Left Ventricular Systolic Dysfunction Is a Possible Independent Risk Factor of Radiation Pneumonitis in Locally Advanced Lung Cancer Patients.
Cai Guoxin,Liang Shuai,Li Chuanbao,Meng Xue,Yu Jinming
Frontiers in oncology
To assess the association between left ventricular (LV) systolic and diastolic dysfunction and grade ≥2 radiation pneumonitis (RP) for locally advanced lung cancer patients receiving definitive radiotherapy. A retrospective analysis was carried out for 260 lung cancer patients treated with definitive radiotherapy between 2015 and 2017. RP was evaluated according to Radiation Therapy Oncology Group (RTOG) toxicity criteria. Logistic regression analysis, 10-fold cross validation, and external validation were performed. The prediction model's discriminative performance was evaluated using the area under the receiver operating characteristic curve (AUC), and calibration of the model was assessed by the Hosmer-Lemeshow test and the calibration curve. Within the first 6 months after radiotherapy, 70 patients (26.9%) developed grade ≥2 RP. Reduced left ventricular ejection fraction (LVEF) before radiotherapy was detected in 53 patients (20.4%). The odds ratio (OR) of developing RP for patients with LVEF <50% was 3.42 [ < 0.001, 95% confidence interval (CI), 1.85-6.32]. Multivariate analysis showed that forced expiratory volume in the first second/forced vital capacity (FEV1/FVC), LVEF, Eastern Cooperative Oncology Group (ECOG) performance status, chemotherapy, and mean lung dose (MLD) were significantly associated with grade ≥2 RP. The AUC of a model including the above five variables was 0.835 (95% CI, 0.778-0.891) on 10-fold cross validation and 0.742 (95% CI, 0.633-0.851) on the external validation set. The -value for the Hosmer-Lemeshow test was 0.656 on 10-fold cross validation and 0.534 on the external validation set. LV systolic dysfunction is a possible independent risk factor for RP in locally advanced lung cancer patients receiving definitive radiotherapy.
10.3389/fonc.2019.01511
Silencing METTL3 inhibits the proliferation and invasion of osteosarcoma by regulating ATAD2.
Zhou Lei,Yang Changsheng,Zhang Ning,Zhang Xin,Zhao Tingbao,Yu Jinming
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BACKGROUND:Osteosarcoma is the most common primary malignant bone tumor in children and young adults. RNA N-methyladenosine (mA) is the most abundant internal modification in mammalian mRNA, which is involved in tumorigenesis and tumor progression. It has been reported that methyltransferase-like 3 (METTL3), the first reported m6A "writer", plays critical roles in cancer progression. However, its role and molecular mechanism in osteosarcoma is poor studied. In this study, we aimed to investigate the functional role and underlying mechanism of METTL3 in the progression of osteosarcoma. METHODS:We detected the mRNA expression of METTL3 in osteosarcoma cell lines, and immunofluorescence assay was performed to observe the location of METTL3. Cell lines with METTL3 gene overexpression or knockdown were established by pcDNA3.1-METTL3 or siRNA interferences in order to determine the function of METTL3 in osteosarcoma in vitro. Transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3 in osteosarcoma. RESULTS:We found that METTL3 localized in cytoplasm and nucleus of osteosarcoma cells. Silencing METTL3 in SAOS-2 and MG63 cells significantly inhibited the mA methylation level, proliferation, migration, and invasion abilities, as well as promoted cell apoptosis. However, up-regulation of METTL3 had no significant effect on the biological behaviors of U2OS cells. Further mechanism analysis suggested that METTL3 knockdown inhibited the expression of ATPase family AAA domain containing 2 (ATAD2). Moreover, ATAD2 knockdown inhibited the proliferation and invasion of SAOS-2 and MG63 cells, while its overexpression showed a significant increase in cell proliferation and invasion. Furthermore, METTL3 knockdown abrogated the promoting effects of ATAD2 overexpression on osteosarcoma cells proliferation and invasion. CONCLUSION:Overall, our study revealed that METTL3 functions as an oncogene in the growth and invasion of osteosarcoma by regulating ATAD2, suggesting a potential therapeutic target for osteosarcoma treatment.
10.1016/j.biopha.2020.109964
A review of radiation-induced lymphopenia in patients with esophageal cancer: an immunological perspective for radiotherapy.
Therapeutic advances in medical oncology
Radiotherapy is a frequently utilized therapeutic modality in the treatment of esophageal cancer (EC). Even though extensive studies are carried out in radiotherapy for EC, the design of the clinical target volume and the radiation dose is not satisfactorily uniform. Radiotherapy acts as a double-edged sword on the immune system; it has both an immunostimulatory effect and an immunosuppressive effect. Radiation-induced lymphopenia and its potential association with tumor control and survival outcomes remain to be understood. The advent of immunotherapy has renewed the focus on preserving a pool of functioning lymphocytes in the circulation. In this review, we summarize the potential impact mechanisms of radiotherapy on peripheral blood lymphocytes and the prognostic role of radiation-induced lymphopenia in patients with EC. We also propose the concept of organs-at-risk of lymphopenia and discuss potential strategies to mitigate its effects on patients with EC. From an immunological perspective, we put forward the hypothesis that optimizing radiation modalities, radiation target volume schemes, and radiation doses could help to reduce radiation-induced lymphopenia risks and maximize the immunomodulatory role of radiotherapy. An optimized radiotherapy plan may further enhance the feasibility and effectiveness of combining immunotherapy with radiotherapy for EC.
10.1177/1758835920926822
MED13L integrates Mediator-regulated epigenetic control into lung cancer radiosensitivity.
Zhang Nasha,Song Yemei,Xu Yeyang,Liu Jiandong,Shen Yue,Zhou Liqing,Yu Jinming,Yang Ming
Theranostics
To date, efforts to improve non-small-cell lung cancer (NSCLC) outcomes with increased radiation dose have not been successful. Identification of novel druggable targets that are capable to modulate NSCLC radiosensitivity may provide a way forward. Mediator complex is implicated in gene expression control, but it remains unclear how Mediator dysfunction is involved in cancer radiotherapy. The biologic functions of miR-4497, MED13L and PRKCA in NSCLC radiosensitivity were examined through biochemical assays including gene expression profilling, cell proliferation assay, colony formation assay, wound healing assay, transwell assay, dual luciferase reporter assay, xenograft models, immunoprecipitation, and chromatin immunoprecipitation sequencing. Clinical implications of miR-4497, MED13L and PRKCA in radiosensitivity were evaluated in NSCLC patients treated with concurrent chemoradiotherapy or radiotherapy alone. We found that radiation can trigger disassemble of Mediator complex via silencing of MED13L by miR-4497 in NSCLC. Although not interrupting structure integrity of the core Mediator or the CDK8 kinase module, suppression of MED13L attenuated their physical interactions and reduced recruitment of acetyltransferase P300 to chromatin via Mediator. Silencing of MED13L therefore diminishes global H3K27ac signals written by P300, activities of enhancer and/or promoters and expression of multiple oncogenes, especially . Inhibition of expression potentiates the killing effect of radiotherapy and . Remarkably, high expression in NSCLC tissues is correlated with poor prognosis of patients received radiotherapy. Our study linking PRKCA to radiosensitivity through a novel mechanism may enable the rational targeting of PRKCA to unlock therapeutic potentials of NSCLC.
10.7150/thno.48247
Clinical Applications of Cerebrospinal Fluid Circulating Tumor DNA as a Liquid Biopsy for Central Nervous System Tumors.
Yan Weiwei,Xu Tingting,Zhu Hui,Yu Jinming
OncoTargets and therapy
Central nervous system (CNS) malignancies are associated with poor prognosis, as well as exceptional morbidity and mortality, likely as a result of low rates of early diagnosis and limited knowledge of the tumor growth and resistance mechanisms, dissemination, and evolution in the CNS. Monitoring patients with CNS malignancies for treatment response and tumor recurrence can be challenging because of the difficulty and risks of brain biopsies and the low specificity and sensitivity of the less invasive methodologies that are currently available. Therefore, there is an urgent need to detect and validate reliable and minimally invasive biomarkers for CNS tumors that can be used separately or in combination with current clinical practices. The circulating tumor DNA (ctDNA) of cerebrospinal fluid (CSF) samples can outline the genetic landscape of entire CNS tumors effectively and is a promising, suitable biomarker, though its role in managing CNS malignancies has not been studied extensively. This review summarizes recent studies that explore the diagnostic, prognostic, and predictive roles of CSF-ctDNA as a liquid biopsy with primary and metastatic CNS malignancies.
10.2147/OTT.S229562
An in silico mechanistic insight into HDAC8 activation facilitates the discovery of new small-molecule activators.
Du Jintong,Li Wen,Liu Bo,Zhang Yingkai,Yu Jinming,Hou Xuben,Fang Hao
Bioorganic & medicinal chemistry
Research interest in the development of histone deacetylase 8 (HDAC8) activators has substantially increased since loss-of-function HDAC8 mutations were found in patients with Cornelia de Lange syndrome (CdLS). A series of N-acetylthioureas (e.g., TM-2-51) have been identified as HDAC8-selective activators, among others; however, their activation mechanisms remain elusive. Herein, we performed molecular dynamics (MD) simulations and fragment-centric topographical mapping (FCTM) to investigate the mechanism of HDAC8 activation. Our results revealed that improper binding of the coumarin group of fluorescent substrates leads to the "flipping out" of catalytic residue Y306, which reduces the enzymatic activity of HDAC8 towards fluorescent substrates. A pocket between the coumarin group of the substrate and thed catalytic residue Y306 was filled with the activator TM-2-51, which not only enhanced binding between HDAC8 and the fluorescent substrate complex but also stabilized Y306 in a catalytically active conformation. Based on this newly proposed substrate-dependent activation mechanism, we performed structure-based virtual screening and successfully identified low-molecular-weight scaffolds as new HDAC8 activators.
10.1016/j.bmc.2020.115607
Research Progress and Existing Problems for Abscopal Effect.
Wang Di,Zhang Xia,Gao Yajie,Cui Xiaonan,Yang Yanqin,Mao Weifeng,Li Minghuan,Zhang Bin,Yu Jinming
Cancer management and research
Radiation therapy plays a vital role in the treatment of tumours. In particular, the occurrence of the "abscopal effect" brings about a favourable turn for the treatment of patients with advanced metastatic malignant tumours. Because of the abscopal effect, non-irradiated areas are also treated. However, the abscopal effect occurs by chance, not through seeking. Although the abscopal effect has been studied enthusiastically, the desired result does not appear to be achieved. Moreover, its combination with immunotherapy appears to be overwhelming. There is an opinion that abscopal effect is difficult to achieve by irradiation of a single tumour, and irradiation of multiple or total lesions is advocated to increase the possibility of obtaining clinically meaningful outcomes. Obviously, there are still questions about the mechanism, condition and possibility underlying the occurrence of the abscopal effect. Can the abscopal effect truly change the future treatment strategy as the researchers expect? What are the current problems? This article reviewed the research in recent years to explore the progress and controversy surrounding the abscopal effect of radiation therapy.
10.2147/CMAR.S245426
Identification of Survival-Associated Alternative Splicing Signatures in Lung Squamous Cell Carcinoma.
Liu Yang,Jia Wenxiao,Li Ji,Zhu Hui,Yu Jinming
Frontiers in oncology
Alternative splicing (AS) is a post-transcriptional process that plays a significant role in enhancing the diversity of transcription and protein. Accumulating evidences have demonstrated that dysregulation of AS is associated with oncogenic processes. However, AS signature specifically in lung squamous cell carcinoma (LUSC) remains unknown. This study aimed to evaluate the prognostic values of AS events in LUSC patients. The RNA-seq data, AS events data and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was performed to identify survival-related AS events and survival-related parent genes were subjected to Gene Ontology enrichment analysis and gene network analysis. The least absolute shrinkage and selection operator (LASSO) method and multivariate Cox regression analysis were used to construct prognostic prediction models, and their predictive values were assessed by Kaplan-Meier analysis and receiver operating characteristic (ROC) curves. Then a nomogram was established to predict the survival of LUSC patients. And the interaction network of splicing factors (SFs) and survival-related AS events was constructed by Spearman correlation analysis and visualized by Cytoscape. Totally, 467 LUSC patients were included in this study and 1,991 survival-related AS events within 1,433 genes were identified. , and were the hub genes in the gene interaction network. Eight prognostic prediction models (seven types of AS and all AS) were constructed and all exhibited high efficiency in distinguishing good or poor survival of LUSC patients. The final integrated prediction model including all types of AS events exhibited the best prognostic power with the maximum AUC values of 0.778, 0.816, 0.814 in 1, 3, 5 years ROC curves, respectively. Meanwhile, the nomogram performed well in predicting the 1-, 3-, and 5-year survival of LUSC patients. In addition, the SF-AS regulatory network uncovered a significant correlation between SFs and survival-related AS events. This is the first comprehensive study to analyze the role of AS events in LUSC specifically, which improves our understanding of the prognostic value of survival-related AS events for LUSC. And these survival-related AS events might serve as novel prognostic biomarkers and drug therapeutic targets for LUSC.
10.3389/fonc.2020.587343
Prognostic Value of a Nomogram Based on the Dynamic Albumin-to-Alkaline Phosphatase Ratio for Patients with Extensive-Stage Small-Cell Lung Cancer.
OncoTargets and therapy
PURPOSE:Small-cell lung cancer (SCLC) is known as the characteristics of high invasion, rapid progression, and poor prognosis. Therefore, identification of patients with high risk of progression and death is critical to improve the survival of patients with extensive-stage SCLC (ES-SCLC). This study was designed to determine the prognostic importance of the albumin-to-alkaline phosphatase ratio (AAPR) in the survival of patients with ES-SCLC and to develop a nomogram based on AAPR dynamics for ES-SCLC prognosis. PATIENTS AND METHODS:Characteristics were reviewed from 300 patients with ES-SCLC. Training and validation cohorts included 200 and 100 patients, respectively. We applied univariate and multivariate Cox models to assess the prognostic value of AAPR for ES-SCLC. The nomogram for progression-free survival (PFS) and overall survival (OS) of ES-SCLC patients was developed based on the multivariate survival analysis of the training cohort. External validation of the established nomogram was performed using the validation cohort. RESULTS:N3 stage, thoracic radiotherapy, and post-AAPR were the independent factors identified for PFS. T stage, thoracic radiotherapy, and high post-AAPR were the independent risk factors identified for death. The prognostic nomogram was established by integrating the independent significant factors for PFS and OS in the training cohort with the c-indices of 0.675 and 0.662, respectively, and validated in the validation cohort. The nomogram had superior prognosis prediction ability than did TNM stage. Decision curve analysis (DCA) also indicated clinical net benefits from the nomogram. CONCLUSION:AAPR was valuable for prognosis prediction in patients with ES-SCLC and was recommended to be dynamically evaluated to guide patient treatment. Additionally, the nomogram covering post-AAPR accurately predicted individual survival probability.
10.2147/OTT.S262084
Heart Dosimetric Parameters Were Associated With Cardiac Events and Overall Survival for Patients With Locally Advanced Esophageal Cancer Receiving Definitive Radiotherapy.
Cai Guoxin,Li Chuanbao,Yu Jinming,Meng Xue
Frontiers in oncology
The aim of this study was to assess the association between heart dosimetric parameters and cardiac events or overall survival (OS) for patients with stage III esophageal cancer receiving definitive radiotherapy. Patients with stage III esophageal cancer receiving definitive radiotherapy at our hospital from 2011 to 2013 were enrolled retrospectively. The primary endpoint was grade ≥ 2 cardiac events, and the second endpoint was 5-year OS. Competing risk analysis and Cox regressions analysis were performed to evaluate the association between heart dose and cardiac events or OS. Three hundred forty-six patients were analyzed. Median follow-up was 30 months. Median prescribed dose was 60 Gy. Seventy-eight patients (22.5%) had 91 grade ≥ 2 cardiac events, at a median of 14 months to first event. Thirty-three patients (9.5%) had 42 grade ≥ 3 cardiac events. Of the 78 patients with grade ≥ 2 cardiac events, 70 (89.7%) had the first cardiac events that occurred within first 3 years after radiotherapy. Multivariable analysis showed that preexisting ischemic heart disease [hazard ratio (HR), 2.26; 95% confidence interval (CI), 1.26-4.06; = 0.006] and mean heart dose (HR, 1.12; 95% CI, 1.04-1.20; = 0.002) were significantly associated with increased risk of grade ≥ 2 cardiac events. Disease progression (HR, 2.60; 95% CI, 1.82-3.70; < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (HR, 0.71; 95% CI, 0.56-0.91; = 0.007), heart volume receiving ≥ 5 Gy (V5, HR, 1.01; 95% CI, 1.00-1.03; = 0.035), and gross tumor volume (GTV; HR, 1.00; 95% CI, 1.00-1.00; = 0.020) were significant predictors of 5-year OS on multivariable analysis. Higher heart dose was significantly associated with an increased cardiac event rate and a worse OS outcome for patients with stage III esophageal cancer treated with definitive radiotherapy. Most of the first cardiac events occurred within first 3 years after treatment.
10.3389/fonc.2020.00153
AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model.
Huang Jiaqi,Zhang Di,Bai Yu,Yang Pamela,Xing Ligang,Yu Jinming
Journal of Cancer
Accumulated extracellular adenosine suppresses antitumor immunity via adenosine 2A receptor (AR). Blockade of AR with DZD2269 can inhibit phosphorylation of cAMP response element-binding protein mediated by adenosine analogue and Irradiation can cause the release of adenosine and lead to a rapid increase in free extracellular adenosine in the tumour area. DZD2269, a novel AR Antagonism, induces incomplete antitumor responses in multiple syngeneic mouse tumour models. Combining DZD2269 with IR can induce a synergistic anticancer effect. IR increases the infiltration of various subtypes of T cells, including CD4+, CD8+ and Foxp3+ T cells, into the tumour area. Combining IR and DZD2269 improves the tumour immune microenvironment, leading to suppressed infiltration of regulatory T (Treg) cells and enhanced IFN-γ expression by tumour-infiltrating lymphocytes. The results support the use of AR antagonism with DZD2269 as a therapeutic strategy for monotherapy or combination therapy with IR.
10.7150/jca.43966
Perspective on treatment for unresectable locally advanced non-small cell lung cancer with oncogene-driven mutation: a narrative review.
Jiang Liyang,Meng Xiangjiao,Zhao Xianguang,Xing Ligang,Yu Jinming
Translational lung cancer research
The standard treatment of unresectable locally advanced non-small cell lung cancer (LA NSCLC) is concurrent chemoradiotherapy. With the addition of immunotherapy, patients with LA NSCLC received a significantly prolonged outcome, while patients with harboring epidermal growth factor receptor (EGFR) mutation benefited less. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of stage IV with harboring EGFR mutation and anaplastic lymphoma kinase rearrangement, but there are few recommendations indicating whether TKI treatment is effective in unresectable NSCLC. Preclinical studies have shown that TKIs could have a radiosensitizing effect, which provided a rationale to consider the application TKI with radiotherapy. In this review, we summarize the clinical studies that have used TKIs in LA-NSCLC as well as ongoing trials, and discuss recent progress in research related to the efficacy of TKI for unresectable LA NSCLC patients. Recent results of small studies evaluating TKI therapy for LA NSCLC patients in combination with radiation or chemoradiation demonstrated promising efficacy, improved outcomes with a tolerable toxicity profile. However, there is a lack of strong evidence for TKI treatment in unresectable LA NSCLC, because of unpowered statistics, lack of molecular selection, or lack of large randomized arms. We prospect the combination of TKI and radiation or chemoradiation therapy might eventually replace the current standard treatment for patients with LA NSCLC harboring oncogene-driven mutation.
10.21037/tlcr-20-722
Identifying optimal first-line interventions for advanced non-small cell lung carcinoma according to PD-L1 expression: a systematic review and network meta-analysis.
Oncoimmunology
This network meta-analysis (NMA), based on one phase II and nine phase III studies, involving 6,124 patients with metastatic NSCLC, indirectly compares Atezolizumab + Bevacizumab + chemotherapy (ABC), Atezolizumab + chemotherapy (AC), Pembrolizumab + chemotherapy (PC), Pembrolizumab alone, Bevacizumab + chemotherapy (BC) and chemotherapy alone. Each of these is recommended as front-line interventions, according to the US FDA and the European Medicines Agency (EMA) for advanced NSCLC without EGFR mutation or ALK rearrangement. Studies were identified through PubMed, EMBASE, the Cochrane Library, Medline, and abstracts found in oncology articles. Primary endpoints, i.e., progression-free survival (PFS) and overall survival (OS) with corresponding hazard ratios (HR), objective response rates (ORR) and adverse event (AEs) with odds risk (OR) were pooled according to frequentist network meta-analytical techniques. PD-L1 expression thresholds, as well as non-squamous/squamous were used to determine subgroups. Immunotherapy plus chemotherapy appeared superior to Pembrolizumab alone for PD-L1-high (i.e., TPS≥50%) NSCLC patients. BC might also be specifically recommended as an initial first-line treatment for PD-L1-high, non-squamous NSCLC patients, since BC was not inferior to Pembrolizumab alone. PC and ABC might be preferred for NSCLC patients with intermediate PD-L1 (1% ≤PD-L1, TPS<50%) expression. BC can also be tentatively recommended specifically for PD-L1-intermediate, non-squamous NSCLC patients. Combined immunotherapies can all be recommended for PD-L1-negative (i.e., TPS<1%) NSCLC patients, although especially the ABC combination for non-squamous NSCLC patients, which was superior to PC in regards of PFS. However, PC performed comparable to ABC in the whole population and in all subgroup save this one. More predictive biomarkers could be factored into further analyses to help identifying the most effective treatment regimens for specific patient groups.
10.1080/2162402X.2020.1746112
Radiation Recall Pneumonitis Induced by Anti-PD-1 Blockade: A Case Report and Review of the Literature.
Chen Yu,Huang Zhaoqin,Xing Ligang,Meng Xiangjiao,Yu Jinming
Frontiers in oncology
Radiation recall pneumonitis (RRP) is an unpredictable but relatively severe subclinical radiation damage which occurs in the previously irradiated fields of pulmonary tissue after administration of a systemic agent. Previous reports of RRP were mainly attributed to chemotherapy and molecular-target agents. RRP induced by immunotherapy has been rarely reported. Here we describe a case of a novel pattern of RRP induced by anti-PD-1 blockade Camrelizumab 2 years after radiotherapy, with some focus on further understanding of this phenomenon. A 64-year-old man with non-small cell lung cancer (NSCLC) received two cycles of chemotherapy with cisplatin and pemetrexed first. Subsequently, he underwent concomitant chemoradiotherapy with cisplatin and pemetrexed to simultaneous integrated boost (SIB) radiotherapy. After 15 months, due to tumor progression and brain metastasis, he started with administration of anti-PD-1 blockade Camrelizumab (200 mg q2w) and stereotactic radiosurgery (SRS). The patient developed fever, dyspnea and cough after the eighth administration of Camrelizumab. Meanwhile, his chest CT revealed patchy consolidation and ground-glass opacities localized within the previously irradiated area. Subsequent treatment regimen was adjusted to 80 mg q12h prednisolone with discontinuation of Camrelizumab. Then the symptoms gradually eased and reexamination of CT showed significant improvement in RRP after 2 weeks. Our case report presents a novel pattern of RRP induced by anti-PD-1 blockade Camrelizumab 2 years after radiotherapy. This indicates that previous radiotherapy combined with subsequent anti-PD-1 blockade has a potential to cause overlapping damage to lung, suggesting that intensive attention might be needed for patients who are treated with anti-PD-1 blockade in conjunction with a prior history of thoracic radiation.
10.3389/fonc.2020.00561
Interobserver Variability of Target Volumes Delineated in the Supine and Prone Positions Based on Computed Tomography Images for External-Beam Partial Breast Irradiation After Breast-Conserving Surgery: A Comparative Study.
Yu Ting,Li YanKang,Wang Wei,Li Fengxiang,Wang Jinzhi,Xu Min,Zhang Yingjie,Li Jianbin,Yu Jinming
Frontiers in oncology
Although the supine position remains the dominant position for external-beam partial breast irradiation (EB-PBI), the advantages of administering EB-PBI in the prone position have been recognized. The interobserver variability between target volumes delineated in the different positions for EB-PBI after breast-conserving surgery needs to be investigated. Twenty-seven patients suitable for EB-PBI were enrolled from July 2016 to April 2017. Supine and prone simulation CT images were sequentially acquired for all enrolled patients during free breathing. Five experienced radiotherapists delineated the target volumes for all patients on supine and prone simulation CT images. The selected parameters, including target volumes, the coefficient of variation (COV), the matching degree (MD), and so on, were calculated to analyze the interobserver variability. Regardless of the patient position, the interobserver variability between tumor bed (TB) and clinical target volume (CTV) measurements in supine and prone positions were statistically significant ( = 31.34, 19.467; 44.000, 41.985; = 0.000, 0.001; 0.000, 0.001). The interobserver variability of COV was significantly greater in the supine position than in the prone position ( = 2.64, = 0.014). Furthermore, the interobserver variabilities of MD and MD were statistically lower in the supine position than in the prone position ( = -3.460, -3.195, = 0.000, 0.001). When delineating the target volume for EB-PBI, the interobserver variability in the prone position was lower than that in the supine position. Hence, the administration of EB-PBI in the prone position during free breathing is a reasonable option.
10.3389/fonc.2020.00323
Looking for the Optimal PD-1/PD-L1 Inhibitor in Cancer Treatment: A Comparison in Basic Structure, Function, and Clinical Practice.
Chen Yu,Pei Yanqing,Luo Jingyu,Huang Zhaoqin,Yu Jinming,Meng Xiangjiao
Frontiers in immunology
Programmed cell death protein-1/ligand 1 (PD-1/L1) targeted immune checkpoint inhibitors have become the focus of tumor treatment due to their promising efficacy. Currently, several PD-1/PD-L1 inhibitors have been approved for clinical practice with several more in clinical trials. Notably, based on available trial data, the selection of different PD-1/PD-L1 inhibitors in the therapeutic application and the corresponding efficacy varies. Widespread attention then is increasingly raised to the clinical comparability of different PD-1/PD-L1 inhibitors. The comparison of the inhibitors could not only help clinicians make in-depth understanding of them, but also further facilitate the selection of the optimal inhibitor for patients in treatment as well as for future clinical research and the development of new related drugs. As we all know, molecular structure could determine molecular function, which further affects their application. Therefore, in this review, we aim to comprehensively compare the structural basis, molecular biological functions, and clinical practice of different PD-1/PD-L1 inhibitors.
10.3389/fimmu.2020.01088
GINS2 attenuates the development of lung cancer by inhibiting the STAT signaling pathway.
Sun Dianmin,Zong Yuanyuan,Cheng Jinling,Li Zhenxiang,Xing Ligang,Yu Jinming
Journal of Cancer
GINS complex subunit 2 (GINS2) controls DNA replication. GINS2 expression is upregulated in several kinds of aggressive tumors. However, the effect of GINS2 in lung cancer remains unclear. We performed TCGA database analysis to confirm the clinical significance of GINS2 in lung cancer. After silencing GINS2 in A549 cells, we performed MTT assays, flow cytometry assays, colony formation assays, cell cycle analyses and RNA sequence analysis to elucidate the effect of GINS2 on lung cancer. Moreover, we assessed tumor growth and analyzed body fluorescence in mice as a measure of tumor burden. The TCGA database analysis demonstrated that GINS2 mRNA and protein was highly expressed in three kinds of lung cancer tissues. Subsequently, knockdown of GINS2 inhibited cell proliferation, colony formation, cell cycle arrest and apoptosis in A549 cells. On the other hand, we also investigated the effect of GINS2 on tumor formation in vivo. The analysis of nude mouse tumors showed that the tumor volume and weight of shGINS2 mice were significantly smaller than those of the control mice. To reveal the mechanism of GINS2 in lung cancer, we collected A549 cells with GINS2 knockdown to examine the downstream gene expression changes. The results showed that STAT1 and STAT2 mRNA and protein expression were significantly upregulated after GINS2 knockdown in A549 cells. Our results suggest that GINS2 inhibits the proliferation of lung cancer cells by inhibiting the STAT signaling pathway, which may be a potential biomarker for the diagnosis or prognosis of lung cancer.
10.7150/jca.46744
Use of Chemoradiotherapy as a Treatment Option for Patients with Limited-Stage Primary Small Cell Carcinoma of the Esophagus.
Zhao Kaikai,Huang Zhaoqin,Si Youjiao,Sun Liangchao,Yu Jinming,Meng Xiangjiao
Cancer management and research
Purpose:Currently, there are no standard treatments for primary small cell carcinoma of the esophagus (PSCCE), particularly in cases of limited-stage disease. This retrospective study aimed to assess the treatment strategies and the relevant prognostic factors of limited-stage PSCCE (LS-PSCCE). Patients and Methods:We retrospectively evaluated 129 patients with LS-PSCCE between June 2009 and December 2018. The χ2 test was performed to examine the frequencies between different groups. The Kaplan-Meier and log-rank methods were used to estimate and compare survival rates. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS). Results:Through a median follow-up of 23 months, the median OS of all patients was 25.0 months and the median recurrence-free survival (RFS) was 15.0 months. Univariate and multivariate analyses showed that alcohol abuse (=0.046) and TNM stage (<0.001) were independent prognostic factors. There was no significant difference in OS and RFS rates between the patients treated with chemoradiotherapy (CRT) and those treated with surgery and chemotherapy with or without radiotherapy (S+CT±RT) (>0.05). Patients who received concurrent CRT had better OS and RFS than those who received sequential CRT (<0.05). Postoperative adjuvant RT for high-risk patients can further improve the local control rate but has no significant effect on OS. Conclusion:LS-PSCCE patients treated with CRT had similar OS and RFS compared to those treated with S+CT±RT. This study shows that concurrent CRT confers a survival advantage for patients with LS-PSCCE compared to those with sequential CRT.
10.2147/CMAR.S278914
Structure-based virtual screening, biological evaluation and biophysical study of novel Mcl-1 inhibitors.
Du Jintong,Liu Lulu,Liu Bo,Yang Jing,Hou Xuben,Yu Jinming,Fang Hao
Future medicinal chemistry
Targeting the protein-protein interactions (PPIs) associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors ( = 5.4 μM) and ( = 0.53 μM) exhibit good selectivity against Bcl-2 and Bcl-xL. Compound exhibits anti-proliferation activity and induces caspase-3 activation in Jurkat cancer cells. Moreover, H⁄N HSQC NMR experiments suggested that compound likely binds in the P2 pocket of Mcl-1 and engages R263 in a salt bridge. Our study provides a good starting point for future discovery of more potent Mcl-1 selective inhibitors.
10.4155/fmc-2020-0114
SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges.
Chen Yu,Gao Min,Huang Zhaoqin,Yu Jinming,Meng Xiangjiao
Journal of hematology & oncology
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1), and others have shown potent clinical efficacy and have revolutionized the treatment protocols of a broad spectrum of tumor types, especially non-small-cell lung cancer (NSCLC). Despite the substantial optimism of treatment with PD-1/PD-L1 inhibitors, there is still a large proportion of patients with advanced NSCLC who are resistant to the inhibitors. Preclinical and clinical trials have demonstrated that radiotherapy can induce a systemic antitumor immune response and have a great potential to sensitize refractory "cold" tumors to immunotherapy. Stereotactic body radiation therapy (SBRT), as a novel radiotherapy modality that delivers higher doses to smaller target lesions, has shown favorable antitumor effects with significantly improved local and distant control as well as better survival benefits in various solid tumors. Notably, research has revealed that SBRT is superior to conventional radiotherapy, possibly because of its more powerful immune activation effects. Thus, PD-1/PD-L1 inhibitors combined with SBRT instead of conventional radiotherapy might be more promising to fight against NSCLC, further achieving more favorable survival outcomes. In this review, we focus on the underlying mechanisms and recent advances of SBRT combined with PD-1/PD-L1 inhibitors with an emphasis on some future challenges and directions that warrant further investigation.
10.1186/s13045-020-00940-z
The Predictive Value of Tumor Volume and Its Change on Short-Term Outcome for Esophageal Squamous Cell Carcinoma Treated With Radiotherapy or Chemoradiotherapy.
Liang Shuai,Li Chengming,Gao Zhenhua,Shang Dongping,Yu Jinming,Meng Xue
Frontiers in oncology
Objectives:To investigate the tumor volume and its change on short-term outcome in esophageal squamous cell carcinoma (ESCC) patients who underwent definitive radiotherapy or chemoradiotherapy. Methods and Materials:All data were retrospectively collected from 418 ESCC patients who received radiotherapy or chemoradiotherapy at our institution between 2015 and 2019. Short-term outcome using the treatment response evaluation was assessed according to the RECIST 1.1. The tumor volume change rate (TVCR) was defined as follows: TVCR {1 [gross tumor volume (GTV) at shrinking irradiation field planning)]/(GTV at the initial treatment planning)} ×100%. Chi square test was used to compare the clinic characteristics in different TVCR groups, and the difference between initial GTV (GTVi) and shrinking GTV (GTVs) was compared using Wilcoxon's sign rank test. Logistic regression analysis and Spearman correlation was performed. Results:There was a significant decrease in GTVi compared to GTVs ( < 0.001). In univariate analysis, age, cT-stage, TNM stage, treatment modality, GTVi, and TVCR were associated with short-term outcome (all 0.05). In multivariate analysis, gender and TVCR were statistically significant ( = 0.010, <0.001) with short-term outcome, and the combined predictive value of gender and TVCR exceeded that of TVCR (AUC, 0.876 0.855). Conclusions:TVCR could serve to forecast short-term outcome of radiotherapy or chemoradiotherapy in ESCC. It was of great significance to guide the individualized treatment of ESCC.
10.3389/fonc.2020.586145
Case Report: Transformation From Cold to Hot Tumor in a Case of NSCLC Neoadjuvant Immunochemotherapy Pseudoprogression.
Jia Wenxiao,Zhu Hui,Gao Qianqian,Sun Jian,Tan Fujian,Liu Qun,Guo Hongbo,Yu Jinming
Frontiers in immunology
A 56-year-old male was diagnosed with right lung upper lobe squamous cancer with right hilar and mediastinum lymph node metastasis. After four cycles of neoadjuvant immunochemotherapy, reexamination by computed tomography showed progressive disease of the primary lesion. Then, the patient underwent a right lung upper lobectomy, and hilar and mediastinum lymph node dissection. Surgical pathology showed a partial response to immunochemotherapy. Single-cell RNA sequencing was used to characterize the infiltrating immune cell atlas after neoadjuvant immunochemotherapy; the most common infiltrating immune cell types were cytotoxic CD8+ T cells, monocyte-derived dendritic cells, and macrophages. Imaging mass cytometry revealed a transformation from cold to hot tumor after neoadjuvant immunochemotherapy. In this case study, we are the first to report a case of neoadjuvant immunochemotherapy pseudoprogression, proved by surgical pathology, single-cell RNA sequencing, and imaging mass cytometry. Both single-cell RNA sequencing and imaging mass cytometry revealed an activated immune microenvironment after neoadjuvant immunochemotherapy.
10.3389/fimmu.2021.633534
Toxicity Profile of Combining PD-1/PD-L1 Inhibitors and Thoracic Radiotherapy in Non-Small Cell Lung Cancer: A Systematic Review.
Li Butuo,Jiang Chao,Pang Linlin,Zou Bing,Ding Mingjun,Sun Xindong,Yu Jinming,Wang Linlin
Frontiers in immunology
Background:The combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) has shown significant clinical activity in patients with non-small cell lung cancer (NSCLC). However, the currently available data on adverse events (AEs) were derived from a small subset of patients included in prospective clinical trials or retrospective studies. Thus, we conducted this systematic review to determine the AEs associated with this combination treatment. Methods:An electronic literature search was performed in databases and conference proceedings of prospective clinical trials assessing the combination of ICIs and TRT for patients with NSCLC. The systematic analysis was conducted to determine the profile and incidence of AEs of combination treatment. We further performed the comparison of AEs between programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, and sequential and concurrent administration of ICIs and TRT to help identify high risk patients. The systematic analyses were conducted with the Review Manager (version 5.3; The Cochrane Collaboration, Oxford, United Kingdom) and Stata version 12.0 (StataCorp, College Station, TX, USA) software. Results:Eleven clinical trials involving 1,113 patients with NSCLC were eligible for analysis. The incidence of all-grade AEs was 95.5%; that of high-grade AEs (grade ≥3) was 30.2%. The most frequent all-grade AE was fatigue (49.7%), while pneumonitis was the most common high-grade AE (3.8%) and grade 5 AE (0.6%). Notably, the toxicity profiles of PD-1 and PD-L1 inhibitors were similar. Concurrent treatment was associated with a higher incidence of higher-grade AEs (41.6% vs 24.8%, P=0.17) and pneumonitis (7.1% vs 3.9%, P=0.14) compared to sequential treatment, but no significant difference was observed. Conclusion:Most AEs of this combination treatment are tolerable; as the most common high-grade AE, pneumonitis deserves the utmost attention of physicians. The toxicity profiles of patients receiving PD-1 or PD-L1 were similar, and no significant difference was observed between concurrent and sequential treatment.
10.3389/fimmu.2021.627197
F-RGD PET/CT imaging reveals characteristics of angiogenesis in non-small cell lung cancer.
Translational lung cancer research
BACKGROUND:The objective of this study was to explore the benefit of F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (denoted as F-RGD PET/CT) imaging for determining the clinical pathologic features of non-small cell lung cancer (NSCLC). METHODS:Seventy-two patients with NSCLC (37 cases of adenocarcinoma and 35 cases of squamous carcinoma) were enrolled to receive F-RGD PET/CT scanning pretreatment. The peak standard uptake value (SUV), mean standard uptake value (SUV), angiogenic tumor volume (ATV) and total lesion angiogenesis (TLA) of tumors were determined using an automated contouring program. Cases were classified according to the tumor, lymph node, metastasis (TNM) stage. RESULTS:Significant differences in ATV and TLA were observed among T1, T2, T3 and T4 cases (ATV, P=0.000; TLA, P=0.000). ATV and TLA also differed significantly among cases of clinical stage I, II, III and IV (ATV, P=0.002; TLA, P=0.011). However, no significant differences in any values were observed between stage III and IV NSCLC cases (SUV, P=0.675; SUV, P=0.668; ATV, P=0.52; TLA, P=0.634). All assessed values were higher in squamous cell carcinoma cases than in adenocarcinoma cases (SUV, P=0.045; SUV, P=0.014; ATV, P=0.003; TLA, P=0.001). For clinical stage III and IV cases specifically, SUV, SUV, and TLA were higher for squamous cell carcinoma than for adenocarcinoma (SUV, P=0.015; SUV, P=0.009; TLA, P=0.036).C F-RGD PET/CT imaging revealed the presence of increased angiogenesis in the tumor microenvironment of NSCLC, especially squamous cell carcinoma, and thus may be valuable in planning therapeutic regimens for individual patients.
10.21037/tlcr-20-187
Estimating Survival in Patients with Non-Small-Cell Lung Cancer and Brain Metastases: A Verification of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA).
Li Ji,Jing Wang,Zhai Xiaoyang,Jia Wenxiao,Zhu Hui,Yu Jinming
OncoTargets and therapy
Purpose:A new tool based on clinical characteristics and molecular factors (Lung-molGPA) was developed to predict the survival of patients with non-small-cell lung cancer but was has not been validated. This study aims to validate the feasibility of the Lung-molGPA in NSCLC. Patients and Methods:Patients diagnosed NSCLC between Feb 2012 and July 2018 were retrospectively reviewed and scored using the Lung-molGPA tool to compare clinical outcomes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by Cox regression analyses. Results:A total of 618 patients (524 adenocarcinoma [ADC], 94 non-adenocarcinoma [non-ADC]) were collected. For all patients, the median survival time (MST) was 33.0 months (33.6 and 28 months in the ADC and non-ADC groups, respectively; = 0.21). In the ADC group, the MST for patients with a Lung-molGPA score of 3.5 to 4 was more than 4 years, while the MST was only 25 months in patients scoring 0-1, 30.0 months in patients scoring 1.5-2, and 35.0 months for scores of 2.5-3 ( = 0.048). For the non-ADC group, the MST for scores 0-1, 1.5-2, 2.5-3, and 3.5-4 were 12.0, 20.2, 29.0, and 33.0 months, respectively ( = 0.017). Conclusion:Our findings provided evidence validating the Lung-molGPA score as a useful tool to determine treatment strategies and to predict prognosis. The model is still exploratory and needs to be evaluated further in combination with additional prognostic markers.
10.2147/OTT.S288928
Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma.
Li Yankang,Zhang Nasha,Zhang Li,Song Yemei,Liu Jie,Yu Jinming,Yang Ming
Carcinogenesis
Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is effective for most advanced non-small-cell lung cancer (NSCLC) patients with mutant EGFR, some patients show little or no response. Germline variations, such as single-nucleotide polymorphisms (SNPs), have been proved to be involved in disease progression after EGFR-TKI therapy. In this study, we hypothesized that the functional HSPH1 SNP may affect gene expression and, thus, prognosis of NSCLC patients treated with EGFR-TKIs. We systematically examined impacts of HSPH1 SNPs on NSCLC survival in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The promoter rs2280059 polymorphism was significantly associated with patient survival in both cohorts. In vitro and In vivo assays elucidated that rs2280059 G allele shows higher capability to drive HSPH1 promoter activities. Silencing HSPH1 significantly increases the antineoplastic effects of gefitinib on NSCLC cells. Our findings demonstrated potential implications of HSPH1 in clinic, which may lead to better understanding and outcome assessment of EGFR-TKI treatment.
10.1093/carcin/bgaa069
Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications.
Teng Feifei,Li Min,Yu Jinming
BMC medicine
BACKGROUND:The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. The overlapping pulmonary toxicity induced by thoracic RT and programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. Thus far, the underlying mechanism of this toxicity remains largely unknown. MAIN TEXT:In this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by PD-1 blockade. The clinical presentation is different from common radiation pneumonitis (RP) or RRP induced by cytotoxic drugs. The immune checkpoint inhibitors may evoke an inflammatory reaction in patients' previously irradiated fields, with infiltrating lymphocytes and potential involvement of related cytokines. All RRP patients have showed durable response to anti-PD-1/PD-L1. RRP is manageable; however, interruption of checkpoint blockades is necessary and immunosuppressive treatment should be started immediately. Further analyses of the predictive factors, including RT dosimetric parameters, tumor-infiltrating lymphocytes (TILs), and PD-L1 expression, are needed given the wide use of immune checkpoint inhibitors and high mortality from lung toxicity with the combination treatment. CONCLUSION:Immune checkpoint inhibitors may evoke an RRP in the patients' previously irradiated fields. Interactions between immune checkpoint inhibitors and radiotherapy should be studied further.
10.1186/s12916-020-01718-3
Early response evaluation using primary tumor and nodal imaging features to predict progression-free survival of locally advanced non-small cell lung cancer.
Zhang Nasha,Liang Rachel,Gensheimer Michael F,Guo Meiying,Zhu Hui,Yu Jinming,Diehn Maximilian,Loo Bill W,Li Ruijiang,Wu Jia
Theranostics
Prognostic biomarkers that can reliably predict early disease progression of non-small cell lung cancer (NSCLC) are needed for identifying those patients at high risk for progression, who may benefit from more intensive treatment. In this work, we aimed to identify an imaging signature for predicting progression-free survival (PFS) of locally advanced NSCLC. : This retrospective study included 82 patients with stage III NSCLC treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were performed. They were randomly placed into two groups: training cohort (n=41) and testing cohort (n=41). All primary tumors and involved lymph nodes were delineated. Forty-five quantitative imaging features were extracted to characterize the tumors and involved nodes at baseline and mid-treatment as well as differences between two scans performed at these two points. An imaging signature was developed to predict PFS by fitting an L1-regularized Cox regression model. : The final imaging signature consisted of three imaging features: the baseline tumor volume, the baseline maximum distance between involved nodes, and the change in maximum distance between the primary tumor and involved nodes measured at two time points. According to multivariate analysis, the imaging model was an independent prognostic factor for PFS in both the training (hazard ratio [HR], 1.14, 95% confidence interval [CI], 1.04-1.24; = 0.003), and testing (HR, 1.21, 95% CI, 1.10-1.33; = 0.048) cohorts. The imaging signature stratified patients into low- and high-risk groups, with 2-year PFS rates of 61.9% and 33.2%, respectively ( = 0.004 [log-rank test]; HR, 4.13, 95% CI, 1.42-11.70) in the training cohort, as well as 43.8% and 22.6%, respectively ( = 0.006 [log-rank test]; HR, 3.45, 95% CI, 1.35-8.83) in the testing cohort. In both cohorts, the imaging signature significantly outperformed conventional imaging metrics, including tumor volume and SUV value (C-indices: 0.77-0.79 for imaging signature, and 0.53-0.73 for conventional metrics). : Evaluation of early treatment response by combining primary tumor and nodal imaging characteristics may improve the prediction of PFS of locally advanced NSCLC patients.
10.7150/thno.50565
Application and Prospects of Molecular Imaging in Immunotherapy.
Wang Weiqing,Gao Zhenhua,Wang Lu,Li Jianing,Yu Jinming,Han Shumei,Meng Xue
Cancer management and research
Recently, immunotherapies that target the interactions of programmed cell death 1 (PD-1) with its major ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), have achieved significant success. To date, several immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have been developed to treat melanoma, non-small cell lung cancer, head and neck cancer, renal cell carcinoma, and urothelial carcinoma. Despite promising outcomes with immunotherapy, there are many limitations to several current immune biomarkers for predicting immune benefits and to traditional imaging for evaluating the efficacy and prognosis of immunotherapy and monitoring adverse reactions. In this review, we recommend a novel imaging method, molecular imaging. This paper reviews the application and prospects of molecular imaging in the context of current immunotherapies in regard to the following aspects: 1) detecting the expression of PD-1/PD-L1; 2) evaluating the efficacy of immunotherapy; 3) assessing patient prognosis with immunotherapy; 4) monitoring the toxicity of immunotherapy; and 5) other targets imaging.
10.2147/CMAR.S269773
Predicting Prognosis and Adverse Events by Hematologic Markers in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Treated with Neoadjuvant Chemoradiotherapy.
Cancer management and research
PURPOSE:Our purpose was to evaluate the association between hematologic markers and mortality and adverse events in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT). PATIENTS AND METHODS:A total of 311 patients with ESCC treated with nCRT from 2012 to 2014 were enrolled retrospectively. The Kaplan-Meier method with a Log rank test was used to calculate five-year overall survival (OS). Receiver operating characteristic (ROC) curves were plotted to determine the cut-off values for hematologic markers. Multivariate analysis was performed using Cox regression analysis model. Model performance was evaluated by predicted nomogram, concordance index (C-index) and calibration curve. RESULTS:Median follow-up was 22 months. High pretreatment platelet to lymphocyte ratio (PLR, p = 0.047) and systemic immune-inflammation index (SII, p = 0.027) were significantly associated with pathologic complete response (pCR). In multivariate analysis, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, invasion depth, lymph node metastasis, PLR, and SII were independent factors to predict five-year OS. Multivariate analysis showed a lower neutrophil to lymphocyte ratio (NLR) at baseline (p = 0.007) was significantly associated with development of grade ≥3 hematologic toxicity, and none of inflammatory biomarkers could predict grade ≥3 non-hematologic toxicity or radiation pneumonitis (RP). CONCLUSION:SII and PLR were independent indicators to predict prognosis in patients with ESCC treated with nCRT, and a lower NLR at baseline was an independent indicator to predict grade ≥3 hematologic toxicity.
10.2147/CMAR.S257058
Timing of Adjuvant Chemoradiation in pT1-3N1-2 or pT4aN1 Esophageal Squamous Cell Carcinoma After R0 Esophagectomy.
Cancer management and research
INTRODUCTION:Postoperative adjuvant radiation therapy (RT) and chemotherapy (aCRT) have been supposed to improve prognosis and outcomes in patients with node-positive thoracic esophageal squamous cell carcinoma (TESCC). Our aim was to analyze the impacts of interval between surgery and aCRT on prognosis, determining the optimal time interval. METHODS:We retrospectively reviewed 520 patients with TESCC between 2007 and 2015 treated with aCRT following radical esophagectomy without neoadjuvant chemotherapy and RT. These patients underwent RT (50-60 Gy) combined with 2-6 cycles chemotherapy after surgery. The time intervals were from 17 days to 145 days and divided into three groups: short interval group (≤28 days, S-Int group), medial interval group (≥29 and ≤ 56 days, M-Int group) and long interval group (≥57 days, L-Int group). RESULTS:Median follow-up was 35.6 months and the 3-, 5-year survival rates and median survival were 49.5%, 36.6% and 35.9 months. The duration of postoperative interval was a predictor of survival outcomes. The median survival and 5-year survival rates in S-Int, M-Int and L-Int groups were 23.6 (32.1%), 44.2 (43.3%) and 32.0 (31.5%) months (P=0.007). The difference was statistically significant between the M-Int and S-Int or L-Int group but was not between the S-Int and L-Int group. Besides, toxic reactions including early, late and adverse events (grade ≥3) in M-Int group were significantly less than S-Int and show no significant differences with L-Int group. CONCLUSION:The optimal time interval was from 29 days to 56 days (5-8 weeks) both in terms of survival outcomes and toxic reactions.
10.2147/CMAR.S276426
Prognostic value of lymphocyte-to-monocyte ratio and systemic immune-inflammation index in non-small-cell lung cancer patients with brain metastases.
Li Aijie,Mu Xiangkui,He Kewen,Wang Peiliang,Wang Duoying,Liu Chao,Yu Jinming
Future oncology (London, England)
We aimed to evaluate the prognostic values of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic immune-inflammation index (SII) in patients with brain metastases from non-small-cell lung cancer (NSCLC). We conducted Kaplan-Meier analysis and multivariable Cox analysis to evaluate the prognostic values of NLR, PLR, LMR and SII. Kaplan-Meier analysis showed that the patients in low LMR, high NLR, PLR and SII groups were associated with shorter overall survival. Multivariable Cox analysis revealed LMR and SII were independent prognostic factors for overall survival (p = 0.002 and p = 0.004, respectively). LMR and SII are of significant values in clinical prognostic evaluation for patients with brain metastases from NSCLC.
10.2217/fon-2020-0423
Increased hippocampal TrkA expression ameliorates cranial radiation‑induced neurogenesis impairment and cognitive deficit via PI3K/AKT signaling.
Ji Shengjun,Wu Haohao,Ding Xin,Chen Qingqing,Jin Xing,Yu Jinming,Yang Ming
Oncology reports
Cognitive deficit is one of the most serious complications of cranial radiotherapy of head and neck cancers. However, the underlying mechanism of this cognitive impairment remains unclear. In the present study, the role of tropomyosin receptor kinase A (TrkA) and its ligand neurotrophin nerve growth factor (NGF) were investigated following whole‑brain irradiation (WBI). Young male Sprague‑Dawley rats underwent WBI at a single dose of 10 Gy. WBI was determined to result in notable memory decline and substantial neurogenesis impairment in the hippocampus 3 months post‑irradiation. Compared with the control group, TrkA protein expression was greater in irradiated rats 1 week after WBI, which then decreased significantly by the 3‑month time‑point. However, no difference in NGF expression was observed from 1 day to 3 months post‑WBI. Overexpression of hippocampal TrkA in rats using adeno‑associated virus ameliorated memory decline induced by irradiation. Additionally, upregulating TrkA expression rescued irradiation‑induced hippocampal precursor cell proliferation and promoted neurogenesis. PI3K, Akt and ERK1/2 phosphorylation were also revealed to be significantly inhibited by WBI, which was ameliorated by TrkA overexpression. Findings of the present study indicated that the TrkA‑dependent signaling pathway may serve a critical role in radiotherapy‑induced cognitive deficit and impairments in neurogenesis.
10.3892/or.2020.7782
Biomarkers of Osimertinib Response in Patients with Refractory, EGFR-T790M-positive Non-Small Cell Lung Cancer and Central Nervous System Metastases: The APOLLO Study.
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:Dynamic biomarker monitoring may inform pathways for treating -T790M-positive non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases with osimertinib. This study aimed to determine the efficacy and safety of osimertinib for real-world patients with -T790M NSCLC and CNS metastases and to explore potential circulating biomarkers of therapeutic response. PATIENTS AND METHODS:APOLLO (ClinicalTrials.gov registration: NCT02972333) was a prospective, single-arm, open-label trial which ran from January 2017 to April 2019. Eligible patients had confirmed -T790M-positive NSCLC, prior treatment with an EGFR-tyrosine kinase inhibitor, and CNS metastases. All enrolled patients received oral osimertinib 80 mg once daily until disease progression or intolerable toxicity. Primary outcome was overall progression-free survival (PFSo) and secondary outcomes included objective response rate (ORR) and adverse events (AE). Exploratory biomarker analysis involved collection of plasma and cerebrospinal fluid (CSF) samples for next-generation sequencing and drug penetration analysis. RESULTS:From January to September 2017, 38 patients were enrolled. After a median follow-up of 8.2 months (range, 0.07-15.6), 23 (60.5%) of 38 patients had disease progression or death. Median PFSo was 8.4 months [95% confidence interval (CI), 5.8-10.9]. Overall ORR was 39.4%. Twelve (31.6%) of 38 patients had ≥1 grade 3-4 AE. Median osimertinib CSF penetration rate was 31.7%. Patients with undetectable plasma mutations at week 6 had improved PFSo compared with those with detectable mutations (not reached vs. 4.5 months; 95% CI, 0.0-1.1; < 0.05). CONCLUSIONS:Osimertinib had potent activity against -T790M-positive NSCLC with CNS metastases. Dynamic monitoring of plasma may suffice for predicting clinical responses, mitigating the need for repeat CSF biopsy..
10.1158/1078-0432.CCR-20-2081
Development of EGFR TKIs and Options to Manage Resistance of Third-Generation EGFR TKI Osimertinib: Conventional Ways and Immune Checkpoint Inhibitors.
Wu Leilei,Ke Linping,Zhang Zhenshan,Yu Jinming,Meng Xue
Frontiers in oncology
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been first-line therapy in the treatment of non-small cell lung cancer (NSCLC) harboring sensitive mutations. Progression inevitably happens after 10-14 months of first- or second-generation EGFR TKIs treatment for acquired resistance. Owing to the successful identification of T790M, third-generation EGFR TKIs such as osimertinib were developed to target such resistance mutation. Nowadays, osimertinib has shown its efficacy both in first-line and second-line after resistance to previous generations of TKI treatment of -mutant NSCLC. However, drug resistance also emerges on third-generation EGFR TKIs. Multiple mechanisms of acquired resistance have been identified, and some novel strategies were reported to overcome third-generation TKI resistance. Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of selected patients. For patients with -addicted metastatic NSCLC, ICIs have also revealed a potential role. In this review, we will take stock of mechanisms of acquired resistance to third-generation TKIs and discuss current challenges and future perspectives in clinical practice.
10.3389/fonc.2020.602762
Pre-radiotherapy lymphocyte count and platelet-to-lymphocyte ratio may improve survival prediction beyond clinical factors in limited stage small cell lung cancer: model development and validation.
Translational lung cancer research
BACKGROUND:Few small sample size studies have reported lymphocyte count was prognostic for survival in small-cell lung cancer (SCLC). This study aimed to validate this finding, to build prediction model for overall survival (OS) and to study whether novel models that combine lymphocyte-related variables can predict OS more accurately than a conventional model using clinical factors alone in a large cohort of limited-stage SCLC patients. METHODS:This study enrolled 544 limited-stage SCLC patients receiving definitive chemo-radiation with pre-radiotherapy lymphocyte-related variables including absolute lymphocyte count (ALC), platelet-to-lymphocyte ratio (P/L ratio), neutrophil-to-lymphocyte ratio (N/L ratio), and lymphocyte-to-monocyte ratio (L/M ratio). The primary endpoint was OS. These patients were randomly divided into a training dataset (n=274) and a validation dataset (n=270). Multivariate survival models were built in the training dataset, and the performance of these models were further tested in the validation dataset using the concordance index (C-index). RESULTS:The median follow-up time was 36 months for all patients. In the training dataset, univariate analysis showed that ALC (P=0.020) and P/L ratio (P=0.023) were significantly correlated with OS, while L/M ratio (P=0.091) and N/L ratio (P=0.436) were not. Multivariate modeling demonstrated the significance of ALC (P=0.063) and P/L ratio (P=0.003), and the improvement for OS prediction in combined models with the addition of ALC (C-index =0.693) or P/L ratio (C-index =0.688) over the conventional model (C-index =0.679). The validation dataset analysis confirmed a modest improvement of C-index with the addition of ALC or P/L ratio. All these models showed reasonable discriminations and calibrations. CONCLUSIONS:This study validated the significant value of pre-radiotherapy ALC and P/L ratio on OS in limited-stage SCLC. The combined model with ALC or P/L ratio showed additional OS prediction values than the conventional model with clinical factors alone.
10.21037/tlcr-20-666
Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy.
Lung cancer (Amsterdam, Netherlands)
INTRODUCTION:B-cell lymphoma 2-like 11 (BCL-2-like 11, BCL2L11, also known as BIM) deletion polymorphism (BIM-del) has been associated with resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and is a poor prognostic factor for EGFR-mutant non-small-cell lung cancer (NSCLC) patients. Nevertheless, the impact of BIM-del in advanced NSCLC patients treated with the third-generation EGFR-TKI osimertinib remains undetermined. This study aims to evaluate the relationship between BIM-del and therapeutic efficacy of osimertinib in pretreated NSCLC patients. METHODS:Patients subjected to EGFR T790 M detection and prior osimertinib treatment between December 2015 and December 2019 in our hospital were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del. RESULTS:In total, 152 Chinese Han NSCLC patients-including 143 T790M-positive and nine T790M-negative patients-were enrolled. BIM-del was detected in only 17.5 % of T790M-positive patients (25/143). The majority of patients were aged <65 years (81.8 %, 117/143), were female (58.7 %, 84/143), were non-smokers (82.5 %, 118/143), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (88.8 %, 129/143), and exhibited metastases in the central nervous system (CNS) (54.5 %, 78/143). There were no associations between the BIM-del and clinical characteristics (including age, sex, histology, smoking status, stage, ECOG PS score, and CNS metastases). Patients with BIM-del had a poorer objective response rate than those without (28.0 % versus 52.5 %, p = 0.026). Besides, BIM-del was associated with a significantly shorter progression-free survival (PFS) and a moderately shorter overall survival (OS) (8.3 versus 10.5 months, p = 0.031 and 15.9 versus 25.2 months, p = 0.1, respectively). Multivariate analysis indicated that BIM-del was an independent prognostic factor for PFS but not for OS in EGFR T790 M NSCLC patients. CONCLUSIONS:BIM-del is associated with poor clinical responses and outcomes, and might be a negative predictive and prognostic biomarker in EGFR T790 M NSCLC patients with osimertinib treatment.
10.1016/j.lungcan.2020.12.002
CD155 Overexpression Correlates With Poor Prognosis in Primary Small Cell Carcinoma of the Esophagus.
Zhao Kaikai,Ma Lin,Feng Lei,Huang Zhaoqin,Meng Xiangjiao,Yu Jinming
Frontiers in molecular biosciences
CD155/TIGIT overexpression has been detected in various human malignancies; however, its expression status in primary small cell carcinoma of the esophagus (PSCCE) and its prognostic significance remain unclear. In this study, we aimed to explore the expression and prognostic value of CD155 and TIGIT in PSCCE. We detected CD155 and TIGIT expression in 114 cases of PSCCE using immunohistochemistry (IHC) and evaluated their relationship with the clinicopathological characteristics and survival of the patients. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards model. Nomogram performance was assessed via the concordance index (C-index) and calibration plots. Decision curve analysis (DCA) was performed to evaluate the net benefit of the nomogram. We found that CD155 and TIGIT were overexpressed in PSCCE tissues, CD155 expression correlated positively with TIGIT ( < 0.001) and was significantly associated with tumor size, T stage, distant metastasis, TNM stage, and Ki-67 score. TIGIT expression was also significantly associated with T stage, distant metastasis, and TNM stage. Patients with high CD155 and TIGIT expression had a significantly shorter overall survival (OS) and progression-free survival (PFS), while the multivariate model showed that CD155 expression and the therapeutic strategy are independent prognostic factors for PSCCE. In the validation step, OS was shown to be well-calibrated (C-index = 0.724), and a satisfactory clinical utility was proven by DCA. In conclusion, our findings revealed that CD155 and TIGIT are highly expressed in patients with PSCCE and are associated with shorter OS and PFS, supporting their role as prognostic biomarker.
10.3389/fmolb.2020.608404
A nomogram for the predicting of survival in patients with esophageal squamous cell carcinoma undergoing definitive chemoradiotherapy.
Wang Peiliang,Yang Maoqi,Wang Xin,Zhao Zongxing,Li Minghuan,Yu Jinming
Annals of translational medicine
Background:Definitive chemoradiotherapy (dCRT) is widely accepted for esophageal squamous cell carcinoma (ESCC), although the outcomes can vary. Therefore, we aimed to develop a nomogram for the pre-treatment prediction of survival after dCRT for ESCC. Methods:This retrospective study evaluated 204 patients (169 patients in a primary cohort and 35 patients in a validation cohort) who received dCRT for ESCC between July 2013 and June 2017. Results:Pre-treatment parameters that predicted long-term survival in this setting were body mass index (BMI), absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), wall thickness, concurrent chemoradiotherapy, radiotherapy modality, and American Joint Committee on Cancer (AJCC) stage. The nomogram incorporated these factors and provided C-index values of 0.691 [95% confidence interval (CI): 0.641-0.740] in the primary cohort and 0.816 (95% CI: 0.700-0.932) in the validation cohort. The calibration curve analysis revealed that the nomogram had good ability to predict 2-year progression-free survival (PFS). The nomogram also performed better than the AJCC staging system by the C-index values (0.691 . 0.560) and the area under the curve values (0.702 . 0.576). Decision curve analysis (DCA) also indicated that the nomogram had better clinical utility. Conclusions:These results suggest that pre-treatment parameters may help predict the efficacy of dCRT for ESCC. Furthermore, as the nomogram provided better prognostic accuracy than the AJCC staging system, the nomogram may be useful in clinical practice for prognostication among patients who are going to receive dCRT for ESCC.
10.21037/atm-20-1460
Efficacy and Safety of Anti-PD-1 Plus Anlotinib in Patients With Advanced Non-Small-Cell Lung Cancer After Previous Systemic Treatment Failure-A Retrospective Study.
Wang Peiliang,Fang Xiaozhuang,Yin Tianwen,Tian Hairong,Yu Jinming,Teng Feifei
Frontiers in oncology
Background:Pre-clinical and clinical evidences support that simultaneous blockade of programmed death-1 (PD-1) and vascular endothelial growth factor receptor (VEGFR) can enhance antigen-specific T-cell migration, and show tolerable toxicity with favorable antitumor activity in patients. In this study, we aimed to assess the safety and efficacy of anlotinib, a novel multitarget tyrosine kinase inhibitor for VEGFR, platelet-derived growth receptor (PDGFR), and the stem cell-factor receptor (c-Kit), combined with anti-PD-1 treatment in patients with advanced NSCLC. Methods:Sixty-seven patients with previously treated advanced NSCLC receiving anti-PD-1 agents concomitant with anlotinib were retrospectively enrolled in an IRB approved study. Anti-PD-1 agents including pembrolizumab, nivolumab, camrelizumab, toripalimab, sintilimab, and tislelizumab were administered every two or three weeks until disease progression or unacceptable toxicity was reached. Anlotinib was administered orally once daily on days 1-14 of a 21-day cycle. The safety and tolerability of the combination treatment were assessed by the incidence of adverse events. The efficacy of the treatment was assessed by the tumor response and survival. Results:With a median follow-up period of 8.7 months, treatment-related adverse events occurred in 85% (57/67) of patients and grade 3-4 adverse events were observed in 27 patients (40%). No unexpected adverse events or significantly increased toxicities were observed. Complete response was not observed, 19 patients had partial response (28.4%), 39 had stable disease (58.2%) and 9 had progressive disease (13.4%). The overall response (ORR) and disease control rates (DCR) were 28.4% and 86.6%, respectively. The median progression-free survival (PFS) was 6.9 months (95% CI, 5.5-8.3 months) and overall survival (OS) was 14.5 months (95% CI, 10.9-18.1 months). The benefit of anti-PD-1 plus anlotinib was also observed in patients with EGFR mutation positive, liver metastases and brain metastases. Conclusion:Anti-PD-1 treatment concomitant with anlotinib has tolerable toxicity and favorable antitumor activity in patients with previously treated advanced NSCLC. Our results add to the growing evidence that supports the benefits of combining immunotherapy with antiangiogenic drugs. This combination could be further evaluated with or without chemotherapy, since no additional toxicity was observed in the combination treatment.
10.3389/fonc.2021.628124
Human leukocyte antigen-G upregulates immunoglobulin-like transcripts and corrects dysfunction of immune cells in immune thrombocytopenia.
Li Xin,Sheng Zi,Sun Yuanxin,Wang Yuanjian,Xu Miao,Zhang Zhiyue,Li Hui,Shao Linlin,Zhang Yanqi,Yu Jinming,Ma Chunhong,Gao Chengjiang,Hou Ming,Ni Heyu,Peng Jun,Ma Ji,Feng Qi
Haematologica
Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibilitycomplex class I antigen with potent immune-inhibitoryfunction. HLA-G benefit patients in allotransplantation andautoimmune diseases by interacting with its receptors, immunoglobulinliketranscripts. Here we observed significantly less HLA-G in plasma fromimmune thrombocytopenia (ITP) patients positive for anti-platelet autoantibodiescompared with autoantibodies-negative patients or healthy controls,while we found that HLA-G is positively correlated with plateletcounts in both patients and healthy controls. We also found less membraneboundHLA-G and immunoglobulin-like transcripts on CD4+ and CD14+cells in patients. Recombinant HLA-G upregulated immunoglobulin-liketranscript 2 expression on CD4+ and immunoglobulin-like transcript 4 onCD14+ cells. HLA-G upregulated IL-4 and IL-10, and downregulated tumornecrosis factor-a, IL-12 and IL-17 secreted by patient peripheral bloodmononuclear cells, suggesting a stimulation of Th2 differentiation anddownregulation of Th1 and Th17 immune response. HLA-G-modulateddendritic cells from ITP patients showed decreased expression of CD80 andCD86, and suppressed CD4+ T-cell proliferation compared to unmodulatedcells. Moreover, HLA-G-modulated cells from patients induced less plateletapoptosis. HLA-G administration also significantly alleviated thrombocytopeniain a murine model of ITP. In conclusion, our data demonstrated thatimpaired expression of HLA-G and immunoglobulin-like transcripts isinvolved in the pathogenesis of ITP; recombinant HLA-G can correct thisabnormality via upregulation of immunoglobulin-like transcripts, indicatingthat HLA-G can be a diagnostic marker and a therapeutic option for ITP.
10.3324/haematol.2018.204040
Immunotherapy for recurrent glioblastoma: practical insights and challenging prospects.
Wang Xin,Lu Jie,Guo Gaochao,Yu Jinming
Cell death & disease
Glioblastoma (GB) is the most common high-grade intracranial malignant tumor with highly malignant biological behavior and a high recurrence rate. Although anti-PD-1/PD-L1 antibodies have achieved significant survival benefits in several kinds of solid tumors, the phase III clinical trial Checkmate 143 demonstrated that nivolumab, which targets PD-1, did not achieve survival benefits compared with bevacizumab in recurrent glioblastoma (rGB) patients. Nevertheless, neoadjuvant anti-PD-1 therapy followed by surgery and adjuvant anti-PD-1 therapy could effectively activate local and systemic immune responses and significantly improve the OS of rGB patients. Furthermore, several studies have also confirmed the progress made in applying tumor-specific peptide vaccination or chimeric antigen receptor-T (CAR-T) cell therapy to treat rGB patients, and successes with antibodies targeting other inhibitory checkpoints or costimulatory molecules have also been reported. These successes inspired us to explore candidate combination treatments based on anti-PD-1/PD-L1 antibodies. However, effective predictive biomarkers for clinical efficacy are urgently needed to avoid economic waste and treatment delay. Attempts to prolong the CAR-T cell lifespan and increase T cell infiltration through engineering techniques are addressing the challenge of strengthening T cell function. In this review, we describe the immunosuppressive molecular characteristics of rGB; clinical trials exploring anti-PD-1/PD-L1 therapy, tumor-specific peptide vaccination, and CAR-T cell therapy; candidate combination strategies; and issues related to strengthening T cell function.
10.1038/s41419-021-03568-0
Corrigendum: Previous Radiotherapy Increases the Efficacy of IL-2 in Malignant Pleural Effusion: Potential Evidence of a Radio-Memory Effect?
Chen Dawei,Song Xinyu,Wang Haiyong,Gao Zhenwu,Meng Wenjuan,Chen Shuquan,Ma Yunfeng,Wang Youda,Li Kong,Yu Jinming,Yue Jinbo
Frontiers in immunology
[This corrects the article DOI: 10.3389/fimmu.2018.02916.].
10.3389/fimmu.2021.649620
Anti-PD-(L)1 immunotherapy for brain metastases in non-small cell lung cancer: Mechanisms, advances, and challenges.
Zhou Shujie,Xie Jingjing,Huang Zhaoqin,Deng Liufu,Wu Leilei,Yu Jinming,Meng Xiangjiao
Cancer letters
The brain is one of the most common metastatic sites in non-small cell lung cancer (NSCLC), which is associated with an extremely poor prognosis. Despite the availability of several therapeutic options, the treatment efficacy remains unsatisfactory for NSCLC brain metastases. Anti-programmed cell death-1 (PD-1) and its ligand (PD-L1) monoclonal antibodies have reshaped therapeutic strategies in advanced NSCLC. Preliminary evidence has shown that anti-PD-(L)1 monotherapy is also effective in NSCLC patients with brain metastases. However, the traditional view asserted that these therapeutic antibodies were incapable of crossing the blood-brain barrier (BBB) with large molecular size, thus most patients with brain metastases were excluded from most studies on anti-PD-(L)1 immunotherapy. Therefore, the efficacy and its mechanisms of action of anti-PD-(L)1 immunotherapy against brain metastases in NSCLC have not been clarified. In this review, we will survey the underlying mechanisms and current clinical advances of anti-PD-(L)1 immunotherapy in the treatment of brain metastases in NSCLC. The trafficking of activated cytotoxic T cells that are mainly derived from the primary tumor and deep cervical lymph nodes is critical for the intracranial response to anti-PD-(L)1 immunotherapy, which is driven by interferon-γ (IFN-γ). Additionally, promising combined strategies with the rationale in the treatment of brain metastases will be presented to provide future directions for clinical study design. Several significant challenges in the preclinical and clinical studies of brain metastases, as well as potential solutions, will also be discussed.
10.1016/j.canlet.2020.12.043
Feasibility of semiquantitative 18F-fluorodeoxyglucose PET/computed tomography in patients with advanced lung cancer for interim treatment evaluation of combining immunotherapy and chemotherapy.
Nuclear medicine communications
OBJECTIVE:This study aimed to investigate the prognosis value of 18F-fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT) in advanced lung cancer patients with immunotherapy combined with chemotherapy. METHODS:Fifty-one advanced lung cancer patients were included in this retrospective study, who underwent 18F-FDG PET/CT imaging before four cycles of immunotherapy combined with chemotherapy at our institution between January 2018 and January 2020. The following PET/CT parameters were calculated: standardized uptake value SUVmax, SUVmean, SUVpeak, SUVsd, metabolic tumor volume (MTV), total lesion glycolysis (TLG), MTV25%, MTV42%, MTV50%, MTV75%, global lung glycolysis (GLG), target-to-background ratio (TBR), SUVpeakwb, MTVwb, TLGwb, SUVmeanwb, SUVmaxwb. Logistics regression analyses were used for assessing the association between baseline metabolic parameters and response to treatment. Kaplan-Meier estimator curves and the log-rank test were constructed for survival analyses. RESULTS:According to RECIST, nine patients (18%) showed partial response, 25 (49%) had SD, and 17 (33%) had progressive disease. The mean ± SD of SUVmax, SUVpeak, MTV were lower in clinical benefit (CB) group than no-clinical benefit (no-CB) group (all P < 0.05). Median PFS was 3.7 months in no-CB group and 9.9 months in CB group (P < 0.001). Multivariate logistic analysis indicated that SUVmax and histology were independent factors significantly related to the evaluation of therapeutic efficiency. Furthermore, SUVmax is an independent predictor of efficacy in non-small cell lung cancer. CONCLUSION:SUVmax can be used to predict interim treatment response of immunotherapy combination with chemotherapy for advanced lung cancer. Moreover, the combination of SUVmax and histology may predict treatment response with acceptable reliability. However, a large prospective multicenter trial is still needed to examine the above finding for lacking limited evidence.
10.1097/MNM.0000000000001428
A preclinical study: correlation between PD-L1 PET imaging and the prediction of therapy efficacy of MC38 tumor with Ga-labeled PD-L1 targeted nanobody.
Qin Songbing,Yu Yang,Guan Hui,Yang Yanling,Sun Fenghao,Sun Yan,Zhu Jiaxing,Xing Ligang,Yu Jinming,Sun Xiaorong
Aging
Although immunotherapy has achieved great clinical success in clinical outcomes, especially the anti-PD-1 or anti-PD-L1 antibodies, not all patients respond to anti-PD-1 immunotherapy. It is urgently required for a clinical diagnosis to develop non-invasive imaging meditated strategy for assessing the expression level of PD-L1 in tumors. In this work, a Ga-labeled single-domain antibody tracer, Ga-NOTA-Nb109, was designed for specific and noninvasive imaging of PD-L1 expression in an MC38 tumor-bearing mouse model. Comprehensive studies including Positron Emission Tomography (PET), biodistribution, blocking studies, immunohistochemistry, and immunotherapy, have been performed in differences PD-L1 expression tumor-bearing models. These results revealed that Ga-NOTA-Nb109 specifically accumulated in the MC38-hPD-L1 tumor. The content of this nanobody in MC38 hPD-L1 tumor and MC38 Mixed tumor was 8.2 ± 1.3, 7.3 ± 1.2, 3.7 ± 1.5, 2.3 ± 1.2%ID/g and 7.5 ± 1.4, 3.6 ± 1.7, 1.7 ± 0.6, 1.2 ± 0.5%ID/g at 0.5, 1, 1.5, 2 hours post-injection, respectively. Ga-NOTA-Nb109 has the potential to further noninvasive PET imaging and therapy effectiveness assessments based on the PD-L1 status in tumors. To explore the possible synergistic effects of immunotherapy combined with chemotherapy, MC38 xenografts with different sensitivity to PD-L1 blockade were established. In addition, we found that PD-1 blockade also had efficacy on the PD-L1 knockout tumors. RT-PCR and immunofluorescence analysis were used to detect the expression of PD-L1. It was observed that both mouse and human PD-L1 expressed among three types of MC38 tumors. These results suggest that PD-L1 on tumor cells affect the efficacy, but it on host myeloid cells might be essential for checkpoint blockade. Moreover, anti-PD-1 treatment activates tumor-reactive CD103 CD39 CD8+T cells (TILs) in tumor microenvironment.
10.18632/aging.202981
Erlotinib Versus Etoposide/Cisplatin With Radiation Therapy in Unresectable Stage III Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter, Randomized, Open-Label, Phase 2 Trial.
Xing Ligang,Wu Gang,Wang Luhua,Li Jiancheng,Wang Jianhua,Yuan Zhiyong,Chen Ming,Xu Yaping,Fu Xiaolong,Zhu Zhengfei,Lu You,Han Chun,Xia Tingyi,Xie Conghua,Li Guang,Ma Shenglin,Lu Bing,Lin Qin,Zhu Guangying,Qu Baolin,Zhu Wanqi,Yu Jinming
International journal of radiation oncology, biology, physics
PURPOSE:This study aimed to compare erlotinib (E) and etoposide/cisplatin (EP) with concurrent radiation therapy (RT) for patients with stage IIIA/B unresectable advanced non-small cell lung cancer with activating epidermal growth factor receptor mutation (EGFRm+). METHODS AND PATIENTS:This was a multicenter, randomized, open-label, phase 2 trial conducted across 19 institutions in China (December 2012 to January 2016). Enrolled patients were randomized (1:1) to E + RT (oral erlotinib 150 mg/d for 2 years or until disease progression or intolerable toxicity and RT 200 cGy/d, 5 d/wk for 6 weeks from the first day of erlotinib) or EP + RT (etoposide 50 mg/m intravenously on days 1-5 and 29-33; cisplatin 50 mg/m intravenously on days 1, 8, 29 and 36; and RT as for E + RT). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate and safety. RESULTS:Two hundred fifty-two patients were screened, and 20 patients with EGFRm+ in each group received the allocated E + RT or EP + RT treatment. Patient characteristics were well balanced between groups. Compared with EP + RT, median PFS with E + RT was significantly longer (24.5 vs 9.0 months [hazard ratio, 0.104; 95% confidence interval, 0.028-0.389; P < .001]). Objective response rate in the E + RT and EP + RT groups was 70% and 61.9%, respectively (P = .744). The incidence of adverse events (any grade) was similar between E + RT and EP + RT groups (88.9% and 84.2%). CONCLUSIONS:The primary endpoint of PFS was met, and the data showed that E + RT might provide PFS improvement compared with EP + RT, with similar tolerability. However, definitive statements regarding the efficacy of concurrent E + RT in patients with unresectable stage III non-small cell lung cancer with activating EGFRm+ cannot be made, and slow patient accrual will likely make it infeasible to conduct a phase 3 study.
10.1016/j.ijrobp.2020.11.026
Computed Tomography-Based Delta-Radiomics Analysis for Discriminating Radiation Pneumonitis in Patients With Esophageal Cancer After Radiation Therapy.
Wang Lu,Gao Zhenhua,Li Chengming,Sun Liangchao,Li Jianing,Yu Jinming,Meng Xue
International journal of radiation oncology, biology, physics
PURPOSE:Our purpose was to construct a computed tomography (CT)-based delta-radiomics nomogram and corresponding risk classification system for individualized and accurate estimation of severe acute radiation pneumonitis (SARP) in patients with esophageal cancer (EC) after radiation therapy. METHODS AND MATERIALS:Four hundred patients with EC were enrolled from 2 independent institutions and were divided into the training (n = 200) and validation (n = 200) cohorts. Eight hundred fifty radiomics features of lung were extracted from treatment planning images, including the positioning CT before radiation therapy (CT) and the resetting CT after receiving 40 to 45 Gy (CT). The longitudinal net changes in radiomics features from CT to CT were calculated and defined as delta-radiomics features. Least absolute shrinkage and selection operator algorithm was performed to features selection and delta-radiomics signature building. Integrating the signature with multidimensional clinicopathologic, dosimetric, and hematological predictors of SARP, a novel CT-based delta-radiomics nomogram was established according to multivariate analysis. The clinical application values of nomogram were both evaluated in the training and validation cohorts by concordance index, calibration curves, and decision curve analysis. Recursive partitioning analysis was used to generate a risk classification system. RESULTS:The delta-radiomics signature consisting of 24 features was significantly associated with SARP status (P < .001). Incorporating it with other high-risk factors, Subjective Global Assessment score, pulmonary fibrosis score, mean lung dose, and systemic immune inflammation index, the developed delta-radiomics nomogram showed increased improvement in SARP discrimination accuracy with concordance index of 0.975 and 0.921 in the training and validation cohorts, respectively. Calibration curves and decision curve analysis confirmed the satisfactory clinical feasibility and utility of nomogram. The risk classification system displayed excellent performance on identifying SARP occurrence (P < .001). CONCLUSIONS:The delta-radiomics nomogram and risk classification system as low-cost and noninvasive means exhibited superior predictive accuracy and provided individualized probability of SARP stratification for patients with EC.
10.1016/j.ijrobp.2021.04.047
Efficacy and toxicity of re-irradiation for esophageal cancer patients with locoregional recurrence: a retrospective analysis.
Radiation oncology (London, England)
INTRODUCTION:There is no standard treatment for locoregional recurrent (LR) esophageal squamous cell carcinoma (ESCC) patients treated with radiotherapy (RT) previously. This retrospective study aimed to examine the efficacy and toxicity of re-irradiation (re-RT) for ESCC patients with LR. PATIENTS AND METHODS:A total of 252 patients were enrolled. Gross tumor volumes for re-RT were defined using contrast enhanced computed tomography and/or positron emission tomography/computed tomography. Overall survival (OS), after recurrence survival (ARS) and toxicities were assessed. RESULTS:Through a median follow-up of 38 months, the median OS and ARS were 39.0 and 13.0 months, respectively. The 6-, 12-, and 24-month ARS rates were 81.9%, 50.5%, and 21.8%, respectively. Multivariate analyses showed that chemotherapy, esophageal stenosis and recurrence-free interval (RFI) may be independent prognostic factors for ARS. The incidence of esophageal fistula/perforation (EP), radiation-induced pneumonitis and esophagorrhagia was 21.4%, 12.8% and 9.1%, respectively. RFI ≤ 12 months, esophageal stenosis and fat space between tumor and adjacent tissue disappeared were independent risk factors for the development of EP after re-RT. CONCLUSIONS:Re-RT was feasible for LR ESCC patients after RT initially, the complication occurred in re-RT is acceptable. Patients with RFI ≤ 12 months, esophageal stenosis and fat space between tumor and adjacent tissue disappeared should be closely observed during and after re-RT.
10.1186/s13014-020-01685-2
The flow-metabolism ratio might predict treatment response and survival in patients with locally advanced esophageal squamous cell carcinoma.
Zhao Kewei,Wang Chunsheng,Mao Qingfeng,Shang Dongping,Huang Yong,Ma Li,Yu Jinming,Li Minghuan
EJNMMI research
BACKGROUND:Perfusion CT can offer functional information about tumor angiogenesis, and F-FDG PET/CT quantifies the glucose metabolic activity of tumors. This prospective study aims to investigate the value of biologically relevant imaging biomarkers for predicting treatment response and survival outcomes in patients with locally advanced esophageal squamous cell cancer (LA ESCC). METHODS:Twenty-seven patients with pathologically proven ESCC were included. All patients had undergone perfusion CT and F-FDG PET/CT using separate imaging systems before receiving definitive chemoradiotherapy (dCRT). The perfusion parameters included blood flow (BF), blood volume (BV), and time to peak (TTP), and the metabolic parameters included maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The flow-metabolism ratio (FMR) was defined as BF divided by SUVmax. Statistical methods used included Spearman's rank correlation, Mann-Whitney U test or two-sample t test, receiver operating characteristic (ROC) curve analysis, the Kaplan-Meier method, and Cox proportional hazards models. RESULTS:The median overall survival (OS) and progression-free survival (PFS) were 18 and 11.6 months, respectively. FMR was significantly positively correlated with BF (r = 0.886, p < 0.001) and negatively correlated with SUVmax (r = - 0.547, p = 0.003) and TTP (r = - 0.462, p = 0.015) in the tumors. However, there was no significant correlation between perfusion and PET parameters. After dCRT, 14 patients (51.9%) were identified as responders, and another 13 were nonresponders. The BF and FMR of the responders were significantly higher than those of the nonresponders (42.05 ± 16.47 vs 27.48 ± 8.55, p = 0.007; 3.18 ± 1.15 vs 1.84 ± 0.65, p = 0.001). The ROC curves indicated that the FMR [area under the curve (AUC) = 0.846] was a better biomarker for predicting treatment response than BF (AUC = 0.802). Univariable Cox analysis revealed that of all imaging parameters, only the FMR was significantly correlated with overall survival (OS) (p = 0.015) and progression-free survival (PFS) (p = 0.017). Specifically, patients with a lower FMR had poorer survival. Multivariable analysis showed that after adjusting for age, clinical staging, and treatment response, the FMR remained an independent predictor of OS (p = 0.026) and PFS (p = 0.014). CONCLUSIONS:The flow-metabolism mismatch demonstrated by a low FMR shows good potential in predicting chemoradiotherapy sensitivity and prognosis in ESCC.
10.1186/s13550-020-00647-9
Preoperative tumor biopsy results in more detected sentinel nodes than intraoperative biopsy in breast cancer patients.
Yuan Chenxi,Wang Xinzhao,Liu Zhaoyun,Li Chao,Bian Mengxue,Shan Jing,Song Xiang,Yu Zhiyong,Yu Jinming
World journal of surgical oncology
BACKGROUND:Sentinel lymph node biopsy (SLNB) plays a vital role in breast cancer surgery, and the identified number of sentinel nodes determines its accuracy for representing the status of the axillae. There are two types of tumor biopsies in breast cancer: preoperative and intraoperative biopsies. We compared the effects of the two different biopsies on the results of SLNB. METHODS:Patients with clinical stages T1-3, N0 (cT1-3 N0) tumors were enrolled in this study. A total of 53% of patients received preoperative tumor biopsy, and 47% received intraoperative excisional biopsy. To identify the sentinel lymph nodes, patients received dual tracer injection. The number of SLNs detected and the false-negative rate were compared between groups. RESULTS:A total of 204 patients were enrolled, 108 received preoperative tumor biopsy, and 96 received intraoperative excisional biopsy. Among all the patients, 160 received axillary lymph node dissection (ALND) following SLNB. Preoperative tumor biopsy detected more SLNs than intraoperative biopsy (mean rank 113.87 vs. 90.9, p = 0.004). The false-negative rates in the preoperative and intraoperative tumor biopsy groups were 3% and 18%, respectively. CONCLUSIONS:Patients in the preoperative tumor biopsy group had more SLNs identified than intraoperative biopsy patients. The false-negative rate was also lower in the preoperative biopsy group.
10.1186/s12957-020-01942-4
The role of exosomes in tumour immunity under radiotherapy: eliciting abscopal effects?
Biomarker research
As a curative treatment of localized tumours or as palliative control, radiotherapy (RT) has long been known to kill tumour cells and trigger the release of proinflammatory factors and immune cells to elicit an immunological response to cancer. As a crucial part of the tumour microenvironment (TME), exosomes, which are double-layered nanometre-sized vesicles, can convey molecules, present antigens, and mediate cell signalling to regulate tumour immunity via their contents. Different contents result in different effects of exosomes. The abscopal effect is a systemic antitumour effect that occurs outside of the irradiated field and is associated with tumour regression. This effect is mediated through the immune system, mainly via cell-mediated immunity, and results from a combination of inflammatory cytokine cascades and immune effector cell activation. Although the abscopal effect has been observed in various malignancies for many years, it is still a rarely identified clinical event. Researchers have indicated that exosomes can potentiate abscopal effects to enhance the effects of radiation, but the specific mechanisms are still unclear. In addition, radiation can affect exosome release and composition, and irradiated cells release exosomes with specific contents that change the cellular immune status. Hence, fully understanding how radiation affects tumour immunity and the interaction between specific exosomal contents and radiation may be a potential strategy to maximize the efficacy of cancer therapy. The optimal application of exosomes as novel immune stimulators is under active investigation and is described in this review.
10.1186/s40364-021-00277-w
Whole brain radiation therapy plus focal boost may be a suitable strategy for brain metastases in SCLC patients: a multi-center study.
Ni Meng,Jiang Aijun,Liu Wenju,Sheng Yanxing,Zeng Haiyan,Liu Ning,Gao Qingxiao,Wang Yong,Yu Jinming,Yuan Shuanghu
Radiation oncology (London, England)
BACKGROUND:The treatment for brain metastases in small cell lung cancer (SCLC) is still controversial. The purpose of this study was to compare different brain radiotherapy treatments on SCLC patients with brain metastases. METHODS:In this multi-center retrospective study, SCLC patients who had undergone whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases from January 2012 to December 2018 were retrospectively screened. RESULTS:A total of 263 eligible SCLC patients were included in this study, among whom, 73 were women and 190 were men. According to accepted brain radiotherapy, the remaining patients were divided into WBRT plus focal radiation boost (WBRT+boost), WBRT, and SRS groups. In pairwise comparisons of the overall survival (OS), WBRT+boost group led to longer survival than did WBRT both in all patients (17.9 vs 8.7 months; P < 0.001) and 140 matched patients (17.9 vs 11.7 months; P = 0.045). There were no significant differences in OS between WBRT+boost and SRS groups in all patients (17.9 vs 14.5 months; P = 0.432). Among 74 matched patients between WBRT+boost and SRS groups, however, patients who received WBRT+boost led to a longer survival than did SRS alone (21.8 vs 12.9 months; P = 0.040). In pairwise comparison of the intracranial progression-free survival time (iPFS), WBRT+boost group also showed survival advantages over WBRT (10.8 vs 6.5 months; P = 0.005) and SRS groups (10.8 vs 7.5 months; P = 0.032). CONCLUSION:Due to the SCLC-derived multiple brain metastases and better survival time, focal radiation boost combined with adjuvant WBRT may be a preferred strategy for SCLC patients with brain metastases.
10.1186/s13014-020-01509-3
Whole Brain Radiation Therapy Plus Focal Radiation Boost May Generate Better Survival Benefit for Brain Metastases From Non-small Cell Lung Cancer.
Ni Meng,Liu Wenju,Jiang Aijun,Wang Yong,Sheng Yanxing,Zeng Haiyan,Liu Ning,Li Li,Qi Yiqiang,Wang Yu,Yu Jinming,Yuan Shuanghu
Frontiers in oncology
Background:Owing to improved systemic therapies, the survival of patients with non-small cell lung cancer (NSCLC) was prolonged, and the risk of brain metastases was consequently increased. This study aims to compare different radiotherapy for brain metastases in patients with NSCLC. Materials and methods:The patients with NSCLC who were treated with whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases at three medical centers between January 2012 and December 2017 were retrospectively analyzed. Results:Of the 684 eligible patients, 217 received WBRT plus focal radiation boost (WBRT+boost), 324 received WBRT, and 143 received SRS. Patients with WBRT+boost lived longer than those with WBRT (median overall survival (OS), 22.2 vs 13.7 months, < 0.001) or SRS (22.2 vs 17.3 months, = 0.011). In subgroup analyses, the survival advantage of WBRT+boost was more obvious among patients with 1 to 3 brain metastases or who received targeted therapy than did SRS. From pair-wise comparisons of intracranial progression-free survival (iPFS), WBRT+boost was also superior to WBRT (12.9 vs 10.6 months, = 0.028) and SRS (12.9 vs 9.1 months, = 0.001). Conclusions:Patients who were treated with WBRT+boost experienced significantly longer OS and iPFS than those with WBRT or SRS alone. WBRT+boost should be a preferred strategy for brain metastases in NSCLC patients.
10.3389/fonc.2020.576700
The landscape of bispecific T cell engager in cancer treatment.
Biomarker research
T cell-based immunotherapies have revolutionized treatment paradigms in various cancers, however, limited response rates secondary to lack of significant T-cell infiltration in the tumor site remain a major problem. To address this limitation, strategies for redirecting T cells to treat cancer are being intensively investigated, while the bispecific T cell engager (BiTE) therapy constitutes one of the most promising therapeutic approaches. BiTE is a bispecific antibody construct with a unique function, simultaneously binding an antigen on tumor cells and a surface molecule on T cells to induce tumor lysis. BiTE therapy represented by blinatumomab has achieved impressive efficacy in the treatment of B cell malignancies. However, major mechanisms of resistance to BiTE therapy are associated with antigen loss and immunosuppressive factors such as the upregulation of immune checkpoints. Thus, modification of antibody constructs and searching for combination strategies designed to further enhance treatment efficacy as well as reduce toxicity has become an urgent issue, especially for solid tumors in which response to BiTE therapy is always poor. In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies. In this review, we depict the landscape of BiTE therapy, including clinical advances with potential response predictors, challenges of treatment toxicity and resistance, and developments of novel immune cell-based engager therapy.
10.1186/s40364-021-00294-9
The post-treatment neutrophil-to-lymphocyte ratio and changes in this ratio predict survival after treatment of stage III non-small-cell lung cancer with conventionally fractionated radiotherapy.
Wang Duoying,Guo Dong,Li Aijie,Wang Peiliang,Teng Feifei,Yu Jinming
Future oncology (London, England)
To investigate the predictive potential of post-treatment neutrophil-to-lymphocyte ratio (NLR) and changes in this ratio (ΔNLR) for stage III non-small-cell lung cancer (NSCLC) patients who received conventionally fractionated radiotherapy (CFRT). The data of 168 NSCLC patients treated at the Shandong Cancer Hospital were analyzed retrospectively. The relationship between progression-free survival (PFS), overall survival (OS) and post-treatment NLR and ΔNLR were analyzed using both Kaplan-Meier and Cox regression methods. Kaplan-Meier survival analyses showed that post-treatment NLR and ΔNLR were associated with PFS (p < 0.001) and OS (p < 0.001) after CFRT. Multivariate analyses revealed that ΔNLR was an independent predictor of PFS (p = 0.001) and OS (p = 0.018). Post-treatment NLR can only be used as an independent predictor of PFS (p = 0.040). Our results demonstrated the prognostic value of the ΔNLR in predicting PFS and OS in stage III NSCLC patients undergoing CFRT. However, post-treatment NLR has predictive value only for PFS.
10.2217/fon-2019-0837
A nomogram to predict short-term outcome of radiotherapy or chemoradiotherapy based on pre/post-treatment inflammatory biomarkers and their dynamic changes in esophageal squamous cell carcinoma.
Liang Shuai,Li Chengming,Gao Zhenhua,Li Jianing,Zhao Heng,Yu Jinming,Meng Xue
International immunopharmacology
OBJECTIVE:We initially aimed to investigate pre/post-treatment inflammatory biomarkers (pre/post-IBs) and their dynamic changes (delta-IBs) on the short-term outcome (STO) of radiotherapy or chemoradiotherapy in esophageal squamous cell carcinoma (ESCC). Furthermore, a nomogram was built to provide an accurate prediction of STO. METHODS:The STO using the treatment response evaluation was assessed according to RECIST 1.1 at 1 month after radiotherapy or chemoradiotherapy. The IBs (absolute lymphocyte counts (ALC), neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR), and lymphocyte/monocyte (LMR)) and clinical variables were collected and analyzed from 398 ESCC patients at Shandong Cancer Hospital between 2015 and 2019. The nomogram was then established for predicting STO. RESULTS:Pre-ALC and pre-LMR significantly increased, pre-NLR and pre-PLR significantly decreased during radiotherapy or chemoradiotherapy (all P < 0.001). Meanwhile, there was a positive correlation between delta-NLR as well as delta-PLR (r = 0.621) and delta-LMR (r = 0.613), whereas a negatively correlated between delta-LMR and delta-PLR (r = -0.573). Multivariate analysis indicated that gender [OR, 0.473; 95%CI, 0.274-0.816; P = 0.007], pre-ALC [OR, 0.554; 95%CI, 0.335-0.915; P = 0.021], pre-NLR [OR, 3.176; 95%CI, 1.733-5.823; P < 0.001], post-NLR [OR, 2.418; 95%CI, 1.271-4.600; P = 0.007] and delta-NLR [OR, 1.929; 95%CI, 1.035-3.595; P = 0.039] were statistically significant with STO. And c-index of the nomogram established by combining all independent predictors for STO was 0.770 [95%CI, 0.719-0.820]. CONCLUSION:Pre-NLR, pre-ALC, post-NLR, and delta-NLR were significant with STO in ESCC patients treated with radiotherapy or chemoradiotherapy. Further, pre-NLR had the best predictive value, and the developed nomogram with superior prediction ability for STO could assist in patients counseling and guide to make individual treatments.
10.1016/j.intimp.2020.107178
A novel nomogram containing acute radiation esophagitis predicting radiation pneumonitis in thoracic cancer receiving radiotherapy.
Tang Wenjie,Li Xiaolin,Yu Haining,Yin Xiaoyang,Zou Bing,Zhang Tingting,Chen Jinlong,Sun Xindong,Liu Naifu,Yu Jinming,Xie Peng
BMC cancer
BACKGROUND:Radiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP. METHODS:Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R" version 3.6.0. RESULTS:A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0-1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. CONCLUSIONS:As an early index that can reflect the tissue's radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future's clinical work.
10.1186/s12885-021-08264-y
Overlap time is an independent risk factor of radiation pneumonitis for patients treated with simultaneous EGFR-TKI and thoracic radiotherapy.
Jia Wenxiao,Gao Qianqian,Wang Min,Li Ji,Jing Wang,Yu Jinming,Zhu Hui
Radiation oncology (London, England)
BACKGROUND:The exact rate and relevant risk factors of radiation pneumonitis (RP) for non-small-cell cancer (NSCLC) patients treated with the combination of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and thoracic radiotherapy have not been reported. Thus, this study aimed to investigate the rate and risk factors of RP for EGFR-positive NSCLC patients simultaneously treated with first-generation EGFR-TKI and TRT. PATIENTS AND METHODS:We retrospectively evaluated NSCLC patients simultaneously treated with first-generation EGFR-TKI and thoracic radiotherapy between January 2012 and December 2019 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed via computed tomography and was classified according to the Common Terminology Criteria for Adverse Events v5.0. The risk factors of RP were identified using uni- and multivariate analyses. RESULTS:Of the 67 patients included, 44.78% (30/67) developed grade ≥ 2 RP. Grade ≥ 2 RP occurred within a median of 3.48 (range 1.07-13.6) months. The EGFR-TKI icotinib, ipsilateral lung V30 > 34%, and overlap time of > 20 days between EGFR-TKI and thoracic radiotherapy were identified to be independent predictive factors of grade ≥ 2 RP. CONCLUSIONS:Grade ≥ 2 RP is highly frequent in NSCLC patients simultaneous treated with first-generation EGFR-TKI and thoracic radiotherapy. Icotinib, ipsilateral lung V30 ≤ 34%, and overlap time of ≤ 20 days for EGFR-TKI and thoracic radiotherapy will be helpful to lower the risk of RP in these patients. The addition of thoracic radiotherapy should be cautious, and the treatment strategies can be optimized to reduce the rate of RP for patients treat with simultaneous EGFR-TKI and thoracic radiotherapy.
10.1186/s13014-021-01765-x