Regulatory role of RGMb in lung injury promoted by the combination of carbon ion irradiation and anti-PD-1 antibody through Erk1/2 and p38 MAPK pathways.

The combination of carbon ion radiotherapy and anti-PD-1 antibody represents a new approach to treating thoracic tumors. However, the lung damage caused by this combination therapy may limit its use, and the potential mechanisms for this are worthy of investigation. The objective of this research was to examine the potential involvement of repulsive guidance molecule b (RGMb) in lung damage promoted by the utilization of carbon ion irradiation combined with an anti-PD-1 antibody. The C57BL/6 mice have been randomly separated into four distinct groups: control, anti-PD-1, whole thorax carbon ion irradiation, and irradiation in combination with anti-PD-1 treatment groups (combination group). Detection of pathological changes in lung tissue using HE staining. Detection of pulmonary fibrosis by Masson staining and the hydroxyproline assay. ELISA to detect TNF-α, TGF-ß, IL-6, and IL-1ß expression levels within lung homogenates. The expression of RGMb, p38 MAPK, and Erk1/2 pathways was detected using a fully automated digital Western blotting system WES (ProteinSimple, USA). Flow cytometry was employed to analyze tissue-resident memory T cells (TRM) within the lung. Subsequently, the siRNA gene was employed to induce the downregulation of RGMb in mice in order to validate the involvement of RGMb in radiation-immune lung injury. The present study observed a significant increase in both inflammatory and fibrotic indicators within the mice group's lung tissue that received the combination treatment. The combination group exhibited elevated levels of TGF-ß, TNF-α, IL-6, and IL-1ß in lung homogenates. Anti-PD-1 antibody and carbon ion irradiation, upregulated RGMb, phospho-p38 MAPK and phospho-Erk1/2. The results obtained from the flow cytometry analysis indicated that the combination group was significantly higher in the number of clonal expansion TRMs, which were predominantly characterized by the expression of CD8+CD103+CD69-TRMs. The downregulate of RGMb via siRNA in mice resulted in a decrease in phospho-p38 MAPK and phospho-Erk1/2. The combination group exhibited a reduction in TNF-α, TGF-ß, IL-6, and IL-1ß in their lung tissues, and the number of CD8+CD103+CD69-TRM was significantly reduced. The combination group exhibited a significant improvement in inflammatory and fibrotic indicators within the lung tissues. Anti-PD-1 antibody and carbon ion irradiation synergistically regulate RGMb, leading to strong clonal expansion of lung TRM through the p38 MAPK and Erk1/2 pathways. The present study offers valuable insights into the treatment of lung injury due to the combined administration of carbon ion radiotherapy and anti-PD-1 antibody therapy.

Preliminary results of randomized phase II study of etoposide plus lobaplatin or etoposide plus cisplatin with concurrent thoracic radiotherapy in the treatment of limited-stage small cell lung cancer.

The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL ( n = 19) or EP ( n = 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7%; and 56.5, 43.5, and 29.0%, respectively ( P = 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8%; and 73.9, 48.4, and 48.4%, respectively ( P = 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% ( P = 0.006) and 20.1% vs. 60.9% ( P = 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower ( P = 0.038), both groups showed a similar incidence of radiation pneumonitis ( P = 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.

Study on the allosteric activation mechanism of SHP2 via elastic network models and neural relational inference molecular dynamics simulation.

As a ubiquitous protein tyrosine phosphatase, SHP2 is involved in PD-1/PD-L1 mediated tumor immune escape and undergoes substantial conformational changes. Therefore, it is considered an ideal target for tumor intervention. However, the allosteric mechanisms of SHP2 binding PD-1 intracellular ITIM/ITSM phosphopeptides remain unclear, which greatly hinders the development of novel structure-based anticancer allosteric inhibitors. In this work, the open and closed structural models of SHP2 are first constructed based on this knowledge; next their motion modes are investigated via elastic network models such as the Gaussian network model (GNM), anisotropic network model (ANM) and adaptive anisotropic network model (aANM); and finally, a possible allosteric signaling pathway is proposed using a neural relational inference molecular dynamics (NRI-MD) simulation embedded with an artificial intelligence (AI) strategy. In GNM and ANM, the N-SH2, C-SH2 and PTP domains all exhibit distinct dynamics partitions, and the N-SH2/C-SH2 regions show a rigid rotation relative to PTP. According to a series of intermediate snapshots given by aANM, N-SH2 is first identified with pY223 specifically, inducing a D'E-loop to change from ß-sheets to random coils, and then, C-SH2 serves as a fulcrum to drive N-SH2 to rotate 110° completely away from the original active sites of PTP. Finally, a possible allosteric signaling-transfer path for SHP2, namely R220-R138-T108-R32, is proposed based on NRI-MD sampling. This work provides a possible allosteric mechanism of SHP2, which is helpful for the following design of novel allosteric inhibitors and is expected to be used in clinical synergies with PD-1 monoclonal antibody.

Silencing of the lncRNA H19 enhances sensitivity to X-ray and carbon-ions through the miR-130a-3p /WNK3 signaling axis in NSCLC cells.

BACKGROUND: The lncRNA H19 is believed to act as an oncogene in various types of tumors and is considered to be a therapeutic target and diagnostic marker. However, the role of the lncRNA H19 in regulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells is unknown. METHODS: The expression profiles of lncRNAs in NSCLC were explored via transcriptome sequencing. CCK-8, EdU incorporation and clonogenic survival assays were conducted to evaluate the proliferation and radiosensitivity of NSCLC cells. Flow cytometry and Western blotting were conducted to measure the level of apoptosis. The binding relationship between the lncRNA H19 and miR-130a-3p was determined by a dual-luciferase reporter assay. A binding relationship was also identified between miR-130a-3p and With-No-Lysine Kinase 3 (WNK3). RESULTS: Expression patterns of lncRNAs revealed that the lncRNA H19 was upregulated in radioresistant NSCLC (A549-R11) cells compared with A549 cells. Knockdown of the lncRNA H19 enhanced the sensitivity of NSCLC cell lines to X-ray and carbon ion irradiation. Mechanistically, the lncRNA H19 serves as a sponge of miR-130a-3p, which downregulates WNK3 expression. The lncRNA H19-miR-130a-3p-WNK3 axis modulates radiosensitivity by regulating apoptosis in NSCLC cell lines. CONCLUSION: Knockdown of the lncRNA H19 promotes the sensitivity of NSCLC cells to X-ray and carbon ion irradiation. Hence, the lncRNA H19 might function as a potential therapeutic target that enhances the antitumor effects of radiotherapy in NSCLC.

Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery for patients with locally advanced rectal cancer: a systematic review and meta-analysis.

BACKGROUND: Controversy persists about whether additional induction chemotherapy (ICT) before neoadjuvant chemoradiation (NCRT) yields improved oncological outcomes. We performed a systematic review and meta-analysis to compare ICT+ NCRT+ surgery(S) with NCRT+ S in patients with locally advanced rectal cancer (LARC). METHODS: We searched the PubMed, EMBASE, Cochrane Library, and China Biology Medicine (CBM) databases. The data were analyzed with Stata version 12.0 software. RESULTS: We identified 9 relevant trials that enrolled 1538 patients. We detected no significant difference in the 5-year overall survival (OS) (OR 1.50, 95% CI 0.48-4.64), disease-free survival (DFS) (OR 1.03, 95% CI 0.73-1.46), local recurrence (LR) (OR 0.80, 95% CI 0.45-1.43), and distant metastasis (DM) rates (OR 1.03, 95% CI 0.55-1.93) between patients who did and did not receive ICT. The addition of ICT before NCRT had a similar pathological complete response rate compared to NCRT (OR 1.26, 95% CI 0.90-1.77). Our findings suggest that between the ICT + NCRT+S and NCRT+S groups, ICT improved the incidence of grade 3 to 4 toxicity effects (OR 4.81, 95% CI 2.38-9.37), but between the ICT + NCRT+S and NCRT+S+ adjuvant chemotherapy (ACT) groups, ICT might reduce toxicity (OR 0.19, 95% CI 0.08-0.50). ICT had no significant impact on surgical complications (OR 0.97, 95% CI 0.63-1.51). CONCLUSIONS: The addition of ICT before NCRT seemingly shows no survival benefit on patients with LARC, and might increase the toxicity.

Pemetrexed plus cisplatin versus docetaxel plus cisplatin for stage IV lung adenocarcinoma based on propensity score matching.

The aim of this study was to compare the clinical efficacy of pemetrexed+cisplatin (PP) versus docetaxel+cisplatin (DP) for the treatment of stage IV lung adenocarcinoma. We retrospectively analyzed the clinical data of 147 patients with stage IV lung adenocarcinoma treated between January 2011 and December 2015, 100 of which were in the DP group whereas 47 were in the DP group. Main inclusion criteria were treatment-naive patients, first-line treatment with PP or DP with no molecular targeted therapy during treatment, 2-6 cycles of first-line chemotherapy with unknown status of epidermal growth factor receptor (EGFR) mutation, 18-75 years of age, and Karnofsky performance status score of at least 70. Prognostic factors for survival were identified by using univariate and multivariate analyses. Propensity score matching was performed to further adjust for confounding. A total of 47 pairs were successfully matched between the two groups. The median overall survival was 9.0 months in the DP group and 17.0 months in the PP group; the 1-year survival rate was 29.8 and 59.6%, respectively; the 2-year survival rate was 12.8 and 21.1%, respectively (χ=4.128, P=0.042); and median progression-free survival was 6.0 and 8.0 months, respectively (χ=4.839, P=0.028). Cox multivariate analysis showed that chemotherapy regimen and number of metastatic organs were independent factors for OS. The effect of the radiotherapy dose on the primary tumor on OS was close to statistically significant. The incidence of grade 3-4 neutropenia was more significantly reduced in the DP group than in the PP group after matching (61.7 vs. 27.7%, P=0.002), with no between-group difference for adverse effects on platelets or hemoglobin. For patients with stage IV lung adenocarcinoma and unknown EGFR mutation status, PP was more effective than DP in prolonging survival and had a less adverse effect on neutrophils.

Is there a role for carbon therapy in the treatment of gynecological carcinomas? A systematic review.

This Systematic Review summarizes the literatures of clinical trials on the efficacy and safety of carbon ion therapy for gynecological carcinomas. The protocol is detailed in the online PROSPERO database, registration no. CRD42019121424, and a final set of eight studies were included. In the treatment of cervical carcinomas, both carbon ion therapy alone and carbon ion therapy concurrent chemotherapy have presented good efficacy. Besides, the efficacy of inoperable endometrial carcinomas and gynecological melanoma are similar to that of surgical treatment. In terms of safety, gastrointestinal and genitourinary toxicities are low and could be controlled by limiting the volume and dose of intestinal tract and bladder. Carbon ion radiotherapy could be considered a safe, effective and feasible therapy for gynecological carcinomas.

Radiation dose and survival of patients with stage IV non-small cell lung cancer undergoing concurrent chemotherapy and thoracic three-dimensional radiotherapy: reanalysis of the findings of a single-center prospective study.

BACKGROUND: The objective of this study was to evaluate the radiation dose and response in terms of local-regional progression-free survival (LRPFS) and overall survival (OS) of patients with stage IV non-small cell lung cancer (NSCLC) undergoing concurrent chemotherapy and thoracic three-dimensional radiotherapy. METHODS: In all, we enrolled 201 patients with stage IV NSCLC in this study and analyzed OS in 159 patients and LRPFS in 120. RESULTS: The 1-, 2-, 3-, and 5-year OS rates were 46.2%, 19.5%, 11.7%, and 5.8%, respectively, the median survival time being 12 months. The median survival times in differential treatment response of primary tumors were 19 of complete response, 13 of partial response, 8 of stable disease, and 6 months of progressive disease, respectively (P = 0.000). The 1-, 2-, 3-, and 5-year LRPFS rates of patients undergoing four to five cycles with doses ≥63 Gy and <63 Gy were 77.4% and 32.6%, 36.2% and 21.7%, 27.2% and 0, and 15.9% and 0, respectively (P = 0.002). According to multivariate analyses, four to five cycles of chemotherapy, gross tumor volume <175.00 cm3 and post-treatment Karnofsky Performance Status score stable or increased by at least 10 units were independent prognostic factors for better OS (P = 0.035, P = 0.008, and P = 0.000, respectively). Radiation dose to the primary tumor ≥63 Gy resulted in better OS (P = 0.057) and LRPFS (P = 0.051), both findings being of borderline significance. CONCLUSIONS: Treatment of IV NSCLC with joint administration of four to five cycles of chemotherapy and three-dimensional radiotherapy may prolong survival, particularly in patients receiving ≥63 Gy radiotherapy, with gross tumor volume <175.00 cm3 and post-treatment Karnofsky Performance Status score not lower than pretreatment values.

Carbon ion irradiation combined with PD-1 inhibitor trigger abscopal effect in Lewis lung cancer via a threshold dose.

Background and goal: Carbon ion beam is radio-biologically more efficient than photons and is beneficial for treating radio-resistant tumors. Several animal experiments with tumor-bearing suggest that carbon ion beam irradiation in combination with immunotherapy yields better results, especially in controlling distant metastases. This implies that carbon ion induces a different anti-tumor immune response than photon beam. More complex molecular mechanisms need to be uncovered. This in vivo and in vitro experiment was carried out in order to examine the radio-immune effects and the mechanism of action of carbon ion beam versus X-ray in combination with PD-1 inhibitors. Methods and Materials: Lewis lung adenocarcinoma cells and C57BL/6 mice were used to create a tumor-bearing mouse model, with the non-irradiated tumor growing on the right hind leg and the irradiated tumor on the left rear. 10Gy carbon ion beam or X-ray radiation, either alone or in combination with PD-1 inhibitor, were used to treat the left back tumor. The expression of molecules linked to immunogenicity and the infiltration of CD8+ T lymphocytes into tumor tissues were both identified using immunohistochemistry. IFN-ß in mouse serum was measured using an ELISA, while CD8+ T cells in mouse peripheral blood were measured using flow cytometry. Lewis cells were exposed to different dose of X-ray and carbon ion. TREX1, PD-L1, and IFN-ß alterations in mRNA and protein levels were identified using Western blot or RT-PCR, respectively. TREX1 knockdown was created by siRNA transfection and exposed to various radiations. Using the CCK8 test, EdU assay, and flow cytometry, changes in cell viability, proliferation, and apoptosis rate were discovered. Results: Bilateral tumors were significantly inhibited by the use of carbon ion or X-ray in combination with PD-1, particularly to non-irradiated tumor(p<0.05). The percentage of infiltrating CD8+ T cells and the level of IFN-ß expression were both raised by 10Gy carbon ion irradiation in the irradiated side tumor, although PD-L1 and TREX1 expression levels were also elevated. Lewis cell in vitro experiment further demonstrated that both X-ray and carbon ion irradiation can up-regulate the expression levels of PD-L1 and TREX1 with dose-dependent in tumors, particularly the trend of up-regulation TREX1 is more apparent at a higher dose in carbon ion, i.e. 8 or 10Gy, while the level of IFN-ß is decreased. IFN-ß levels were considerably raised under hypofractionated doses of carbon ion radiation by gene silencing TREX1. Conclusions: By enhancing tumor immunogenicity and increasing CD8+T infiltration in TME through a threshold dosage, X-ray or carbon ion radiation and PD-1 inhibitors improve anti-tumor activity and cause abscopal effect in Lewis lung adenocarcinoma-bearing mice. TREX1 is a possible therapeutic target and prognostic marker.

Overall survival and toxicities regarding thoracic three-dimensional radiotherapy with concurrent chemotherapy for stage IV non-small cell lung cancer: results of a prospective single-center study.

BACKGROUND: The role of chemotherapy given concurrently with thoracic three-dimensional radiotherapy for stage IV non-small cell lung cancer (NSCLC) is not well defined. We performed this study to investigate overall survival and toxicity in patients with stage IV NSCLC treated with this modality. METHODS: From 2003 to 2010, 201 patients were enrolled in this study. All patients received chemotherapy with concurrent thoracic three-dimensional radiotherapy. The study endpoints were the assessment of overall survival (OS) and acute toxicity. RESULTS: For all patients, the median survival time (MST) was 10.0 months, and the 1-, 2- and 3-year OS rates were 40.2%, 16.4%, and 9.6%, respectively. The MST was 14.0 months for patients who received a total radiation dose ≥63 Gy to the primary tumor, whereas it was 8.0 months for patients who received a total dose <63 Gy (P = 0.000). On multivariate analysis, a total dose ≥63 Gy, a single site of metastatic disease, and undergoing ≥4 cycles of chemotherapy were independent prognostic factors for better OS (P = 0.007, P = 0.014, and P = 0.038, respectively); radiotherapy involving metastatic sites was a marginally significant prognostic factor (P = 0.063). When the whole group was subdivided into patients with metastasis at a single site and multiple sites, a higher radiation dose to the primary tumor remained a significant prognostic factor for improved OS. For patients who received ≥4 cycles of chemotherapy, high radiation dose remained of benefit for OS (P = 0.001). Moreover, for the subgroup that received <4 chemotherapy cycles, the radiation dose was of marginal statistical significance regarding OS (P = 0.063). Treatment-related toxicity was found to be acceptable. CONCLUSIONS: Radiation dose to primary tumor, the number of metastatic sites, and the number of chemotherapy cycles were independent prognostic factors for OS in stage IV NSCLC patients treated with concurrent chemoradiotherapy. In addition to systemic chemotherapy, aggressive thoracic radiotherapy was shown to play an important role in improving OS. TRIAL REGISTRATION: Registered on (ChiCTR-TNC-10001026).

Failure pattern and radiotherapy exploration in malignant pleural effusion non-small cell lung cancer treated with targeted therapy.

Purpose: Actionable mutations are common in non-small cell lung cancer(NSCLC)with malignant pleural effusion(MPE)(MPE-NSCLC). The pattern of failure in MPE-NSCLC treated with targeted therapy after MPE control remains unclear. We aimed to investigate the failure pattern of such patients in a cohort study and explore the possibility of radiotherapy. Patients and methods: Computed tomography scans of 86 patients were reviewed in this study. We classified first pattern of failure after MPE control as initial disease sites only (IF), new distant sites only (NF), or IF and NF detected simultaneously (INF). Patients evaluated suitable for radiotherapy after disease progression were divided into two groups: D group without radiotherapy and RD group with radiotherapy. The Kaplan-Meier method and log-rank test were used for survival analyses. Results: Disease progression after MPE control was observed in 42 patients with complete serial imaging. Median time to any progression was 9.5 months. Rate of the IF, NF and INF were 50%, 17% and 33% for all patients,60%,0% and 40% for patients with MPE recurrence (n=10,23.8%) and 47%, 22% and 31% for patients (n=32,76.2%) without MPE recurrence, respectively. Out of 10 patients(23.8%) with MPE recurrence, 7 patients simultaneous underwent primary tumor progression and 5 MPE were cytologically confirmed in 7 patients with examination. The overall survival (OS )rates at 1, 2, 3 years for the RD group and D group were 88.2%, 50.5%, 21.7% and 80.0%, 20.3%, 0%, respectively; the corresponding MST were 26.1 months and 17.5 months, respectively (χ2 = 4.959, p =0.026). Conclusions: Our data indicates that 50% of patients with actionable mutations MPE- NSCLC after MPE control are likely to fail at their initial sites of disease and the use of radiotherapy may bring OS benefits during the course of their disease. Multicenter RCT is necessary to confirm the result in the future.

Carbon Ions Suppress Angiogenesis and Lung Metastases in Melanoma by Targeting CXCL10.

Carbon-ion radiotherapy (CIRT) enhanced local control in patients with malignant melanoma. In several in vitro studies, carbon ions (C ions) have been also shown to decrease the metastatic potential of melanoma cells. CXC motif 10 (CXCL10) has been shown to play a crucial role in regulating tumor metastasis and it significantly increase in human embryonic kidney cells after heavy ion irradiations. This study sought to explore the regulatory effect of C ions on melanoma metastasis, emphasizing the role of CXCL10 in this process. To explore the potential regulatory effect of C ions on tumor metastasis in vivo, we developed a lung metastasis mouse model by injecting B16F10 cells into the footpad and subjected all mice to treatment with X rays and C ions. Subsequently, a series of assays, including histopathological analysis, enzyme-linked immunosorbent assay, real-time PCR, and western blotting, were conducted to assess the regulatory effects of C ions on melanoma. Our results showed that mice treated with C ions exhibited significantly less tumor vascularity, enhanced tumor necrosis, alleviated lung metastasis, and experienced longer survival than X-ray irradiated mice. Moreover, VEGF expression in B16F10 cells was significantly reduced by C-ion treatment, which could be alleviated by CXCL10 knockdown in vitro. Further investigations revealed that co-culturing with HUVECs resulted in a significant inhibition of proliferation, migration, and tube formation ability in the C-ion treated group, while the opposite effect was observed in the C-ion treated with si-CXCL10 group. In conclusion, our findings demonstrate that treatment with carbon-ion radiation can suppress angiogenesis and lung metastases in melanoma by specifically targeting CXCL10. These results suggest the potential utility of carbon ions in treating melanoma.

Impact of thoracic tumor radiotherapy on survival in non-small-cell lung cancer with malignant pleural effusion treated with targeted therapy: Propensity score matching study.

BACKGROUND: EGFR-mutant (EGFR-M) and ALK-positive (ALK-P)are common in malignant pleural effusion (MPE) with metastatic non-small-cell lung cancer (NSCLC) (MPE-NSCLC). The impact of thoracic tumor radiotherapy on survival in such patients remains unclear. We aimed to investigate whether thoracic tumor radiotherapy could improve overall survival (OS) in such patients. METHODS: According to whether or not patients accepted thoracic tumor radiotherapy, 148 patients with EGFR-M or ALK-P MPE-NSCLC treated with targeted therapy were classified into two groups: DT group without thoracic tumor radiotherapy and DRT group with thoracic tumor radiotherapy. Propensity score matching (PSM) was performed to balance clinical baseline characteristics. Overall survival was analyzed by Kaplan-Meier, compared by log-rank test, and evaluated using Cox proportional hazards model. RESULTS: Median survival time (MST) was 25 months versus 17 months in the DRT group and DT group. The OS rates at 1, 2, 3, 5 years in the DRT group and DT group were 75.0%, 52.8%, 26.8%, 11.1% and 64.5%, 28.4%, 9.2%, 1.8%, respectively (χ2 = 12.028, p = 0.001). Compared with DT group, the DRT group still had better survival after PSM (p = 0.007). Before and after PSM, factors associated with better OS through multivariable analysis were that thoracic tumor radiotherapy, radiotherapy, N0-2 , and ALK-TKIs. Grades 4-5 radiation toxicities were not observed in patients; 8 (11.6%) and 7 (10.1%) out of the DRT group suffered from Grade 3 radiation esophagitis and radiation pneumonitis, respectively. CONCLUSION: Our results for EGFR-M or ALK-P MPE-NSCLC showed that thoracic tumor radiotherapy may be crucial factor in improving OS with acceptable toxicities. Potential biases should not be neglected: Further randomized controlled trials are necessary to confirm this result.

Bevacizumab is an effective treatment for symptomatic cerebral necrosis after carbon ion therapy for recurrent intracranial malignant tumours: A case report.

Carbon ion therapy (CIT) is a form of particle therapy, which not only spares normal tissues but may also improve local control of recurrent intracranial tumours. Cerebral radiation necrosis (RN) is one of the most serious adverse reactions of recurrent brain tumours following reirradiation, which may lead to neurological decline or even death. Bevacizumab is an anti-vascular endothelial growth factor antibody, which has been used to treat symptomatic RN. However, studies on bevacizumab for the treatment of CIT-induced RN are sparse. The present study described two cases that were successfully treated with bevacizumab for symptomatic RN following CIT for recurrent intracranial malignant tumours. The two recurrent intracranial malignant tumours, a chondrosarcoma in the right cavernous sinus and an anaplastic meningioma in the right frontal lobe, were enrolled in a clinical trial of CIT. Both cases were treated intravenously with bevacizumab when deterioration that appeared to be symptomatic brain RN was observed. Just before CIT, enhanced magnetic resonance imaging (MRI) was performed in each case to confirm tumour recurrence. Both cases exhibited a deterioration in symptoms, as well as on MRI, at 12-month intervals following CIT. The first case underwent positron emission tomography/computed tomography to confirm no increase in fluorodeoxyglucose uptake in lesion areas. Both cases were diagnosed as having symptomatic brain RN and began intravenous administration of four cycles of 5 mg/kg bevacizumab biweekly. The patients responded well, with rapid and marked improvements on MRI, and in clinical symptoms. No tumour progression was observed 24 months after CIT. In conclusion, bevacizumab was revealed to exert marked effects on symptomatic brain RN following CIT. Notably, cycles of bevacizumab should be administered specifically based on the aim of treating brain necrosis, and long-term or prophylactic applications are not recommended.

Non-Small Cell Lung Cancer with Malignant Pleural Effusion May Require Primary Tumor Radiotherapy in Addition to Drug Treatment.

Purpose: The impact of primary tumour radiotherapy on the prognosis for non-small-cell lung cancer (NSCLC) with controlled malignant pleural effusion (MPE-C) (MPE-C-NSCLC) is unclear. This study aimed to analyze the efficacy and safety of primary tumor radiotherapy in patients with MPE-C-NSCLC. Patients and Methods: A total of 186 patients with MPE-C-NSCLC were enrolled and divided into two groups. The patients in the D group were treated with only drugs. Those in the RD group were treated with drugs plus primary tumour radiotherapy. The Kaplan-Meier method was used for survival analysis, and the Log rank test was used for between-group analysis and univariate prognostic analysis. The Cox proportional hazards model was used to perform multivariate analyses to assess the impacts of factors on survival. Propensity score matching (PSM) was matched based on clinical characteristics, systematic drug treatment and drug response to further adjust for confounding factors. Results: The overall survival (OS) rates at 1, 2, and 3 years for the RD group and D group were 54.4%, 26.8%, and 13.3% and 31.1%, 11.5%, and 4.4%, respectively; the corresponding MSTs were 14 months and 8 months, respectively (χ 2=15.915, p<0.001). There was a significant difference in survival by PSM (p=0.027).Before PSM, multivariate analysis showed that metastasis status (organ≤3 and metastasis≤5), primary tumour radiotherapy, chemotherapy cycles≥4, and drug best response (CR+PR) were independent predictors of prolonged OS. After PSM, primary tumour radiotherapy and drug best response (CR+PR) were independent predictors of prolonged OS were still independent predictors of prolonged OS. There were no grade 4-5 radiation toxicities. Conclusion: For MPE-C-NSCLC, the response of systemic drug treatment plays a crucial role in survival outcomes, and we also should pay attention to primary tumour radiotherapy in addition to systematic drug treatment.

Effect of PD-1 Inhibitor Combined with X-Ray Irradiation on the Inflammatory Microenvironment and Lung Tissue Injury in Mice.

PURPOSE: This study was designed to evaluate the effects of PD-1 inhibitor on lung tissue morphology and the immune system in a mouse model of radiation-induced lung injury (RILI) and to assess interactions between radiation therapy and PD-1 inhibition. METHODS: Twenty C57BL/6 mice were divided randomly into four groups of five mice each. Mice were treated with an anti-mouse PD-1 monoclonal antibody, whole thorax irradiation, both or neither. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining; lung fibrosis was assessed by Masson staining and analysis of hydroxyproline; CD3+, CD4+, and CD8+ T lymphocytes in lung tissues were detected immunohistochemically; and the concentrations of transforming growth factor-ß1 (TGF-ß1) and interleukin-6 (IL-6) in lung tissue were evaluated by cytokine multiplex analysis. RESULTS: Lung injury scores and indicators of pulmonary fibrosis were higher in mice administration whole thorax irradiation than in control mice. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions and hydroxyproline contents in lung tissues were all significantly higher in mice administered PD-1 inhibitor plus irradiation than in the other three groups. Similarly, the percentages of CD3+ and CD8+T cells and the concentrations of IL-6 and TGF-ß1 in lung tissue were significantly higher in mice treated with radiation and PD-1 inhibitor than in the other groups. However, PD-1 inhibitor and irradiation interacted significantly only in the elevation of TGF-ß1 level. CONCLUSION: Whole thorax X-ray irradiation in mice can cause pulmonary injury and fibrosis, which could be exacerbated by PD-1 inhibitors. Radiotherapy combined with PD-1 inhibitors may aggravate RILI by synergistically upregulating TGF-ß1 expression, thereby affecting the immune-inflammatory microenvironment in the lungs.

The Effect of PD-1 Inhibitor Combined with Irradiation on HMGB1-Associated Inflammatory Cytokines and Myocardial Injury.

Purpose: To explore the effect of PD-1 inhibitors combined with irradiation on myocardial injury and the changes of HMGB1-associated inflammatory markers. Methods: Four groups of five mice were used, each groupformed by randomly dividing 20 mice (group A control; group B PD-1 inhibitors; group C Irradiation; group D PD-1 inhibitors+irradiation; n = 5 for each). The mice were treated with either PD-1 inhibitors or a 15 Gy dose of single heart irradiation, or both. Hematoxylin-eosin staining assessed the morphology and pathology of heart tissue; Masson staining assessed heart fibrosis; Tunel staining evaluated heart apoptosis; flow cytometry detected CD3+, CD4+, and CD8+ T lymphocytes in heart tissues; enzyme linked immunosorbent assay evaluated IL-1ß, IL-6, and TNF-ɑ of heart tissue; Western blot and quantitative real-time PCR (qPCR) detected the expression of protein and mRNA of HMGB1, TLR-4, and NF-κB p65 respectively. Results: The degree of heart injury, collagen volume fraction (CVF) and apoptotic index (AI) in groups B, C, and D were higher than group A, but the differences between the CVF and AI of group A and group B were not statistical significance (P>0.05). Similarly, the absolute counts and relative percentage of CD3+ and CD8+ T lymphocytes and the concentrations of IL-1ß, IL-6, and TNF-α in heart tissue with group D were significantly higher than the other groups (P<0.05). In addition, compared with group A, the expression of protein and mRNA of HMGB1 and NF-κB p65 in other groups were higher, and the differences between each group were statistically significant while TLR4 was not. In addition, interaction by PD-1 inhibitors and irradiation was found in inflammatory indicators, especially in the expression of the HMGB1 and CD8+ T lymphocytes. Conclusion: PD-1 inhibitors can increase the expression of HMGB1-associated inflammatory cytokines and aggravate radiation-induced myocardial injury.

Reasonable Timing of Radiotherapy for Stage IV Non-Small-Cell Lung Cancer During Targeted Therapy Based on Tumour Volume Change.

PURPOSE: The aim of this study was to investigate the reasonable timing of radiotherapy for stage IV non-small-cell lung cancer (NSCLC) with EGFR-positive mutations during targeted therapy based on tumour volume change (TVC). PATIENTS AND METHODS: Simulation Computed Tomography Scan (SCTS) measurements were taken to test TVC in patients with stage IV NSCLC during targeted therapy at intervals of 10 days. The SCTS measurement was terminated when the tumour volume shrinkage rate in the latter simulation compared with the previous simulation was ≤5% or when the time after treatment was 90 days. Then, primary tumour radiotherapy was performed. Related parameters of the radiotherapy plan were compared between the implementation and simulation plans. RESULTS: Twenty-seven patients were enrolled in the analysis. After treatment, shrinkage of the primary tumour was observed in all patients, but the rate and speed were inconsistent. The average tumour volume decreased obviously within 40 days and was significantly different every 10 days (P ≤ 0.001). The average volume decreased slowly and tended to be stable (P>0.05) after 40 days. After the termination of SCTSs, 21 patients accepted primary tumour radiotherapy. No patients experienced grade 3+ acute radiation toxicity. The implementation radiotherapy plan was significantly better than that before treatment (all P<0.05) but not better than that on the 40th day after treatment (all P>0.05). CONCLUSIONS: To obtain a high radiation dose and control radiation toxicity, the 40th day after targeted therapy may be a reasonable time to start radiotherapy for stage IV NSCLC with EGFR-positive mutations. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT03258671, identifier, NCT03258671.

Corrigendum: Effect of Carbon Ion Radiation Induce Bystander Effect on Metastasis of A549 Cells and Metabonomic Correlation Analysis.

[This corrects the article DOI: 10.3389/fonc.2020.601620.].

Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: A combination of programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non-small-cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta-analysis to summarize the related research. METHODS: We searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta-analysis. RESULTS: The study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non-combination therapy, combination therapy using PD-1/PD-L1 inhibitors and RT was associated with prolonged overall survival (OS) (1-year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35-2.33, p = 0.000; 2-year OS: OR 1.77, 95% CI 1.35-2.33, p = 0.000) and progression-free survival (PFS) (0.5-year PFS: OR 1.83, 95% CI 1.13-2.98, p = 0.014; 1-year PFS: OR 2.09, 95% CI 1.29-3.38, p = 0.003; 2-year PFS: OR 2.47, 95% CI 1.13-5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06-7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21-2.68, p = 0.004). This meta-analysis showed that compared with non-combination therapy, combination therapy using PD-1/PD-L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1-2 immune-related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD-1/PD-L1 inhibitors followed RT outperformed in which concurrent PD-1/PD-L1 inhibitor and RT followed PD-1/PD-L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD-1/PD-L1 inhibitors may be more effective than a combination of conventional RT with PD-1/PD-L1 inhibitors in patients with advanced NSCLC. CONCLUSION: Combination therapy using PD-1/PD-L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis.