PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6.

Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that is implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, the molecular mechanism underlying how Atx2 aggregation contributes to the proteinopathies remains elusive. Here, we investigated the influence of Atx2 aggregation on the assembly and functionality of cellular processing bodies (P-bodies) by using biochemical and fluorescence imaging approaches. We have revealed that polyQ-expanded (PQE) Atx2 sequesters the DEAD-box RNA helicase (DDX6), an essential component of P-bodies, into aggregates or puncta via some RNA sequences. The N-terminal like-Sm (LSm) domain of Atx2 (residues 82-184) and the C-terminal helicase domain of DDX6 are responsible for the interaction and specific sequestration. Moreover, sequestration of DDX6 may aggravate pre-mRNA mis-splicing, and interfere with the assembly of cellular P-bodies, releasing the endoribonuclease MARF1 that promotes mRNA decay and translational repression. Rescuing the DDX6 protein level can recover the assembly and functionality of P-bodies, preventing targeted mRNA from degradation. This study provides a line of evidence for sequestration of the P-body components and impairment of the P-body homeostasis in dysregulating RNA metabolism, which is implicated in the disease pathologies and a potential therapeutic target.

Confinement-Induced Indium Oxide Nanolayers Formed on Oxide Support for Enhanced CO2 Hydrogenation Reaction.

An enclosed nanospace often shows a significant confinement effect on chemistry within its inner cavity, while whether an open space can have this effect remains elusive. Here, we show that the open surface of TiO2 creates a confined environment for In2O3 which drives spontaneous transformation of free In2O3 nanoparticles in physical contact with TiO2 nanoparticles into In oxide (InOx) nanolayers covering onto the TiO2 surface during CO2 hydrogenation to CO. The formed InOx nanolayers are easy to create surface oxygen vacancies but are against over-reduction to metallic In in the H2-rich atmospheres, which thus show significantly enhanced activity and stability in comparison with the pure In2O3 catalyst. The formation of interfacial In-O-Ti bonding is identified to drive the In2O3 dispersion and stabilize the metastable InOx layers. The InOx overlayers with distinct chemistry from their free counterpart can be confined on various oxide surfaces, demonstrating the important confinement effect at oxide/oxide interfaces.

Conversion chemoradiotherapy combined with nab-paclitaxel plus cisplatin in patients with locally advanced borderline-resectable or unresectable esophageal squamous cell carcinoma: a phase i/ii prospective cohort study.

BACKGROUND: To evaluate the efficacy and safety of nab-paclitaxel plus cisplatin as the regimen of conversional chemoradiotherapy (cCRT) in locally advanced borderline resectable or unresectable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC (cT3­4, Nany, M0­1, M1 was limited to lymph node metastasis in the supraclavicular area) were enrolled. All the patients received the cCRT of nab-paclitaxel plus cisplatin. After the cCRT, those resectable patients received esophagectomy; those unresectable patients continued to receive the definitive chemoradiotherapy (dCRT). The locoregional control (LRC), overall survival (OS), event-free survival (EFS), distant metastasis free survival (DMFS), pathological complete response (pCR), R0 resection rate, adverse events (AEs) and postoperative complications were calculated. RESULTS: 45 patients with ESCC treated from October 2019 to May 2021 were finally included. The median follow-up time was 30.3 months. The LRC, OS, EFS, DMFS at 1 and 2 years were 81.5%, 86.6%, 64.3%, 73.2 and 72.4%, 68.8%, 44.8%, 52.7% respectively. 21 patients (46.7%) received conversional chemoradiotherapy plus surgery (cCRT+S). The pCR rate and R0 resection rate were 47.6 and 84.0%. The LRC rate at 1 and 2 years were 95.0%, 87.1% in cCRT+S patitents and 69.3%, 58.7% in dCRT patients respectively (HR, 5.14; 95%CI, 1.10-23.94; P = 0.021). The toxicities during chemoradiotherapy were tolerated, and the most common grade 3-4 toxicitiy was radiation esophagitis (15.6%). The most common postoperative complication was pleural effusion (38.1%) and no grade ≥ IIIb complications were observed. CONCLUSION: nab-paclitaxel plus cisplatin are safe as the regimen of conversional chemoradiotherapy of ESCC.

Hippocampal avoidance whole-brain radiotherapy with simultaneous integrated boost in lung cancer brain metastases and utility of the Hopkins verbal learning test for testing cognitive impairment in Chinese patients: a prospective phase II study.

BACKGROUND: This study aimed to evaluate the efficiency of hippocampal avoidance whole-brain radiotherapy with a simultaneous integrated boost (HA-WBRT-SIB) treating brain metastases (BM) and utility of the Hopkins Verbal Learning Test-Revised (HVLT-R) (Chinese version) in Chinese lung cancer patients. METHODS: Lung cancer patients with BM undergone HA-WBRT-SIB at our center were enrolled. Brain magnetic resonance imaging, The HVLT total learning score, and side effects were evaluated before radiotherapy and 1, 3, 6, and 12 months after radiotherapy. This study analyzed the overall survival rate, progression-free survival rate, and changes in HVLT-R immediate recall scores. RESULTS: Forty patients were enrolled between Jan 2016 and Jan 2020. The median follow-up time was 14.2 months. The median survival, progression-free survival, and intracranial progression-free survival of all patients were 14.8 months, 6.7 months and 14.8 months, respectively. Multivariate analysis indicated that male sex and newly diagnosed stage IV disease were associated with poor overall survival and progression-free survival, respectively. HVLT-R scores at baseline and 1, 3, and 6 months after radiotherapy were 21.94 ± 2.99, 20.88 ± 3.12, 20.03 ± 3.14, and 19.78 ± 2.98, respectively. The HVLT-R scores at 6 months after radiotherapy decreased by approximately 9.8% compared with those at baseline. No grade 3 toxicities occurred in the entire cohort. CONCLUSIONS: HA-WBRT-SIB is of efficiency and cognitive-conserving in treating Chinese lung cancer BM. TRIAL REGISTRATION: This study was retrospectively registered on ClinicalTrials.gov in 24th Feb, 2024. The ClinicalTrials.gov ID is NCT06289023.

Higher immune cell radiation dose is correlated with poor tumor control and survival in patients with non-small cell lung cancer receiving postoperative radiotherapy.

INTRODUCTION: The estimated dose of radiation to immune cells (EDRIC) has been shown to correlate with the overall survival (OS) of patients who receive definitive thoracic radiotherapy. However, the planning target volume (PTV) may be a confounding factor. We assessed the prognostic value of EDRIC for non-small cell lung cancer (NSCLC) in patients who underwent postoperative radiotherapy (PORT) with homogeneous PTV. METHODS: Patients with NSCLC who underwent PORT between 2004 and 2019 were included. EDRIC was computed as a function of the number of radiation fractions and mean doses to the lungs, heart, and remaining body. The correlations between EDRIC and OS, disease-free survival (DFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed using univariate and multivariate Cox models. Kaplan-Meier analysis was performed to assess the survival difference between low- and high-EDRIC groups. RESULTS: In total, 345 patients were analyzed. The mean EDRIC was 6.26 Gy. Multivariate analysis showed that higher EDRIC was associated with worse outcomes in terms of OS (hazard ratio [HR] 1.207, P = .007), DFS (HR 1.129, P = .015), LRFS (HR 1.211, P = .002), and DMFS (HR 1.131, P = .057). In the low- and high-EDRIC groups, the 3-year OS was 81.2% and 74.0%, DFS 39.8% and 35.0%, LRFS 70.4% and 60.5%, and DMFS 73.9% and 63.1%, respectively. CONCLUSIONS: EDRIC is an independent prognostic factor for survival in patients with NSCLC undergoing PORT. Higher doses of radiation to the immune system are associated with tumor progression and poor survival. Organs at risk for the immune system should be considered during radiotherapy planning.

In-Situ Dynamic Carburization of Mo Oxide with Unprecedented High CO Formation Rate in Reverse Water-Gas Shift Reaction.

In-situ construction of active structure under reaction conditions is highly desired but still remains challenging in many important catalytic processes. Herein, we observe structural evolution of molybdenum oxide (MoOx) into highly active molybdenum carbide (MoCx) during reverse water-gas shift (RWGS) reaction. Surface oxygen atoms in various Mo-based catalysts are removed in H2-containing atmospheres and then carbon atoms can accumulate on surface to form MoCx phase with the RWGS reaction going on, both of which are enhanced by the presence of intercalated H species or Pt-dopants in MoOx. The structural evolution from MoOx to MoCx is accompanied by enhanced CO2 conversion, which is positively correlated with the surface C/Mo ratio but negatively with the surface O/Mo ratio. As a result, an unprecedented CO formation rate of 7544.6 mmol·gcatal-1·h-1 at 600 °C has been achieved over in-situ carbonized H-intercalated MoO3 catalyst, which is even higher than those from noble metal catalysts. During 100 h stability test only a minimal deactivation rate of 2.3% is observed.

Effectiveness and safety of combined nimotuzumab and S-1 chemotherapy with concurrent radiotherapy for locally advanced esophageal cancer in malnourished and elderly patients: A prospective phase II study.

Objective: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score. Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate. Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred. Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

Synergistic effects of Ω-3 polyunsaturated fatty acid supplementation and programmed cell death protein 1 blockade on tumor growth and immune modulation in a xenograft model of esophageal cancer.

BACKGROUND: Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC), remains a significant global health challenge with limited survival rates. This study aimed to elucidate the combined effects of immune-modulating nutrition (IMN) with Ω-3 polyunsaturated fatty acid (PUFA) supplementation and anti-programmed cell death protein 1 (PD-1) treatment on tumor growth and immune responses in a xenograft model of ESCC. METHODS: A total of 36 C57BL/6 mice were used to construct a xenograft model using the mouse esophageal cancer cell line AKR. Mice were subjected to treatment with anti- PD-1 antibody combined with either Ω-3 PUFA-rich or Ω-3 PUFA-deficient nutrition. Tumor growth, immune markers, cytokine profiles, and metabolic changes were evaluated. RESULTS: The combination of anti-PD-1 and Ω-3 PUFA supplementation significantly inhibited tumor growth more effectively than anti-PD-1 treatment alone. Enhanced expression of immune markers PD-L1 and CD3 was observed in Ω-3 PUFA-fed mice. Additionally, compared with anti-PD-1 therapy and anti-PD-1 plus Ω-3 PUFA-deficient nutrition, Ω-3 PUFAs intensified alterations in key chemokines and cytokines, including elevated IL-12, IFN-γ, and GM-CSF levels, and reduced CXCL12 levels. However, Ω-3 PUFAs did not significantly alter the glycolysis and tryptophan metabolic program induced by anti-PD-1. CONCLUSION: Our findings indicated the potential synergetic therapeutic benefits of combining anti-PD-1 treatment with Ω-3 PUFA supplementation in ESCC, which offered promising avenue for further research.

[Application of intra-articular graft length measurement in total anterior cruciate ligament reconstruction].

OBJECTIVE: To investigate the clinical efficacy of arthroscopic measurement of intra-articular graft length in the application of total internal reconstruction of the anterior cruciate ligament(ACL). METHODS: The 60 patients with ACL injury treated between January 2020 and January 2022 were retrospectively analyzed. There were 37 males and 23 females, aged from 22 to 44 years. According to the different surgical methods, they were divided into two groups:conventional surgery group (conventional group) and pull-line measurement group (measurement group), with 30 cases in each group. In the conventional group, there were 20 males and 10 females, with an average age of (30.00±3.95) years old;the body mass index (BMI) was (22.58±1.41) kg·m-2;there were 9 cases on the left side and 21 cases on the right side;the time from injury to operation was (3. 00±1.35) days. In the measurement group, there were 17 males and 13 females, with an average of(32.00±4.29) years;BMI was (23.29±1.39) kg·m-2;there were 12 cases on the left side and 18 cases on the right side;the time from injury to operation was (3.00±1.27) days. The clinical data of the patients before surgery, 6 months after surgery and 12 months after surgery were collected and recorded. The clinical efficacy of the two methods was compared in terms of postoperative VAS, KOOS, Lysholm score, IKDC score, knee stability (Lachman test, anterior drawer test and axial shift test), the degree of widening of bone tunnel diameter measured by CT at different stages of the postoperative period and MRI scoring system. RESULTS: At 12 months after surgery, the VAS of the measurement group was lower than that of the conventional group(P<0.001). At 12 months after surgery, KOOS scores in the measurement group were higher than those in the conventional group, and there were statistically significant differences in all scores except symptom scores (P<0.05). Six months after operation, Lysholm total score and IKDC total score in the measurement group were higher than those in the conventional group, and the difference was statistically significant (P<0.05). At 12 months after surgery, knee stability tests were performed, and the differences between the Lachman test, anterior drawer test and axial shift test measurement group and the conventional group were not statistically significant (P>0.05). However, overall knee instability analysis showed that the knee stability of the measurement group was better than that of the control group, and the difference between the groups was statistically significant (P=0.038). The imaging assessment of patients in both groups at 6 months after surgery showed that the widening of tendon tunnel diameter in both femur and tibia was reduced in the measurement group compared with the conventional group after surgery, and the difference was statistically significant(P<0.05);MRI scores were higher in all patients in the measurement group those in the conventional group, at 6 months and 12 months agter surgery(P<0.05). CONCLUSION: Arthroscopic measurement of intra-articular cavity graft length in total internal technique for ACL reconstruction, high tendon utilization, good stability, the knee joint function has recovered satisfactorily within one year, and the therapeutic effect is affirmed.

Ataxin-2 sequesters Raptor into aggregates and impairs cellular mTORC1 signaling.

Ataxin-2 (Atx2) is a polyglutamine (polyQ) protein, in which abnormal expansion of the polyQ tract can trigger protein aggregation and consequently cause spinocerebellar ataxia type 2 (SCA2), but the mechanism underlying how Atx2 aggregation leads to proteinopathy remains elusive. Here, we investigate the molecular mechanism and cellular consequences of Atx2 aggregation by molecular cell biology approaches. We have revealed that either normal or polyQ-expanded Atx2 can sequester Raptor, a component of mammalian target of rapamycin complex 1 (mTORC1), into aggregates based on their specific interaction. Further research indicates that the polyQ tract and the N-terminal region (residues 1-784) of Atx2 are responsible for the specific sequestration. Moreover, this sequestration leads to suppression of the mTORC1 activity as represented by down-regulation of phosphorylated P70S6K, which can be reversed by overexpression of Raptor. As mTORC1 is a key regulator of autophagy, Atx2 aggregation and sequestration also induces autophagy by upregulating LC3-II and reducing phosphorylated ULK1 levels. This study proposes that Atx2 sequesters Raptor into aggregates, thereby impairing cellular mTORC1 signaling and inducing autophagy, and will be beneficial for a better understanding of the pathogenesis of SCA2 and other polyQ diseases.

Preoperative CT-based radiomic prognostic index to predict the benefit of postoperative radiotherapy in patients with non-small cell lung cancer: a multicenter study.

BACKGROUND: The value of postoperative radiotherapy (PORT) for patients with non-small cell lung cancer (NSCLC) remains controversial. A subset of patients may benefit from PORT. We aimed to identify patients with NSCLC who could benefit from PORT. METHODS: Patients from cohorts 1 and 2 with pathological Tany N2 M0 NSCLC were included, as well as patients with non-metastatic NSCLC from cohorts 3 to 6. The radiomic prognostic index (RPI) was developed using radiomic texture features extracted from the primary lung nodule in preoperative chest CT scans in cohort 1 and validated in other cohorts. We employed a least absolute shrinkage and selection operator-Cox regularisation model for data dimension reduction, feature selection, and the construction of the RPI. We created a lymph-radiomic prognostic index (LRPI) by combining RPI and positive lymph node number (PLN). We compared the outcomes of patients who received PORT against those who did not in the subgroups determined by the LRPI. RESULTS: In total, 228, 1003, 144, 422, 19, and 21 patients were eligible in cohorts 1-6. RPI predicted overall survival (OS) in all six cohorts: cohort 1 (HR = 2.31, 95% CI: 1.18-4.52), cohort 2 (HR = 1.64, 95% CI: 1.26-2.14), cohort 3 (HR = 2.53, 95% CI: 1.45-4.3), cohort 4 (HR = 1.24, 95% CI: 1.01-1.52), cohort 5 (HR = 2.56, 95% CI: 0.73-9.02), cohort 6 (HR = 2.30, 95% CI: 0.53-10.03). LRPI predicted OS (C-index: 0.68, 95% CI: 0.60-0.75) better than the pT stage (C-index: 0.57, 95% CI: 0.50-0.63), pT + PLN (C-index: 0.58, 95% CI: 0.46-0.70), and RPI (C-index: 0.65, 95% CI: 0.54-0.75). The LRPI was used to categorize individuals into three risk groups; patients in the moderate-risk group benefited from PORT (HR = 0.60, 95% CI: 0.40-0.91; p = 0.02), while patients in the low-risk and high-risk groups did not. CONCLUSIONS: We developed preoperative CT-based radiomic and lymph-radiomic prognostic indexes capable of predicting OS and the benefits of PORT for patients with NSCLC.

Multileaf Collimator Modeling and Commissioning for Complex Radiation Treatment Plans Using 2-Dimensional (2D) Diode Array MapCHECK2.

Purpose: This study aims to develop a data-collecting package ExpressMLC and investigate the applicability of MapCHECK2 for multileaf collimator (MLC) modeling and commissioning for complex radiation treatment plans. Materials and methods: The MLC model incorporates realistic parameters to account for sophisticated MLC features. A set of 8 single-beam plans, denoted by ExpressMLC, is created for the determination of parameters. For the commissioning of the MLC model, 4 intensity modulated radiation therapy (IMRT) plans specified by the AAPM TG 119 report were transferred to a computed tomography study of MapCHECK2, recalculated, and compared to measurements on a Varian accelerator. Both per-beam and composite-beam dose verification were conducted. Results: Through sufficient characterization of the MLC model, under 3%/2 mm and 2%/2 mm criteria, MapCHECK2 can be used to accurately verify per beam dose with gamma passing rate better than 90.9% and 89.3%, respectively, while the Gafchromic EBT3 films can achieve gamma passing rate better than 89.3% and 85.7%, respectively. Under the same criteria, MapCHECK2 can achieve composite beam dose verification with a gamma passing rate better than 95.9% and 90.3%, while the Gafchromic EBT3 films can achieve a gamma passing rate better than 96.1% and 91.8%; the p-value from the Mann Whitney test between gamma passing rates of the per beam dose verification using full MapCHECK2 package calibrated MLC model and film calibrated MLC model is .44 and .47, respectively; the p-value between those of the true composite beam dose verification is .62 and .36, respectively. Conclusion: It is confirmed that the 2-dimensional (2D) diode array MapCHECK2 can be used for data collection for MLC modeling with the combination of the ExpressMLC package of plans, whose doses are sufficient for the determination of MLC parameters. It could be a fitting alternative to films to boost the efficiency of MLC modeling and commissioning without sacrificing accuracy.

Unrevealing the therapeutic benefits of radiotherapy and consolidation immunotherapy using ctDNA-defined tumor clonality in unresectable locally advanced non-small cell lung cancer.

Progression occurs in approximately two-thirds of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving chemoradiation and consolidation immunotherapy. Molecular indicators for outcome prediction are under development. A novel metric, the ratio of mean to max variant allele frequency (mmVAF), was derived from 431 pre-treatment tissue biopsies from The Cancer Genome Atlas and evaluated in serial circulating tumor DNA (ctDNA) from 70 LA-NSCLC patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT) with/without immunotherapy. High mmVAFs in pre-treatment tissue biopsies, indicating clonal predominant tumors (P < 0.01), were associated with inferior overall survival [OS, hazard ratio (HR): 1.48, 95 % confidence interval (CI): 1.11-1.98]. Similar associations of mmVAF with clonality (P < 0.01) and OS (HR: 2.24, 95 % CI: 0.71-7.08) were observed in pre-treatment ctDNA. At 1-month post-RT, ctDNA mmVAF-high patients receiving consolidation immunotherapy exhibited improved progression-free survival (PFS) compared to those who did not (HR: 0.14, 95 % CI: 0.03-0.67). From the baseline to week 4 of RT and/or 1-month post-RT, survival benefits from consolidation immunotherapy were exclusively observed in ctDNA mmVAF-increased patients (PFS, HR: 0.39, 95 % CI: 0.14-1.15), especially in terms of distant metastasis (HR: 0.11, 95 % CI: 0.01-0.95). In summary, our longitudinal data demonstrated the applicability of ctDNA-defined clonality for prognostic stratification and immunotherapy benefit prediction in LA-NSCLC.

Induction PD-1 inhibitor toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab for bulky locally advanced non-small-cell lung cancer: protocol for a randomized phase II trial (InTRist study).

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage I-II NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary. Methods: This randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus non-squamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments. Discussion: The InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response. Clinical trial registration: ClinicalTrials.gov, identifier NCT05888402.

The time-series behavior of systemic inflammation-immune status in predicting survival of locally advanced non-small cell lung cancer treated with chemoradiotherapy.

Background: Systematic inflammation is believed to play a crucial role in tumorigenesis and metastasis. This study aims at evaluating the prognostic value of time-series behavior of systematic inflammation-immune status before and after definitive chemoradiotherapy (dCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Methods: The relationship between systematic inflammation-immune score (SIS, defined as pretreatment peripheral platelet count × neutrophil count/lymphocyte count) and the prognosis was tested in a retrospective study of 386 consecutive LA-NSCLC patients (Group A) with pretreatment SIS and 161 patients (Group B) with SIS before and one month after the dCRT. Results: SIS of 1400 × 109 was found to be an optimal cutoff point to stratify the patients into high (>1400 × 109) and low (≤1400 × 109) SIS groups. Univariate and multivariate analyses revealed that the SIS, whether before or after dCRT, was an independent predictor for overall survival (OS), progress-free survival (PFS), and distant metastasis-free survival (DMFS). High SIS (>1400 × 109) was shown to predict poor 3-year OS (P=0.006, hazard ratio [HR]=2.427), PFS (P=0.001, HR=2.442) and DMFS (P=0.015, HR=2.119). However, SIS was not related to local regional recurrence-free survival in either Group A (P=0.346) or Group B (P=0.486). Further, the area under the receiver operating characteristic curve of the SIS for OS was higher than the neutrophil count/lymphocyte count ratio, platelet count/lymphocyte count ratio, and other conventional clinic-pathological indices. Conclusions: The SIS is a stable and more sensitive survival predictor than other inflammation-based factors and conventional clinical indices, which may aid in more accurately stratifying patients for risk assessment and treatment decisions.