Cumulative incidence and risk factors of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from IMpower130, IMpower131, and IMpower150.

BACKGROUND: The objective of this study was to explore the abilities of atezolizumab plus chemotherapy in preventing brain metastases (BMs) among metastatic non-small cell lung cancer (NSCLC) without initial BMs, as well as the risk factors of BMs. METHODS: Individual patient data from three trials involving first-line atezolizumab for metastatic NSCLC (IMpower130, IMpower131, and IMpower150) were pooled. Among patients without baseline BMs and without epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutations, those receiving atezolizumab + chemotherapy ± bevacizumab were classified as the atezolizumab plus chemotherapy group and those receiving placebo + chemotherapy ± bevacizumab were classified as the chemotherapy group. The cumulative incidences of BM (CI-BMs) between the two groups were compared. Other factors associated with the CI-BM were analyzed by Cox regression analyses. RESULTS: With a median follow-up of 17.6 months (range, 0.03-33.64 months), 74 (3.1%) of the 2380 enrolled patients developed BMs, including 50 (3.1%) and 24 (3.0%) in the atezolizumab plus chemotherapy group (n = 1589) and the chemotherapy group (n = 791), respectively. The CI-BMs at 6, 12, and 24 months were 1.7%, 2.8%, and 3.3%, respectively. After taking competing risk events into account, there was no significant difference in the CI-BMs between the two groups (p = .888). Nevertheless, the use of bevacizumab and the histology of nonsquamous NSCLC were found to be independently associated with the risk of BMs. CONCLUSIONS: In patients with metastatic EGFR/ALK wild-type NSCLC without baseline BMs, adding atezolizumab in the first-line treatment might not reduce the CI-BM. However, the administration of bevacizumab may reduce the risk of BMs.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy.

OBJECTIVES: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). RESULTS: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001). CONCLUSION: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

Prognostic value of genomic mutation signature associated with immune microenvironment in southern Chinese patients with esophageal squamous cell carcinoma.

The genomic landscape of esophageal squamous cell cancer (ESCC), as well as its impact on the regulation of immune microenvironment, is not well understood. Thus, tumor samples from 92 patients were collected from two centers and subjected to targeted-gene sequencing. We identified frequently mutated genes, including TP53, KMT2C, KMT2D, LRP1B, and FAT1. The most frequent mutation sites were ALOX12B (c.1565C > T), SLX4 (c.2786C > T), LRIG1 (c.746A > G), and SPEN (c.6915_6917del) (6.5%). Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling. A 17-mutated gene-related risk model was constructed using random survival forest analysis and showed significant prognostic value in both our cohort and the validation cohort. Based on the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression (ESTIMATE) algorithm, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm, and the MCPcounter algorithm, we found that the risk score calculated by the risk model was significantly correlated with stimulatory immune checkpoints (TNFSF4, ITGB2, CXCL10, CXCL9, and BTN3A1; p < 0.05). Additionally, it was significantly associated with markers that are important in predicting response to immunotherapy (CD274, IFNG, and TAMM2; p < 0.05). Furthermore, the results of immunofluorescence double staining showed that patients with high risk scores had a significantly higher level of M2 macrophage than those with low risk scores (p < 0.05). In conclusion, our study provides insights into the genomic landscape of ESCC and highlights the prognostic value of a genomic mutation signature associated with the immune microenvironment in southern Chinese patients with ESCC.

NGS-based Tissue-Blood TMB Comparison and Blood-TMB Monitoring in Stage-III Non-Small Cell Lung Cancer Treated with Concurrent Chemoradiotherapy.

In this study, we analyzed the blood-based TMB (b-TMB) and its dynamic changes in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received concurrent chemoradiotherapy. Baseline tissue and blood TMB from 15 patients showed a strong positive correlation (Pearson correlation = 0.937), and nearly all mutations were markedly reduced in the later course of treatment, indicating a treatment-related response. This study suggests that in patients with LA-NSCLC, b-TMB is a reliable biomarker, and its dynamic monitoring can help distinguish patients who might benefit most from the consolidated immunotherapy.

Enhancing the prediction of symptomatic radiation pneumonitis for locally advanced non-small-cell lung cancer by combining 3D deep learning-derived imaging features with dose-volume metrics: a two-center study.

OBJECTIVE: This study aims to examine the ability of deep learning (DL)-derived imaging features for the prediction of radiation pneumonitis (RP) in locally advanced non-small-cell lung cancer (LA-NSCLC) patients. MATERIALS AND METHODS: The study cohort consisted of 90 patients from the Fudan University Shanghai Cancer Center and 59 patients from the Affiliated Hospital of Jiangnan University. Occurrences of RP were used as the endpoint event. A total of 512 3D DL-derived features were extracted from two regions of interest (lung-PTV and PTV-GTV) delineated on the pre-radiotherapy planning CT. Feature selection was done using LASSO regression, and the classification models were built using the multilayered perceptron method. Performances of the developed models were evaluated by receiver operating characteristic curve analysis. In addition, the developed models were supplemented with clinical variables and dose-volume metrics of relevance to search for increased predictive value. RESULTS: The predictive model using DL features derived from lung-PTV outperformed the one based on features extracted from PTV-GTV, with AUCs of 0.921 and 0.892, respectively, in the internal test dataset. Furthermore, incorporating the dose-volume metric V30Gy into the predictive model using features from lung-PTV resulted in an improvement of AUCs from 0.835 to 0.881 for the training data and from 0.690 to 0.746 for the validation data, respectively (DeLong p < 0.05). CONCLUSION: Imaging features extracted from pre-radiotherapy planning CT using 3D DL networks could predict radiation pneumonitis and may be of clinical value for risk stratification and toxicity management in LA-NSCLC patients. CLINICAL RELEVANCE STATEMENT: Integrating DL-derived features with dose-volume metrics provides a promising noninvasive method to predict radiation pneumonitis in LA-NSCLC lung cancer radiotherapy, thus improving individualized treatment and patient outcomes.

Prophylactic cranial irradiation in small cell lung cancer: an update.

PURPOSE OF REVIEW: The current review presents recent updates in the seminal literature of research on prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC). RECENT FINDINGS: Brain MRI restaging before the administration of PCI reveals a substantial proportion of brain metastasis in baseline brain metastasis free extensive-stage SCLC (ES-SCLC) and limited-stage SCLC (LS-SCLC). Posthoc analyses from the CASPIAN and IMpower133 trials revealed decreases in brain metastasis rates in ES-SCLC treated with chemoimmunotherapy relative to the brain metastasis rates in ES-SCLC treated with chemotherapy alone. A recent meta-analysis of literature published after the landmark 1999 Auperin meta-analysis confirmed the survival benefit of PCI in LS-SCLC patients. A recent study employing PET before and after PCI demonstrated that hippocampal avoidance -PCI (HA-PCI) preserved the metabolic activity of the hippocampi compared with regular PCI. Two phase III trials evaluating neurocognitive functions after HA-PCI versus PCI have yielded conflicting results. Ongoing clinical trials (MAVERICK, PRIMALung, NRG CC003, NCT04535739, NCT04829708 and NCT03514849) regarding PCI versus MRI surveillance and HA-PCI versus PCI were also discussed. SUMMARY: Currently, the indications for PCI in SCLC are under question in the modern MRI era. Result from prospective phase III, MRI staged and MRI monitored RCTs are expected to elucidate the role of PCI in LS-SCLC and ES-SCLC. Preliminary results indicated that adding immunotherapy to chemotherapy may reduce brain metastasis rate in SCLC. Further data to this aspect are warranted to determine the role of PCI in the immuno-chemotherapy era. The future direction for PCI should be the comprehensive integration of personalized patient selection, HA-PCI utilization and potential employment of other neurocognitive preservation strategies.

STING signaling activation modulates macrophage polarization via CCL2 in radiation-induced lung injury.

BACKGROUND: Radiation-induced lung injury (RILI) is a prevalent complication of thoracic radiotherapy in cancer patients. A comprehensive understanding of the underlying mechanisms of RILI is essential for the development of effective prevention and treatment strategies. METHODS: To investigate RILI, we utilized a mouse model that received 12.5 Gy whole-thoracic irradiation. The evaluation of RILI was performed using a combination of quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), histology, western blot, immunohistochemistry, RNA sequencing, and flow cytometry. Additionally, we established a co-culture system consisting of macrophages, lung epithelial cells, and fibroblasts for in vitro studies. In this system, lung epithelial cells were irradiated with a dose of 4 Gy, and we employed STING knockout macrophages. Translational examinations were conducted to explore the relationship between STING expression in pre-radiotherapy lung tissues, dynamic changes in circulating CCL2, and the development of RILI. RESULTS: Our findings revealed significant activation of the cGAS-STING pathway and M1 polarization of macrophages in the lungs of irradiated mice. In vitro studies demonstrated that the deficiency of cGAS-STING signaling led to impaired macrophage polarization and RILI. Through RNA sequencing, cytokine profiling, and rescue experiments using a CCL2 inhibitor called Bindarit, we identified the involvement of CCL2 in the regulation of macrophage polarization and the development of RILI. Moreover, translational investigations using patient samples collected before and after thoracic radiotherapy provided additional evidence supporting the association between cGAS-STING signaling activity, CCL2 upregulation, and the development of radiation pneumonitis. CONCLUSIONS: The cGAS-STING signaling pathway plays a crucial role in regulating the recruitment and polarization of macrophages, partly through CCL2, during the pathogenesis of RILI.

Caution against simultaneous integrated boost radiotherapy for upper thoracic esophageal squamous cell carcinoma: results from a single-arm phase II trial.

PURPOSE: To explore the feasibility and safety of simultaneous integrated boost technology (SIB) with elective nodal irradiation (ENI) to the cervical and upper mediastinal lymph node (LN) regions in upper thoracic esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS: Patients with pathologically proven unresectable upper thoracic ESCC were assigned 50.4 Gy/28 fractions (F) to the clinical target volume (encompassing the ENI area of cervical and upper mediastinal LN regions) and a boost of 63 Gy/28 F to the gross tumor volume. Chemotherapy consisted of courses of concurrent cisplatin (20 mg/m2) and docetaxel (20 mg/m2) weekly for 6 weeks. The primary endpoint was toxicity. RESULTS: Between Jan 2017 and Dec 2019, 28 patients were included. The median follow-up time for all patients was 24.6 months (range 1.9-53.5). Radiation-related acute toxicity included esophagitis, pneumonia and radiodermatitis, all of which were well managed and reversed. Late morbidity included esophageal ulcer, stenosis, fistula and pulmonary fibrosis. Grade III esophageal stenosis and fistula was seen in 11% (3/28) and 14% (4/28) patients, respectively. The cumulative incidence rate of late esophageal toxicity was 7.7%, 19.2% and 24.6% at 6, 12 and 18 months, respectively. There was significant difference of the occurrence of severe late esophageal toxicity among the different volume levels of the esophagus, and cervical and upper mediastinal LNs which received ≥ 63 Gy stratified by the tertiles (p = 0.014). CONCLUSIONS: Despite the acceptably tolerated acute toxicity of SIB in concurrent CRT with ENI to the cervical and upper mediastinal LN regions for upper thoracic ESCC, the incidence of severe late esophageal toxicity was relatively high. Cautions are provided against easy clinical application of SIB (50.4 Gy/28F to the CTV, 63 Gy/28F to the GTV) in upper thoracic ESCC. Further exploration on dose optimization is warranted.

Overall survival benefit of osimertinib and clinical value of upfront cranial local therapy in untreated EGFR-mutant nonsmall cell lung cancer with brain metastasis.

Osimertinib, as a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), showed more potent efficacy against brain metastasis (BM) in untreated EGFR-mutant nonsmall cell lung cancer (NSCLC) in the FLAURA study. However, the overall survival (OS) benefit of osimertinib and clinical value of cranial local therapy (CLT) in these patients remain undetermined. Here we conducted a retrospective study involving untreated EGFR-mutant NSCLC patients with BMs receiving first-line osimertinib or first-generation EGFR-TKIs. Upfront CLT was defined as CLT performed before disease progression to the first-line EGFR-TKIs. Pattern of treatment failure and survival outcomes were extensively investigated. Among the 367 patients enrolled, first-generation EGFR-TKI was administered in 265, osimertinib in 102 and upfront CLT performed in 140. Patients receiving osimertinib had more (P < .001) and larger BMs (P = .003) than those receiving first-generation EGFR-TKIs. After propensity score matching, osimertinib was found to prolong OS (37.7 vs 22.2 months, P = .027). Pattern of failure analyses found that 51.8% of the patients without upfront CLT developed their initial progressive disease (PD) in the brain and 59.0% of the cranial PD occurred at the original sites alone, suggesting potential clinical value of upfront CLT. Indeed, upfront stereotactic radiosurgery (SRS) and/or surgery was associated with improved OS among those receiving first-generation EGFR-TKIs (P = .019) and those receiving osimertinib (P = .041). In summary, compared to first-generation EGFR-TKIs, osimertinib is associated with improved OS in untreated EGFR-mutant NSCLC with BMs. Meanwhile, upfront SRS and/or surgery may provide extra survival benefit, which needs to be verified in future studies.

A brief report on incidence, radiographic feature and prognostic significance of brain MRI changes after anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer.

INTRODUCTION: Neurologic immune-related adverse events (nirAEs) are uncommon but potentially lethal complications of immune checkpoint inhibitor (ICI) treatment. However, the incidence, radiographic features and prognostic significance of brain magnetic resonance imaging (MRI) changes after ICI treatment remain largely unknown. METHODS: Consecutive patients with advanced non-small cell lung cancer (NSCLC) at three participating institutions receiving anti-PD-1/PD-L1 therapy from June 2017 to September 2020 were screened, and those who received brain MRI within 6 weeks before ICI initiation and at least one follow-up brain MRI after ICI treatment were included. Serial brain MRI images were independently reviewed by two experienced radiologists. RESULTS: With a median follow-up of 13.2 months, 27 (20.0%) of the 135 enrolled patients developed certain kind of brain MRI aberration. The 1-, 2- and 3-year cumulative incidence of brain MRI aberration was 17.1%, 36.3% and 52.2%, respectively. Brain MRI aberration indicative of stroke, mimicking typical white matter lesions and presenting as T2-hyperintensity suggestive of CNS vasculitis or encephalitis, was documented in 11, 9 and 4 patients, respectively. Patients with brain MRI aberration had higher clinical benefit rate (p = 0.030), longer progression-free survival (p = 0.015) and a tendency of improved overall survival (p = 0.054). CONCLUSIONS: Brain MRI aberrations developed after ICI treatment are not uncommon, and their manifestations vary a lot. Patients developing brain MRI aberrations tended to have better prognosis, which needed to be further investigated.

Clinical outcomes of advanced non-small cell lung cancer patients harboring distinct subtypes of EGFR mutations and receiving first-line tyrosine kinase inhibitors: brain metastasis and de novo T790M matters.

BACKGROUND: The clinical features, survival outcomes and patterns of treatment failure of advanced non-small cell lung cancer (NSCLC) patients harboring distinct subtypes of EGFR mutations and receiving first-line EGFR tyrosine kinases inhibitor (TKIs) are not fully understood. METHODS: Consecutive metastatic EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs from October 2010 to March 2020 were enrolled and classified into two main groups based on the EGFR mutation subtypes: common mutation (L858R or exon 19 deletion), uncommon mutation (other EGFR mutations). RESULTS: Of the 1081 patients included, 74 (6.8%) harbored uncommon mutations. The baseline characteristics were generally balanced between the two groups, except that bone metastasis developed less frequently in patients with uncommon mutations (p = 0.02). No significant difference of survival outcomes was found between the two groups, except that among patients with baseline brain metastasis, the intracranial time to progression was significantly shorter in patients with uncommon mutations. Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). The patterns of treatment failure were generally consistent between the two groups, except which patients with uncommon mutations had a higher risk developing progressive disease in the brain. CONCLUSION: First-line EGFR-TKIs seemed to be less effective in controlling and preventing brain metastasis in patients with uncommon EGFR mutations and Osimertinib was associated with promising efficacy in patients with de novo T790M mutation, which warranted further validation.

A Phase II Study of Apatinib in Patients with Chemotherapy-Refractory Esophageal Squamous Cell Carcinoma (ESO-Shanghai 11).

LESSONS LEARNED: Apatinib has potential as an effective and safe second-line or higher treatment for patients with chemotherapy-refractory esophageal squamous cell carcinoma (ESCC). Clinical safety is of potential concern when administering apatinib to patients with uncontrolled esophageal lesions or severe invasion of trachea, bronchi, or major blood vessels. To the best of the authors' knowledge, this is the first prospective phase II study to investigate apatinib for patients with chemotherapy-refractory ESCC. Apatinib could provide an alternative option for ESCC after first-line or higher therapy in carefully selected patients. BACKGROUND: The aim of this study was to evaluate the efficacy and adverse effects of the oral vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitor apatinib in patients with chemotherapy-refractory esophageal squamous cell carcinoma (ESCC). METHODS: We enrolled patients with chemotherapy-refractory ESCC. All patients received continuous apatinib 500 mg once daily. RESULTS: Between July 2017 and August 2018, 40 patients were recruited, of whom 5 (12.5%) had uncontrolled primary tumors. Additionally, three patients with partial response (PR) and 23 with stable disease (SD) were observed for overall response rate (ORR) of 7.5% and disease control rate (DCR) of 65.0%. Median progression-free survival (PFS) was 3.8 months (95% confidence interval [CI], 2.2-5.4); median overall survival (OS) was 5.8 months (95% CI, 3.2-8.4). Common adverse effects were fatigue (15%), hypertension (12.5%), and palmar-plantar erythrodysesthesia syndrome (10%). Two cases of death from massive bronchopulmonary hemorrhage were observed, and esophageal fistula occurred in another two patients. Notably, both patients with esophageal fistula and one patient with massive fatal bronchopulmonary hemorrhage were individuals with uncontrolled primary tumors (3/5, 60%). Fatal bronchopulmonary hemorrhage in a second patient was associated with major blood vessel invasion. CONCLUSION: Apatinib has potential as an effective and safe treatment for patients with chemotherapy-refractory ESCC whose primary tumors are controlled and without severe invasion of trachea, bronchi, or major blood vessels.

Local therapy for oligometastatic esophageal squamous cell carcinoma: a prospective, randomized, Phase II clinical trial.

For patients with oligometastatic esophageal squamous cell carcinoma, the efficacy of local therapy is still controversial because of patient selection and lack of adequate controls in most studies. Here the authors design the ESO-Shanghai 13 trial, a prospective, multicenter, randomized, Phase II trial, to assess the impact of combined local therapy and systemic therapy on progression and survival compared with systemic therapy alone for patients with four or less metastases. A total of 102 patients will be recruited over 3 years from approximately five centers and randomized in a 1:1 ratio to receive either systemic therapy alone or systemic therapy and local therapy, such as radiation, surgery and thermal ablation. The primary endpoint is progression-free survival. The secondary endpoints are overall survival, local control, toxicity and quality of life. Clinical trial registration: NCT03904927 (ClinicalTrials.gov).

Lay abstract The ESO-Shanghai 13 trial is a prospective, multicenter, randomized, Phase II trial to assess the impact of combined local treatment (such as radiotherapy, surgery and thermal ablation) and chemical drugs for patients with esophageal squamous cell carcinoma. Patients with four or less metastases and controlled esophageal lesion will be enrolled. The authors will recruit a total of 102 patients over 3 years from approximately five centers. All patients will be randomized and receive either chemical drugs alone or chemical drugs plus local treatment with the same probability. Patients will then be observed after treatment until disease progression or death or the end of the trial. Patients will need to report their symptoms and physical status and fill out quality of life scales during the treatment and follow-up period.

A novel angular dependency model for MatriXX response and its application to true composite dose verification for IMRT plans.

PURPOSE: This paper proposes a model for the angular dependency of MatriXX response and investigates whether MatriXX, with the angular-model-based approach can be applied to true composite dose verification for IMRT plans. METHOD: This model attributes the angular dependence of MatriXX response to dynamical translation of its effective measurement plane (EMP) due to the change of beam angle. Considering this mechanism, true composite dose verifications for IMRT plans specified in AAPM TG 119 report using both MatriXX and Gafchromic EBT3 films were undertook and compared to validate the applicability of MatriXX for patient specific QA of composite beam IMRT plans. Dose verifications using MatriXX with and without angular-model-based approach were performed. RESULTS: MatriXX with angular-model-based approach achieved gamma passing rates with 3%/3 mm and 3%/2 mm criteria better than 98.3% and 98.1% respectively for true composite dose verification of plans in AAPM TG 119 report. The 3%/3 mm and 3%/2 mm gamma passing rates using MatriXX without angular-model-based approach ranged from 85.8% to 98.2% and from 81.3% to 96.5%, respectively. The p-values from the single sided paired t-test indicated no statistical difference between the passing rates from MatriXX with angular-model-based approach and from films, and significant difference between the passing rates from uncorrected MatriXX and from films. CONCLUSION: The proposed model for angular dependent MatriXX response is necessary and effective. Dose verification using MatriXX with angular-model-based approach is acceptable for true composite beam IMRT plans with required accuracy to simplify patient specific QA.

microRNA-messenger RNA regulatory network of esophageal squamous cell carcinoma and the identification of miR-1 as a biomarker of patient survival.

Emerging evidence indicates that microRNAs (miRNAs) play an important role in tumor carcinogenesis and progression by targeting gene expression. The goal of this study was to comprehensively analyze the vital functional miRNAs and their target genes in esophageal squamous cell carcinoma (ESCC) and to explore the clinical significance and mechanisms of miR-1 in ESCC. First, the miRNA and messenger RNA (mRNA) expression profiles of ESCC were determined with microarray technology. Using an integrated analysis of miRNAs and their target genes with multistep bioinformatics methods, the miRNA-mRNA regulatory network in ESCC was constructed. Next, miR-1 expression in 292 ESCC patients and its relationship with clinicopathological features and prognosis were detected by in situ hybridization. Furthermore, the biological functions of miR-1 were determined with in vitro and in vivo functional experiments. Finally, real-time quantitative reverse transcription polymerase chain reaction, Western blot analysis, and luciferase reporter assays were performed to verify the target genes of miR-1. In this study, 67 miRNAs and 2992 genes were significantly differentially expressed in ESCC tissues compared with their expression in adjacent normal tissues, and an miRNA-mRNA regulatory network comprising 59 miRNAs and 162 target mRNAs was identified. Low miR-1 expression was correlated with pathological T stage, lymph node metastasis, vessel invasion, and poor clinical outcome. miR-1 suppressed ESCC cell proliferation and invasion and promoted ESCC cell apoptosis. Fibronectin 1 (FN1) was verified as a direct target of miR-1. Taken together, the present results suggest that miR-1 may be a valuable prognostic predictor for ESCC, and the miR-1/FN1 axis may be a therapeutic target.

Predicting the Value of Adjuvant Therapy in Esophageal Squamous Cell Carcinoma by Combining the Total Number of Examined Lymph Nodes with the Positive Lymph Node Ratio.

BACKGROUND: The value of adjuvant therapy for esophageal squamous cell carcinoma (ESCC) has been controversial, at least partially due to the lack of efficient criteria for selecting suitable patients. This study aimed to explore the existence of parameters related to lymph node (LN) status that can predict the value of adjuvant therapy in ESCC. METHODS: The study included 298 patients with ESCC who had undergone radical esophagectomy with lymphadenectomy. Adjuvant therapy was defined as reception of adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. For the study, LN ratio (LNR), total number of resected LNs (TLNs), and pN stage were selected for Cox regression analyses, including their correlations and prognostic values for survival. Log-rank tests were used to compare the survival rates of the patients with and without adjuvant therapy stratified by pN stage, TLNs, LNR, or their combinations. RESULTS: The independent prognostic factors for survival were TLNs, LNR, and pN stage. Whereas pN stage was significantly related to TLNs and LNR, TLNs were not correlated with LNR. The survival rates between the patients with and those without adjuvant therapy stratified by pN stage, TLNs, or LNR did not differ significantly. We used the median values of TLNs and LNR to group the patients into four groups. The patients in the group with fewer TLNs and higher LNR who had undergone adjuvant therapy showed a significantly better survival than those without adjuvant therapy (p = 0.030). CONCLUSIONS: In contrast to TLNs, LNR, and pN stage as single factors, the combination of TLNs and LNR can predict the value of adjuvant therapy.

Extended Right Thoracic Approach Compared With Limited Left Thoracic Approach for Patients With Middle and Lower Esophageal Squamous Cell Carcinoma: Three-year Survival of a Prospective, Randomized, Open-label Trial.

OBJECTIVE: To investigate whether survival is improved by using the right thoracic approach (extended lymphadenectomy) compared with the left thoracic approach (limited lymphadenectomy) for esophageal cancer. BACKGROUND: The optimal surgical technique for esophageal cancer remains unclear. METHODS: Between May 2010 and July 2012, 300 patients with middle and lower thoracic esophageal carcinoma were randomized to receive esophagectomy through either the right or left thoracic approach. Of these, 286 patients with squamous cell carcinoma determined by postoperative pathology were included in this analysis. Disease-free survival (DFS) and overall survival (OS) were compared between the right (n = 146) and left thoracic groups (n = 140). RESULTS: The median follow-up was 55.9 months [95% confidence interval (CI): 53.1-58.6]. The 3-year DFS rates were 62% and 52% in the right and left thoracic arms, respectively [hazard ratio (HR) 0.709; 95% CI, 0.506-0.995; P = 0.047, log-rank test]. The 3-year OS rates were 74% and 60%, respectively (HR, 0.663; 95% CI, 0.457-0.961; P = 0.029). Subgroup analyses revealed longer DFS in the right thoracic arm (vs left thoracic arm) in patients with lymph node involvement (HR, 0.632; 95% CI, 0.412-0.969, P = 0.034), but not in patients without lymph node involvement (HR, 0.757; 95% CI, 0.434-1.320, P = 0.325), and in patients with R1-2 resection margins (HR, 0.495; 95% CI, 0.290-0.848, P = 0.009), but not R0 margins (HR, 0.944; 95% CI, 0.603-1.477, P = 0.801). CONCLUSIONS: Compared with the left thoracic approach, the right thoracic approach associated with increased DFS and OS in esophageal squamous cell carcinoma patients, particularly in those with lymph node involvement and/or R1-2 resection margins.

[Motion analysis on patients with knee osteoarthritis merged with varus deformity].

Aiming at comparing the pre-operative and post-operative gait characteristics and therefore establishing post-operative rehabilitation guidance for patients with end-stage knee osteoarthritis (KOA) merged with varus deformity, this study captured the level walking and sit-to-stand trials of 9 patients with 3-dimensional motion analysis system and after which musculoskeletal multi-body dynamic analysis was conducted. The study indicated that the average range of motion (ROM) of the proposed-surgical knee was 24.4°-57.6° and that of the non-surgical knee was 22.5°-71.5°. The knee ROM of control group during level walking was 7.2°-62.4°. When the unilateral KOA patients stood up from chair to complete the sit-to-stand movement, the ground reaction forces (GRFs) symmetry was 0.72-0.85, which means that the non-surgical limb bear the majority of body weight. The GRFs of the bilateral KOA patients were smallest during the sit-to-stand movement. The strategy that the non-surgical limb dominates in loading bearing taken by the unilateral KOA patients to cover most post-operative daily activities could increase the risk of KOA among non-surgical side joints as a result of long-term excessive loading-bearing. The study, on kinematics and biomechanical characteristics of patients with KOA merged with varus deformity, could help to understand the pathogenesis of KOA merged with varus deformity from the perspective of biomechanics and to provide strong clinic guidance for the pre-operative evaluation, prevention and post-operative recovery for patients.

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.