the platform's registered physicians to assess the specific areas of patient care and to quantify their before and after experiences, including the number of patients managed, time spent, dropout rate, visit rate, and follow-up data. Descriptive and inferential statistical analyses were performed on the data sets. RESULTS: Over a period of 15 months, 16,035 unique users (13,888 patients, 1539 friends and family members, and 174 physician groups with 608 individuals) registered on the platform. More than 382,000 messages including text, reminders, and pictures were generated by physicians when communicating with patients. The survey was completed by 78 group leaders (45% of the 174 physician groups). Of the participants, 84% (65.6/78; SD 8.7) reported a positive experience, with efficient communication, remote supervision, quicker response to questions, adverse event prevention, more complete follow-up data, patient risk reduction, cross-organization collaboration, and a reduction in in-person visits. The majority of the participants (59/78, 76% to 76/78, 97.4%) estimated improvements in time spent, number of patients managed, the drop-off rate, and access to medical history, with the average ranging from 57% to 105%. When compared with prior platforms, responses from physicians indicated better experiences in terms of time spent, the drop-off rate, and medical history, while the number of patients managed did not significantly change. CONCLUSIONS: This study suggests that a telehealth platform, equipped with comprehensive, real-world data via a live feed, is feasible and effective for cancer patient care. It enhances inpatient management by improving time efficiencies, reducing drop-off rates, and providing easy access to medical history. Moreover, it fosters a positive experience in physician-patient interactions.

Association between microsomal epoxide hydrolase 1 polymorphisms and susceptibility to esophageal cancer: a meta-analysis.

Microsomal epoxide hydrolase 1 (EPHX1) plays an important role in the detoxification of carcinogenic polycyclic aromatic hydrocarbons. EPHX1 Tyr113His and His139Arg polymorphisms have been reported to have some impacts on the EPHX1 activity. Previous case-control studies assessing the associations between EPHX1 polymorphisms and esophageal cancer risk reported conflicting results. To quantitatively summarize the associations of EPHX1 Tyr113His and His139Arg polymorphisms with esophageal cancer risk, a systemic review and meta-analysis of published studies were performed. Published literatures from PubMed, Embase, and China National Knowledge Infrastructure databases were searched. The strength of the associations between EPHX1 polymorphisms and esophageal cancer risk was estimated by the pooled odds ratios (ORs) with its 95 % confidence interval (95 %CI). This meta-analysis yielded nine case-control studies, which included nine studies for Tyr113His polymorphism (1,291 cases and 2,120 controls) and seven studies for His139Arg polymorphism (899 cases and 1,615 controls). Overall, meta-analysis showed that EPHX1 Tyr113His polymorphism was not associated with esophageal cancer risk under all genetic models. Meta-analysis of these seven studies for EPHX1 His139Arg polymorphism showed that EPHX1 His139Arg polymorphism was also not associated with esophageal cancer risk under all genetic models. However, subgroup analysis by ethnicity further showed that there was an obvious association between EPHX1 His139Arg polymorphism and decreased risk of esophageal cancer in Caucasians (ArgArg versus HisArg/HisHis: OR = 0.52, 95 %CI 0.27-0.97, P = 0.041). This meta-analysis suggests that EPHX1 His139Arg polymorphism is associated with decreased risk of esophageal cancer in Caucasians. In addition, more studies with large samples are needed to get a more precise estimation on the associations mentioned above.

MicroRNA-150-5p inhibits the proliferation and invasion of human larynx epidermiod cancer cells though regulating peptidyl-prolyl cis/trans isomerase.

OBJECTIVE: This study aimed to investigate the molecular mechanism of miR-150-5p regulating the malignant biological behavior of Human Epidermoid cancer cell (HEp-2) by targeting peptidyl-prolyl cis/trans isomerase NIMA-Interacting-1 (PIN1). METHODS: Firstly, qRT-PCR and Western blot were adopted to detect the expression levels of miR-150-5p and PIN1 in cancer tissue and paracancerous tissues of patients with LSCC, and those in human bronchial epithelial cells (16 HBE) and HEp-2. Next, the targeted relationship between miR-150-5p and PIN1 was assessed by bioinformatics website and dual-luciferase reporter assay, followed by their correlation analysis. Besides, after interfering with miR-150-5p or PIN1 expression in HEp-2 cells, CCK-8, cell colony formation assay, and transwell assay were utilized to detect the proliferation, viability, and invasion of cells, respectively. Subsequently, the protein levels of MMP-2, MMP-9, and EMT-related proteins in HEp-2 cells were checked by Western blot. RESULTS: Expression of miR-150-5p was down-regulated in LSCC tissues and HEp-2 cells. Moreover, miR-150-5p suppressed proliferation and invasion of HEp-2 cells, affected protein expression related to MMP and EMT, thereby inhibiting development of cancer. The expression of PIN1 was significantly increased in cancer tissues and HEp-2 cells, and there was a targeted relationship and negative correlation between miR-150-5p and PIN1 in cancer tissue. However, overexpression of PIN1 could reverse the effect of miR-150-5p on the proliferation and invasion of HEp-2 cells. CONCLUSION: In a nutshell, there is a targeted relationship between PIN1 and miR-150-5p. Besides, miR-150-5p can inhibit the proliferation and invasion of HEp-2 cells by regulating the expression of PIN1.

Enhancing Prediction for Tumor Pathologic Response to Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Cancer by Dynamic Parameters from Clinical Assessments.

To develop accurate and accessible prediction methods for assessing pathologic response following NICT prior to surgery, we conducted a retrospective study including 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after two cycles of NICT between January 2019 and March 2022 at our center. We collected clinical parameters to evaluate the dynamic changes in the primary tumor. Univariate and multivariate analyses were performed to determine the correlations between these parameters and the pathologic response of the primary tumor. Subsequently, we constructed prediction models for pCR and MPR using multivariate logistic regression. The MPR prediction Model 2 was internally validated using bootstrapping and externally validated using an independent cohort from our center. The univariate logistic analysis revealed significant differences in clinical parameters reflecting tumor regression among patients with varying pathologic responses. The clinical models based on these assessments demonstrated excellent predictive performance, with the training cohort achieving a C-index of 0.879 for pCR and 0.912 for MPR, while the testing cohort also achieved a C-index of 0.912 for MPR. Notably, the MPR prediction Model 2, with a threshold cut-off of 0.74, exhibited 92.7% specificity and greater than 70% sensitivity, indicating a low rate of underestimating residual tumors. In conclusion, our study demonstrated the high accuracy of clinical assessment-based models in pathologic response prediction, aiding in decision-making regarding organ preservation and radiotherapy adjustments after induction immunochemotherapy.

A decision support framework for postoperative radiotherapy in patients with pathological N2 non-small cell lung cancer.

INTRODUCTION: Postoperative radiotherapy (PORT) plays a highly controversial role in pathological N2 (pN2) non-small cell lung cancer (NSCLC) disease. Recent studies reveal that not all patients can benefit from PORT. Further research is needed to identify predictors of PORT. METHODS: A total of 1044 pathologic stage T1-3N2M0 NSCLC patients were analyzed. Risk factors of distant metastasis were identified by the log-rank tests and the multivariable Cox models. We integrated risk factors of distant metastasis and our previously published loco-regional recurrence (LRR) related prognostic index into a decision support framework (DSF) to predict the outcomes of PORT. An independent cohort was used to validate the DSF. RESULTS: We defined patients with more than two of three identified LRR-related features (heavy cigarette smoking history, clinical N2 status, and more than four positive lymph nodes) as a high LRR risk group. We found the high-intermediate-risk histological type (with micropapillary and/or solid components) was associated with a higher risk of distant metastasis (HR = 1.207, 95 % CI 1.062 to 1.371, P =  0.0038), but not LRR. We built the DSF by combining these two types of features. Patients were stratified into four groups by using the DSF. PORT significantly improved OS only in the subgroup without high-risk histological features (without micropapillary or solid components) and with a high risk for LRR (three-year OS: 66.7 % in the PORT group vs 50.2 % in the non-PORT group; P = 0.023). CONCLUSIONS: A particular pN2 subgroup with a high risk of LRR and without micropapillary or solid components could benefit from PORT.

Practice Patterns of Treatment Strategy of Limited-Stage Small-Cell Lung Cancer: Survey of Chinese Oncologists.

Background: Thoracic radiotherapy (TRT) with concurrent chemotherapy is the standard treatment of limited-stage small-cell lung cancer (LS-SCLC). However, there is still a controversy surrounding the treatment strategy especially optimal dosing and fractionation schedule. Current practice patterns among Chinese oncologists are unknown. Materials and Methods: We surveyed 212 Chinese oncologists using a questionnaire including 50 questions designed by experienced oncologists. Questions covered demographic data, treatment recommendations, and self-assessed knowledge of guidelines or key clinical trials for SCLC. The chi-square test and Fisher's exact test were utilized to describe the result of the study. Results: The response rate was 97% (207/212). Of all the respondents, 69% preferred TRT QD, 29% preferred BID, and 2% chose HFRT. For those who prefer TRT QD, 72% preferred a total dose of 60 Gy, followed by 15% opting for 66 Gy, 12% for <60 Gy, and 1% for 70 Gy. Of those who prefer BID, 79% preferred a total dose of 45 Gy, with 4% choosing 30 Gy, 8% choosing 50 Gy, 7% choosing 54 Gy, and 2% choosing >54 Gy. Regarding PCI, 82% of participants believed that PCI should be performed when treatment is completed and 13% believed that PCI should begin immediately after concurrent chemoradiotherapy. As for other therapies, 26% of participants choose concurrent anti-angiogenic therapy during SCLC treatment, and 49% recommended small-molecule TKI as the main anti-angiogenic therapy. Conclusion: Substantial variation exists in how Chinese oncologists approach TRT dosing and fractionation for LS-SCLC. Almost 70% of respondents reported administering TRT QD more often in daily work. The most common doses were 60 Gy QD and 45 Gy BID.

International consensus on radiotherapy in metastatic non-small cell lung cancer.

Background: Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. While radiotherapy has historically served as a palliative modality in metastatic NSCLC, considerable advances in its technology and the continuous development of cutting-edge therapeutic agents, such as targeted therapy and immune checkpoint inhibitors (ICIs), are increasing its role in the multi-disciplinary management of the disease. Methods: International radiotherapy experts were convened to consider and reach consensuses on the clinical utilities of radiotherapy in metastatic NSCLC, with the aim to provide patient-focused, up to date, evidence-based, recommendations to assist cancer specialists in the management of patients with metastatic NSCLC worldwide. Results: Timely radiotherapy can offer rapid symptom alleviation and allow subsequent aggressive treatment approaches in patients with heavy tumor burden and/or oncologic emergencies. In addition, appropriate incorporation of radiotherapy as concurrent, consolidation, or salvage therapy makes it possible to achieve long-term survival, or even cure, for patients with oligo-metastatic disease. Cranial radiotherapy plays an important role in the management of brain metastasis, potentially augmenting the response and prolonging survival associated with targeted agents and ICIs. However, key questions remain, such as the appropriate choice of radiation techniques, optimal sequence of systemic therapies and radiotherapy, and optimal patient selection for such combination strategies. Although a strong rationale for combining radiotherapy and ICIs exists, its optimal parameters in this setting remain to be established. Conclusions: In the modern era, radiotherapy serves not only as a palliative tool in metastatic NSCLC, but also plays active roles in patients with oligo-focal disease, CNS metastasis and receiving ICIs.

Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis.

BACKGROUND/AIMS: To elucidate the clinicopathological and prognostic significance of epidermal growth factor receptor (EGFR) over-expression in esophageal squamous cell carcinoma (ESCC). METHODOLOGY: A meta-analysis of previous studies was performed to assess the effects of EGFR over-expression on clinicopathological parameters and overall survival (OS) in patients with ESCC, using pooled odds ratio (OR) with its 95% confidence interval (CI) and pooled hazard ratio (HR) with its 95% CI, respectively. RESULTS: A total of nine studies including 802 patients were subjected to the final analysis. The overall results suggested that over-expression of EGFR was significantly correlated with, not only the lymph node status and tumour differentiation grade, with a pooled OR of 0.64 (95% CI: 0.46-0.89; Z=2.62; p=0.009) and 1.60 (95% CI: 1.09-2.37; Z=2.37; p=0.018), respectively, but also the poorer OS with a pooled HR of 1.60 (95% CI: 1.05-2.43; Z=2.19 p=0.028). CONCLUSIONS: This meta-analysis suggests that over-expression of EGFR might play an important role in the progression of ESCC, and it might be useful as a predictive biomarker in clinical practice, yet the predictive value of EGFR in ESCC still needs further confirmation by prospective trials.

Patterns of Failure in Patients With Advanced Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

OBJECTIVE: The advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm of non-small cell lung cancer (NSCLC). Despite the durability of response to ICIs, the vast majority of patients will later develop progression. However, the failure patterns of ICI treatment are unknown. Here, our study explored the failure patterns in advanced NSCLC patients treated with ICIs. METHODS: A cohort of 156 IIIB or IV NSCLC patients treated with first-/second-line ICIs were retrospectively analyzed. Patients who experienced clinical benefit and then developed progression were identified. The disease progression patterns were divided into three categories: progression in new sites, progression in existing sites, and combined progression. The number of progression sites was also recorded. RESULTS: Before the cutoff date, 91 (77.1%) patients had experienced disease progression; 34% of patients had progressed in the last 9 months of the first year. Fifty-three (58.2%) patients had developed progression at existing lesions, and 56 (61.5%) patients had shown ≤2 progression sites (oligo-progression). In patients with oligo-progression, the median time of disease progression was 8.23 months and the counterpart (systemic progression) was 5.97 months. The oligo-progression patients showed prolonged median overall survival (27.23 months) compared with patients with systemic progression (18.87 months). CONCLUSIONS: Failure patterns of ICI therapy were predominantly "existing" sites, and the most common lesions of progression were the lung and lymph nodes. Most patients experienced oligo-progression which occurred later than systemic progression and showed prolonged overall survival. The control of the local lesions might be beneficial to improve ICI treatment efficacy.

Genetic variations in DNA repair gene NEIL1 associated with radiation pneumonitis risk in lung cancer patients.

BACKGROUND: Radiation pneumonitis (RP) is a common side effect in lung cancer patients who received radiotherapy. Our previous study found genetic variations in DNA repair gene NEIL1 may be a predictor of RP in patients with esophageal cancer. So, we hypothesis genetic variations in NEIL1 gene could affect the risk of RP in lung cancer patients following radiotherapy. METHODS: Genetic variations rs4462560 G>C and rs7402844 C>G in NEIL1 gene were genotyped in 174 lung cancer patients received radio(chemo)therapy. Luciferase assay, real-time PCR and Western blot were used to access the effect of the variants on NEIL1 in HELF and HEF cell lines which were transfected with plasmids containing rs4462560 G>C and rs7402844 C>G. RESULTS: Patients with rs4462560 CC genotype had a lower risk of RP grade ≥2 than GG genotype. Compared with the CC genotype, rs7402844 GG genotype was associated with an increased RP grade ≥2 risk. What is more, rs4462560 G decreased the relative luciferase activity of NEIL1 gene promoter compared with the negative control in vitro, while rs4462560 C can increase the relative luciferase activity. The mRNA and protein level of the NEIL1 gene in rs4462560 G were lower than rs4462560 C. CONCLUSIONS: Genetic variants of NEIL1 are associated with RP risk through regulation of NEIL1 expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.