Differential regulation of phosphorylation, structure, and stability of circadian clock protein FRQ isoforms.

Neurospora crassa is an important model organism for circadian clock research. The Neurospora core circadian component FRQ protein has two isoforms, large FRQ (l-FRQ) and small FRQ (s-FRQ), of which l-FRQ bears an additional N-terminal 99-amino acid fragment. However, how the FRQ isoforms operate differentially in regulating the circadian clock remains elusive. Here, we show l-FRQ and s-FRQ play different roles in regulating the circadian negative feedback loop. Compared to s-FRQ, l-FRQ is less stable and undergoes hypophosphorylation and faster degradation. The phosphorylation of the C-terminal l-FRQ 794-aa fragment was markedly higher than that of s-FRQ, suggesting the l-FRQ N-terminal 99-aa region may regulate the phosphorylation of the entire FRQ protein. Quantitative label-free LC/MS analysis identified several peptides that were differentially phosphorylated between l-FRQ and s-FRQ, which were distributed in FRQ in an interlaced fashion. Furthermore, we identified two novel phosphorylation sites, S765 and T781; mutations S765A and T781A showed no significant effects on conidiation rhythmicity, although T781 conferred FRQ stability. These findings demonstrate that FRQ isoforms play differential roles in the circadian negative feedback loop and undergo different regulations of phosphorylation, structure, and stability. The l-FRQ N-terminal 99-aa region plays an important role in regulating the phosphorylation, stability, conformation, and function of the FRQ protein. As the FRQ circadian clock counterparts in other species also have isoforms or paralogues, these findings will also further our understanding of the underlying regulatory mechanisms of the circadian clock in other organisms based on the high conservation of circadian clocks in eukaryotes.

Effect of intramuscular diazepam infusion on herpes zoster-related pain in older patients: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: This study evaluated the effectiveness, psychological effects, and sleep quality using intramuscular diazepam infusion compared with placebo in patients with herpes zoster (HZ)-related pain. METHODS: The patients were randomized to either the diazepam or control group. The diazepam group received an intramuscular injection of diazepam for 3 consecutive days, while the control group received an intramuscular injection of 0.9% normal saline. The primary outcome was pain relief on posttreatment day 4, as measured using the Visual Analog Scale (VAS). Moreover, anxiety and depression were evaluated using the Generalized Anxiety Disorder-7 (GAD7) and Patient Health Questionnaire-9 (PHQ9), respectively. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: In total, 78 patients were enrolled in the trial. The mean differences in VAS scores between the two groups were 0.62 (P = 0.049) on posttreatment day 3 and 0.66 (P = 0.037) on posttreatment day 4. The effective rates of pain management in the diazepam group ranged from 10.26 to 66.67%, which were higher than those in the control group on posttreatment days 3 and 4 (P < 0.05). The mean difference in PSQI scores between the diazepam and control groups was 1.36 (P = 0.034) on posttreatment day 7. No differences were found in the incidence of analgesia-adverse 1reactions between the diazepam and placebo groups. CONCLUSIONS: The intramuscular injection of diazepam for 3 consecutive days provides effective pain management and improves the quality of life. Our study suggests that diazepam is more effective than the placebo in patients with HZ-related pain. TRIAL REGISTRATION: The study was prospectively registered at https://www.isrctn.com/trialist(Registration date: 24/01/2018; Trial ID: ISRCTN12682696).

Prediction of the effects of radiation therapy in esophageal cancer using diffusion and perfusion MRI.

Chemoradiation therapy (CRT) of locally advanced esophageal cancer (LAEC), although improving outcomes of patients, still results in 50% of local failure. An early prediction could identify patients at high risk of poor response for individualized adaptive treatment. We aimed to investigate physiological changes in LAEC using diffusion and perfusion magnetic resonance imaging (MRI) for early prediction of treatment response. In the study, 115 LAEC patients treated with CRT were enrolled (67 in the discovery cohort and 48 in the validation cohort). MRI scans were performed before radiotherapy (pre-RT) and at week 3 during RT (mid-RT). Gross tumor volume (GTV) of primary tumor was delineated on T2-weighted images. Within the GTV, the hypercellularity volume (VHC ) and high blood volume (VHBV ) were defined based on the analysis of ADC and fractional plasma volume (Vp) histogram distributions within the tumors in the discovery cohort. The median GTVs were 28 cc ± 2.2 cc at pre-RT and 16.7 cc ± 1.5 cc at mid-RT. Respectively, VHC and VHBV decreased from 4.7 cc ± 0.7 cc and 5.7 cc ± 0.7 cc at pre-RT to 2.8 cc ± 0.4 cc and 3.5 cc ± 0.5 cc at mid-RT. Smaller VHC at mid-RT (area under the curve [AUC] = 0.67, P = .05; AUC = 0.66, P = .05) and further decrease in VHC at mid-RT (AUC = 0.7, P = .01; AUC = 0.69, P = .03) were associated with longer progression-free survival (PFS) in both discovery and validation cohort. No significant predictive effects were shown in GTV and VHBV at any time point. In conclusion, we demonstrated that VHC represents aggressive subvolumes in LAEC. Further analysis will be carried out to confirm the correlations between the changes in image-phenotype subvolumes and local failure to determine the radiation-resistant tumor subvolumes, which may be useful for dose escalation.

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.

Aim: 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). Patients & methods: 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. Results: 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). Conclusion: 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.

Prognostic value of lymphocyte-to-monocyte ratio and systemic immune-inflammation index in non-small-cell lung cancer patients with brain metastases.

Aim: 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). Materials & methods: We conducted Kaplan-Meier analysis and multivariable Cox analysis to evaluate the prognostic values of NLR, PLR, LMR and SII. Results: 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). Conclusion: LMR and SII are of significant values in clinical prognostic evaluation for patients with brain metastases from NSCLC.

CD103+CD8+ T lymphocytes in non-small cell lung cancer are phenotypically and functionally primed to respond to PD-1 blockade.

CD103+CD8+ tumor infiltrating lymphocytes (TILs) have been linked to prolonged survival in various types of cancer including non-small cell lung cancer (NSCLC). However, the factors associated with the retention of CD103+CD8+ TILs in lung cancer tissues remain largely unknown. Additionally, the contribution of CD103+CD8+ TILs to effective PD-1 based immunotherapy has not been fully elucidated. In this study, we identified that the expression levels of E-cadherin and TGF-ß were significantly correlated with the distribution and the density of CD103+ TILs in lung cancer tumor tissues. Unexpectedly, we observed that CD103+CD8+ TILs that expressed higher levels of PD-1 co-express Ki-67. Moreover, CD103+CD8+ TILs expressed an increased level of T-bet compared to their counterparts, indicating these cells may be better armed for immunotherapy. Lastly, PD-1 pathway blockade led to a significantly increased production of IFN-γ by CD103+CD8+ TILs, suggesting CD103+CD8+ TILs could serve as a predictive biomarker for PD-1 based immunotherapy.

The HpSGNi system: A compact approach for genetic suppression without sequence limitation in Escherichia coli.

Targeted gene regulation is indispensable for exploring gene functions in microbes and the development of microbial cell factories. While most loci can be regulated by CRISPRi, it cannot be used for targets lacking protospacer adjacent motifs (PAM) or protospacer flanking sequences (PFS). Here, we characterized a genetic suppression approach named the hpDNA-assisted structure-guided nuclease mediating interference system (HpSGNi). It was composed of a flap endonuclease 1 (FEN1) and mis-hairpin DNA probes (mis-hpDNA) to suppress the expression of target genes simply and efficiently in microbe without sequence restrictions. By inhibiting the initiation and elongation of the transcription, HpSGNi successfully silenced the transcription of exogenous fluorescent protein genes, ampicillin resistance gene and endogenous folP/sulA genes in Escherichia coli BL21(DE3) and K-12 MG1655. Meanwhile, aiming at optimizing the mis-hpDNA, we displayed the characteristics by detecting the tolerance to the single base mismatch and length of the guide sequence. This DNA-guided recognition platform provides a simple approach for selectively inhibiting gene expression.

[Retracted] LINC01094 promotes the invasion of ovarian cancer cells and regulates the Wnt/ß­catenin signaling pathway by targeting miR­532­3p.

[This retracts the article DOI: 10.3892/etm.2021.10662.].

Noninvasive radiomic biomarkers for predicting pseudoprogression and hyperprogression in patients with non-small cell lung cancer treated with immune checkpoint inhibition.

This study aimed to develop a computed tomography (CT)-based radiomics model capable of precisely predicting hyperprogression and pseudoprogression (PP) in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. We retrospectively analyzed 105 patients with NSCLC, from three institutions, treated with immune checkpoint inhibitors (ICIs) and categorized them into training and independent testing set. Subsequently, we processed CT scans with a series of image-preprocessing techniques, and 6008 radiomic features capturing intra- and peritumoral texture patterns were extracted. We used the least absolute shrinkage and selection operator logistic regression model to select radiomic features and construct machine learning models. To further differentiate between progressive disease (PD) and hyperprogressive disease (HPD), we developed a new radiomics model. The logistic regression (LR) model showed optimal performance in distinguishing PP from HPD, with areas under the receiver operating characteristic curve (AUC) of 0.95 (95% confidence interval [CI]: 0.91-0.99) and 0.88 (95% CI: 0.66-1) in the training and testing sets, respectively. Additionally, the support vector machine model showed optimal performance in distinguishing PD from HPD, with AUC of 0.97 (95% CI: 0.93-1) and 0.87 (95% CI: 0.72-1) in the training and testing sets, respectively. Kaplan‒Meier survival curves showed clear stratification between PP predicted by the radiomics model and true progression (HPD and PD) (hazard ratio = 0.337, 95% CI: 0.200-0.568, p < 0.01) in overall survival. Our study demonstrates that radiomic features extracted from baseline CT scans are effective in predicting PP and HPD in patients with NSCLC treated with ICIs.

Using MRI radiomics to predict the efficacy of immunotherapy for brain metastasis in patients with small cell lung cancer.

BACKGROUND: Brain metastases (BMs) are common in small cell lung cancer (SCLC), and the efficacy of immune checkpoint inhibitors (ICIs) in these patients is uncertain. In this study we aimed to develop and validate a radiomics nomogram based on magnetic resonance imaging (MRI) for intracranial efficacy prediction of ICIs in patients with BMs from SCLC. METHODS: The training and validation cohorts consisted of 101 patients from two centers. The interclass correlation coefficient (ICC), logistic univariate regression analysis, and random forest were applied to select the radiomic features, generating the radiomics score (Rad-score) through the formula. Using multivariable logistic regression analysis, a nomogram was created by the combined model. The discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. Kaplan-Meier curves were plotted based on the nomogram scores. RESULTS: Ten radiomic features were selected for calculating the Rad-score as they could differentiate the intracranial efficacy in the training (area under the curve [AUC], 0.759) and the validation cohort (AUC, 0.667). A nomogram was created by combining Rad-score, treatment lines, and neutrophil-to-lymphocyte ratio (NLR). The training cohort obtained an AUC of 0.878 for the combined model, verified in the validation cohort (AUC = 0.875). Kaplan-Meier analyses showed the nomogram was associated with progression-free survival (PFS) (p = 0.0152) and intracranial progression-free survival (iPFS) (p = 0.0052) but not overall survival (OS) (p = 0.4894). CONCLUSION: A radiomics nomogram model for predicting the intracranial efficacy of ICIs in SCLC patients with BMs can provide suggestions for exploring individual-based treatments for patients.

IInception-CBAM-IBiGRU based fault diagnosis method for asynchronous motors.

Aiming at the problems of insufficient extraction of asynchronous motor fault features by traditional deep learning algorithms and poor diagnosis of asynchronous motor faults in robust noise environments, this paper proposes an end-to-end fault diagnosis method for asynchronous motors based on IInception-CBAM-IBiGRU. The method first uses a signal-to-grayscale image conversion method to convert one-dimensional vibration signals into two-dimensional images and initially extracts shallow features through two-dimensional convolution; then the Improved Inception (IInception) module is used as a residual block to learning features at different scales with a residual structure, and extracts its important feature information through the Convolutional Block Attention Module (CBAM) to extract important feature information and adjust the weight parameters; then the feature information is input to the Improved Bi-directional Gate Recurrent Unit (IBiGRU) to extract its timing features further; finally, the fault identification is achieved by the SoftMax function. The primary hyperparameters in the model are optimized by the Weighted Mean Of Vectors Algorithm (INFO). The experimental results show that the method is effective in fault diagnosis of asynchronous motors, with an accuracy rate close to 100%, and can still maintain a high accuracy rate under the condition of low noise ratio, with good robustness and generalization ability.

Development and validation of an MRI-Based nomogram to predict the effectiveness of immunotherapy for brain metastasis in patients with non-small cell lung cancer.

Introduction: The variability and unpredictability of immune checkpoint inhibitors (ICIs) in treating brain metastases (BMs) in patients with advanced non-small cell lung cancer (NSCLC) is the main concern. We assessed the utility of novel imaging biomarkers (radiomics) for discerning patients with NSCLC and BMs who would derive advantages from ICIs treatment. Methods: Data clinical outcomes and pretreatment magnetic resonance images (MRI) were collected on patients with NSCLC with BMs treated with ICIs between June 2019 and June 2022 and divided into training and test sets. Metastatic brain lesions were contoured using ITK-SNAP software, and 3748 radiomic features capturing both intra- and peritumoral texture patterns were extracted. A clinical radiomic nomogram (CRN) was built to evaluate intracranial progression-free survival, progression-free survival, and overall survival. The prognostic value of the CRN was assessed by Kaplan-Meier survival analysis and log-rank tests. Results: In the study, a total of 174 patients were included, and 122 and 52 were allocated to the training and validation sets correspondingly. The intratumoral radiomic signature, peritumoral radiomic signature, clinical signature, and CRN predicted intracranial objective response rate. Kaplan-Meier analyses showed a significantly longer intracranial progression-free survival in the low-CRN group than in the high-CRN group (p < 0.001). The CRN was also significantly associated with progression-free survival (p < 0.001) but not overall survival. Discussion: Radiomics biomarkers from pretreatment MRI images were predictive of intracranial response. Pretreatment radiomics may allow the early prediction of benefits.

TaqTth-hpRNA: a novel compact RNA-targeting tool for specific silencing of pathogenic mRNA.

Pathogenic allele silencing is a promising treatment for genetic hereditary diseases. Here, we develop an RNA-cleaving tool, TaqTth-hpRNA, consisting of a small, chimeric TaqTth, and a hairpin RNA guiding probe. With a minimal flanking sequence-motif requirement, in vitro and in vivo studies show TaqTth-hpRNA cleaves RNA efficiently and specifically. In an Alzheimer's disease model, we demonstrate silencing of mutant APPswe mRNA without altering the wild-type APP mRNA. Notably, due to the compact size of TaqTth, we are able to combine with APOE2 overexpression in a single AAV vector, which results in stronger inhibition of pathologies.

Human Pluripotent Stem Cells Derived Endothelial Cells Repair Choroidal Ischemia.

Choroidal atrophy is a common fundus pathological change closely related to the development of age-related macular degeneration (AMD), retinitis pigmentosa, and pathological myopia. Studies suggest that choroidal endothelial cells (CECs) that form the choriocapillaris vessels are the first cells lost in choroidal atrophy. It is found that endothelial cells derived from human pluripotent stem cells (hPSC-ECs) through the MESP1+ mesodermal progenitor stage express CECs-specific markers and can integrate into choriocapillaris. Single-cell RNA-seq (scRNA-seq) studies show that hPSC-ECs upregulate angiogenesis and immune-modulatory and neural protective genes after interacting with ex vivo ischemic choroid. In a rat model of choroidal ischemia (CI), transplantation of hPSC-ECs into the suprachoroidal space increases choroid thickness and vasculature density. Close-up examination shows that engrafted hPSC-ECs integrate with all layers of rat choroidal vessels and last 90 days. Remarkably, EC transplantation improves the visual function of CI rats. The work demonstrates that hPSC-ECs can be used to repair choroidal ischemia in the animal model, which may lead to a new therapy to alleviate choroidal atrophy implicated in dry AMD, pathological myopia, and other ocular diseases.

Supervised Attention-Based Bidirectional Long Short-Term Memory Network for Nonlinear Dynamic Soft Sensor Application.

Soft sensors are mathematical methods that describe the dependence of primary variables on secondary variables. A nonlinear characteristic commonly appears in modern industrial process data with increasing complexity and dynamics, which has brought challenges to soft sensor modeling. To solve these issues, a novel supervised attention-based bidirectional long short-term memory (SA-BiLSTM) is first proposed in this paper to handle the nonlinear industrial process modeling with dynamic features. In this SA-BiLSTM model, an attention mechanism is introduced to calculate the correlation between hidden features in each time step, thus avoiding the loss of important information. Furthermore, this approach combines historical quality information and a moving window through a supervised strategy of quality variables. Such manipulation not only extracts and exploits nonlinear dynamic latent information from the process and quality variables but also enhances the model's learning efficiency and overall prediction performance. Finally, two real industrial examples demonstrate the superiority of the proposed method compared to conventional methods.

Optimum fractionation of radiation to combine PD-1 blockade.

The optimum fractionation of radiation to combine with immune checkpoint blockade is controversial. This study aimed to investigate the fractionated radiation to maximize immunity during combination therapy. To evaluate the abscopal effect, C57BL/6 hPD-1 knock-in mice bearing two syngeneic contralateral MC38 murine colon cancer tumors were treated with four distinct regimens of radiotherapy. Three fractions of 8 Gy were chosen as the optimal fractionation to combine with anti-PD-1 as the optimal fractionation for maximizing immunity. Anti-PD-1 administration enhanced both local and systemic antitumor immunity in a cytotoxic T cell-dependent manner. Meanwhile, the spleen exhibited decreased myeloid-derived suppressor cells (MDSCs) under combination treatment. Furthermore, RNA-sequencing revealed significantly increased tumor necrosis factor (TNF) receptors and cytokines associated with lymphocyte infiltration in the combining group. Here we demonstrate that the hypofractionation of 8 Gy × 3f was the optimum-fractionated dosage to maximize immunity, and the combination of anti-PD-1 showed promising results in boosting abscopal effect. Underlying mechanisms may include the activation of T cells and the reduction of MDSCs, which is achieved through the action of TNF and related cytokines. This study indicates a radioimmunotherapy dosage painting method that can be developed to overcome present limitations in tumor immunosuppression.

Sensory input-dependent gain modulation of the optokinetic nystagmus by mid-infrared stimulation in pigeons.

Neuromodulation serves as a cornerstone for brain sciences and clinical applications. Recent reports suggest that mid-infrared stimulation (MIRS) causes non-thermal modulation of brain functions. Current understanding of its mechanism hampers the routine application of MIRS. Here, we examine how MIRS influences the sensorimotor transformation in awaking-behaving pigeons, from neuronal signals to behavior. We applied MIRS and electrical stimulation (ES) to the pretectal nucleus lentiformis mesencephali (nLM), an essential retinorecipient structure in the pretectum, and examined their influences on the optokinetic nystagmus, a visually guided eye movement. We found MIRS altered eye movements by modulating a specific gain depending on the strength of visual inputs, in a manner different than the effect of ES. Simultaneous extracellular recordings and stimulation showed that MIRS could either excite and inhibit the neuronal activity in the same pretectal neuron depending on its ongoing sensory responsiveness levels in awake-behaving animals. Computational simulations suggest that MIRS modulates the resonance of a carbonyl group of the potassium channel, critical to the action potential generation, altering neuronal responses to sensory inputs and as a consequence, guiding behavior. Our findings suggest that MIRS could be a promising approach toward modulating neuronal functions for brain research and treating neurological diseases.

Oral application of magnesium-L-threonate enhances analgesia and reduces the dosage of opioids needed in advanced cancer patients-A randomized, double-blind, placebo-controlled trial.

PURPOSE: To investigate the effects of oral administration of magnesium-L-threonate, a novel magnesium compound, on the analgesic effect of opioids in patients with advanced cancer. METHODS: We performed a prospective, randomized, double-blind trial at a tertiary hospital in Shanghai, China. Eligible cancer patients who took opioids orally were assigned randomly to receive L-TAMS capsules (1.5 g or 2.0 g according to weight) or a placebo (starch capsules). The primary outcome was the increase in the daily oral dose of morphine in each of the two groups, measured at 7, 14, 21, 30, 60, and 90 days during this trial. RESULTS: A total of 116 patients from the oncology and pain departments, including inpatients and outpatients, were screened; 83 were enrolled. The increases in daily morphine doses began to differ from day 30 (L-TAMS group 9.85 mg/d vs. Placebo group 20.49 mg/d, p < 0.05); the differences persisted on day 60 (L-TAMS group 15.96 mg/d vs. Placebo group 29.06 mg/d, p < 0.05) and on day 90 (L-TAMS group 21.20 mg/d vs. Placebo group 40.44 mg/d, p < 0.01). CONCLUSIONS: L-TAMS outperforms a placebo in enhancing the analgesic effect of opioids and reducing the necessary opioid dosage. Moreover, L-TAMS can significantly relieve opioid-induced constipation. These advantages may be beneficial to patients with advanced cancer.

Treatment-related lymphopenia impairs the treatment response of anti-PD-1 therapy in esophageal squamous cell carcinoma.

PURPOSE: Great interest has been focused on radiotherapy (RT) with immunotherapy. We sought to investigate the significance of treatment-related lymphopenia (TRL) in esophageal squamous cell carcinoma (ESCC) patients receiving anti-PD-1 therapy and the factors associated with TRL, especially RT. METHODS: 167 patients with ESCC that received anti-PD-1 therapy wereidentified, 72 of them received RT. TRL was defined as absolute lymphocyte count (ALC) < 0.50 × 109 cells/L at the start of immunotherapy and/or during immunotherapy. Depending on the presence of TRL, patients were divided into two groups. RESULTS: At median follow-up of 6.5 months, the ORR of patients without TRL (n = 65; 38.9%) reached 29.4% while patients (n = 102; 61.1%) with TRL was 23.1%, DCR was 81.4% and 75.4% respectively. Patients with TRL showed shorter progression-free survival (PFS) compared with patients without TRL (median PFS: 4.8 vs. 7.0 months, P = 0.009). Multivariate analyses confirmed TRL is an independent prognostic factor for poorer PFS (HR, 1.855; P = 0.008). RT significantly increased the occurrence of TRL (OR = 0.502, P = 0.035). Patients receiving ICIs < 33.5 days after RT showed a poorer PFS compared to that ≥ 33.5 days (median PFS: 4.1 vs 7.3 months, P = 0.008). The explanation is that patients with shorter time interval had a higher incidence of TRL (P = 0.028). CONCLUSION: TRL was an independent predictor of poor outcomes in ESCC patients receiving anti-PD-1 therapy. RT was a key factor affecting TRL. A shorter time interval of < 33.5 days between RT and anti-PD-1 therapy can lead to a poor prognosis by increasing the occurrence of TRL.

Efficacy of single-site radiotherapy plus PD-1 inhibitors vs PD-1 inhibitors for oligometastatic non-small cell lung cancer.

PURPOSE: Growing numbers of clinical trials test the efficacy of radiotherapy (RT) plus immune checkpoint inhibitors (ICIs), but the number of irradiated sites is not uniform. We aimed to evaluate the efficacy of single-site RT plus immunotherapy in oligometastatic non-small cell lung cancer (NSCLC) with smaller disease burdens and low tumor heterogeneity. METHODS: We retrospectively identified oligometastatic NSCLC (< 4 metastatic sites) patients treated with PD-1 pathway inhibitors with or without RT to a single lesion in our institution between 2018 and 2020. The primary endpoints were the best objective response rate (ORR) and progression-free survival (PFS). RESULTS: Of the 152 patients enrolled, 93 and 59 were identified as the ICI alone group and the ICI plus RT group, respectively. The addition of RT to ICI therapy significantly increased the best ORR from 31.2% to 50.8% (p = 0.015). The out-of-field (abscopal effect) response rate could reach 41.3% (95%CI 26.5%-56.1%) in the ICI plus RT group. Median PFS was 8.9 months (95%CI 4.7-13.1 months) with ICI alone versus 13.8 months (95%CI 9.5-18.1 months) with ICI plus radiotherapy (hazard ratio [HR] 0.556; p = 0.035). In an exploratory subgroup analysis of PFS, the addition of RT brought greater benefits in patients aged < 65 years (p = 0.016), patients with ECOG PS = 0 (p = 0.048), and patients with 1-2 metastatic sites (p = 0.024). No unexpected adverse events or significantly increased toxicities were observed in the experimental arm. CONCLUSION: Single-site RT plus anti-PD-1 inhibitors significantly increased systemic responses and improved survival outcomes in oligometastatic NSCLC patients.