The role of radiotherapy in extensive-stage small cell lung cancer after durvalumab-based immunochemotherapy: A retrospective study.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide(EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs. 12.3 months (hazard ratio [HR]: 0.38, 95% CI: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs. 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs. 14.7 months) and PFS (9.1 months vs. 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs. 13.7 months and median PFS of 9.8 months vs. 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs. 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs. 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION: Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.

Clinical treatment patterns, molecular characteristics and survival outcomes of ROS1-rearranged non-small cell lung cancer: A large multicenter retrospective study.

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.

Retraction Notice to: lncRNA UCA1 Promotes Gefitinib Resistance as a ceRNA to Target FOSL2 by Sponging miR-143 in Non-small Cell Lung Cancer.

[This retracts the article DOI: 10.1016/j.omtn.2019.10.047.].

An online survey on public awareness of drug clinical trials in inland cities of northern China.

Objective: The aims of this survey were to investigate the public awareness of drug clinical trials (DCTs) and willingness to participate the DCTs, and provide references for propaganda and science popularization of DCTs. Methods: A self-designed questionnaire named "an online survey questionnaire on public awareness of DCTs" was used to conduct an online survey from January to March 2022. The demographic characteristics and the response of participants to the awareness and willingness to participate the DCTs were collected. The factors affecting the public awareness of DCTs were analyzed by single factor and binary logistic regression analysis. Results: One thousand three hundred eighty valid questionnaires were collected, and the respondents' awareness rate of DCTs was 61.1%. Thirteen demographic characteristics including age, gender, education, occupation, work fields, household type, marital status, city type, income, medical insurance, medical expenditure, pressure to seek medical care, financial pressure, both significantly affected the qualified rate of participants' awareness of DCTs (p < 0.001) by single factor analysis. Binary logistic regression analysis indicated that education level, work fields, city type, medical insurance, and medical expenditure affected independently the participants' awareness rate of DCTs (p < 0.001). 52.9% of the participants were willing to take part in DCTs. "to promote medical progress" (54.4%) or "believe doctors" (31.1%) were the most frequent reasons for subjects participating in DCTs. Conclusion: The public awareness rate of DCTs and the willingness to participate in drug clinical were significantly affected by the demographic characteristics of subjects. Thus, targeting the needs of the public, propaganda, and science popularization of DCTs should be carried out and served public health.

Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization.

BACKGROUND: Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. METHODS: We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. RESULT: Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. CONCLUSIONS: Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.

Glycolysis­related lncRNA may be associated with prognosis and immune activity in grade II­III glioma.

Glucose metabolism, as a novel theory to explain tumor cell behavior, has been intensively studied in various tumors. The present study explored the long non-coding RNAs (lncRNAs) related to glycolysis in grade II-III glioma, aiming to provide a promising target for further research. Pearson correlation analysis was used to identify glycolysis-related lncRNAs. Univariate/multivariate Cox regression analysis and the Least Absolute Shrinkage and Selection Operator algorithm were applied to identify glycolysis-related lncRNAs to construct a prognosis prediction model. Subsequently, multi-dimensional evaluations were used to verify whether the risk model could predict the prognosis and survival rate of patients with grade II-III glioma. Finally, it was verified by functional experiments. The present study finally identified seven glycolysis-related lncRNAs (CRNDE, AC022034.1, RHOQ-AS1, AL159169.2, AL133215.2, AC007098.1 and LINC02587) to construct a prognosis prediction model. The present study further investigated the underlying immune microenvironment, somatic landscape and functional enrichment pathways. Additionally, individualized immunotherapeutic strategies and candidate compounds were identified to guide clinical treatment. The experimental results demonstrated that CRNDE could increase the proliferation of SHG-44 cells. In conclusion, a large sample of human grade II-III glioma in The Cancer Genome Atlas database was used to construct a risk model using glycolysis-related lncRNAs to predict the prognosis of patients with grade II-III glioma.

Spinal Lymphatic Dysfunction Aggravates the Recovery Process After Spinal Cord Injury.

We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway.

MET overexpression correlated with prognosis of EGFR-mutant treatment­naïve advanced lung adenocarcinoma: a real­world retrospective study.

BACKGROUND: About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). METHODS: A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. RESULTS: Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. CONCLUSIONS: MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Pathological Response and Tumor Immune Microenvironment Remodeling Upon Neoadjuvant ALK-TKI Treatment in ALK-Rearranged Non-Small Cell Lung Cancer.

BACKGROUND: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI; ALKi) have shown potent antitumor activity in metastatic non-small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+); however, their efficacy in neoadjuvant settings has been poorly explored. OBJECTIVE: This retrospective study aimed to examine the clinical activity and tumor immune microenvironment (TIME) changes of neoadjuvant ALKi therapy. METHODS: ALK+ NSCLC patients treated with neoadjuvant ALKi at three hospitals in China between February 2018 and January 2023 were assessed. Data on clinical features and radiographic and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pretreatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. RESULTS: A total of 12 patients with stage IIA-IIIB NSCLC who received neoadjuvant ALKi therapy were analyzed. The objective response rate was 91.7% (11/12) and the major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed a significant increase in immune infiltration of CD8+ cells (histochemistry score [H-score]: median 10.51 vs. 24.01, p = 0.028; density: median 128.38 vs. 694.09 cells/mm2, p = 0.028; percentage: median 3.53% vs. 15.92%, p = 0.028) and CD4+ cells (density: median 275.56 vs. 651.82 cells/mm2, p = 0.028; percentage: median 5.98% vs. 10.46%, p = 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB- cells. However, macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. CONCLUSION: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME changes by neoadjuvant ALKi therapy and merits further investigation.

Bone-to-Bone Ligament Preserving Laminoplasty with Ultrasonic Osteotome Assistance for Intraspinal Tumors: A Technical Note and Clinical Follow-Up.

OBJECTIVE: Laminectomy has been widely used for intraspinal tumor resection. However, the tilted spinous process and narrow lateral laminae of the thoracic spine along with the hypertrophic ligamentum flavum of the lumbar spine pose certain problems for the laminae removal of the traditional laminectomy. We improved the laminectomy method with ultrasonic osteotome to treat thoracolumbar tumors and assessed its safety and superiority. METHODS: A retrospective analysis was performed in 86 patients with thoracolumbar (T4-L5) spinal tumors treated by resection, including 44 with the lamina removed using the traditional method and 42 with the lamina removed using the bone-to-bone ligament preserving (BLP) laminoplasty, which preserves the posterior ligament complex. Age, sex, and tumor size, location, and depth were compared between the two groups. The length of incision and bone window, time to remove the vertebral lamina, and epidural effusion volume were recorded at 2 weeks after surgery in the two groups. Postoperative reexamination by magnetic resonance imaging (MRI) at 2 weeks and 3 months after surgery was compared with preoperative MRI to assess the change in vertebral lamina displacement. RESULTS: There were no statistical differences in age, sex, and tumor size, depth, or location between the two groups. The BLP laminectomy did not increase the risk of dural, spinal cord, or nerve injuries. The difference between the incision and tumor length, as well as the difference between the bone window and tumor length in the BLP laminectomy group, were smaller than those in the traditional laminectomy group, and the BLP laminectomy took less time compared to that of the traditional laminectomy (p < 0.05). There was no significant difference in the volume of epidural effusion between the two groups at 2 weeks postoperatively, or in the displacement of the returned vertebral plate observed in sagittal and axial positions. The same was true for the displacement at 3 months postoperatively in the axial position. However, the sagittal displacement in the BLP laminectomy group was smaller than that in the traditional laminectomy group (p < 0.05). CONCLUSIONS: The BLP laminectomy is safe for the resection of thoracolumbar spinal canal tumors. It is less traumatic and faster, with less displacement of the returned lamina, resulting in a stable repair of the spine.

MPC-n (IgG) improves long-term cognitive impairment in the mouse model of repetitive mild traumatic brain injury.

BACKGROUND: Contact sports athletes and military personnel who suffered a repetitive mild traumatic brain injury (rmTBI) are at high risk of neurodegenerative diseases such as advanced dementia and chronic traumatic encephalopathy (CTE). However, due to the lack of specific biological indicators in clinical practice, the diagnosis and treatment of rmTBI are quite limited. METHODS: We used 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules to deliver immunoglobulins (IgG), which can increase the delivery efficiency and specific target of IgG while reducing the effective therapeutic dose of the drug. RESULTS: Our results demonstrated that MPC-capsuled immunoglobulins (MPC-n (IgG)) significantly alleviated cognitive impairment, hippocampal atrophy, p-Tau deposition, and myelin injury in rmTBI mice compared with free IgG. Furthermore, MPC-n (IgG) can also effectively inhibit the activation of microglia and the release of inflammatory factors. CONCLUSIONS: In the present study, we put forward an efficient strategy for the treatment of rmTBI-related cognitive impairment and provide evidence for the administration of low-dose IgG.

Efficacy of Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With ROS1-Rearranged Advanced Lung Adenocarcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) exert robust antitumor activity in non-small-cell lung cancer (NSCLC) without actionable mutations. Apart from isolated case reports, the efficacy of PD-1 blockade in ROS1-rearranged NSCLC is currently unknown. METHODS: This retrospective cohort study included 23 patients with ROS1-rearranged advanced lung adenocarcinoma who received ICI plus chemotherapy regardless of the treatment setting. ICI plus chemotherapy was received as a later-line regimen by 14 patients, as the first-line regimen by six patients, and after chemoradiotherapy by three patients. RESULTS: All three patients who received chemoradiotherapy followed by ICI plus chemotherapy achieved partial response (PR) and had a progression-free survival (PFS) of >17.9 months. Of the six patients who received first-line ICI plus chemotherapy, five patients achieved PR and one had stable disease (SD), with a median PFS of 24.3 months (95% CI, 4.9 to 43.7). Of the 14 previously treated patients who received later-line ICI plus chemotherapy, the Objective Response Rate (ORR) was 28.6%, the Disease Control Rate (DCR) was 92.9%, and the median PFS was 5.8 months (95% CI, 0.2 to 9.4). The median time on ICI therapy was 10.0 months (95% CI, 1.5 to 32.5). The duration of response was 24.3 months (95% CI, 5.4 to 43.2) and 4.8 months (95% CI, 2.3 to 12.7) for first-line (n = 5) and subsequent-line (n = 4) ICI plus chemotherapy, respectively. Of the 10 patients with brain metastasis before receiving ICI plus chemotherapy, four patients achieved intracranial PR and five patients achieved intracranial SD, achieving an intracranial ORR of 40.0% and an intracranial DCR of 90.0%. CONCLUSION: Our retrospective study provides real-world clinical evidence that ROS1-rearranged NSCLCs benefit from ICI plus chemotherapy in any treatment setting, including patients who present with brain metastasis.

Radiation therapy in the era of immune treatment for hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in recent years and provide new opportunities to treat hepatocellular carcinoma (HCC). To date, several ICIs have been approved by the FDA for advanced HCC in first-line or second-line therapy. Downstaging conversion therapy for potentially resectable HCC to provide opportunities for surgical intervention is challenging. ICIs have become a hot spot in this field due to their high response rate. However, HCC has various etiologies and can evade the immune system through multiple mechanisms, which limit the efficacy of ICI monotherapy and demand novel combination strategies. Radiation therapy (RT) is also a candidate for conversion therapy in HCC and is currently gaining increasing attention as a good combination partner with ICIs due to its ability to modulate the tumor microenvironment. In this review, we illustrate the current indications for ICIs and RT in HCC, the rationale for their synergistic combination, and the current clinical trials in combination therapy. We also speculate on predictive biomarkers and novel future strategies to further enhance the efficacy of this combination. This review aims to provide references for future research on radiation and immunotherapy to arrive at a promising new era of HCC treatment.

MET overexpression in EGFR L858R mutant treatment-naïve advanced lung adenocarcinoma correlated with poor prognosis: a real-world retrospective study.

BACKGROUND: Mesenchymal epithelial transition (MET) overexpression has been reported in approximately 50-60% of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers. However, the prognostic significance of MET overexpression has not been established in advanced lung adenocarcinoma (ADC) patients with EGFR-sensitive mutations. METHODS: A retrospective study was performed on a total of 406 treatment-naïve advanced ADC patients with EGFR mutation detection and MET expression information. EGFR mutations were detected by next-generation sequencing or amplification refractory mutation system-polymerase chain reaction. Immuno-histochemistry staining of MET expression was evaluated by H-score and overexpression was defined as an H-score ≥ 200. Overall survival (OS) and progression-free survival (PFS) were analyzed according to MET expression. RESULTS: Among the 406 patients, 208 patients had EGFR mutations, including 102 exon 19_del mutations, 94 L858R mutations and 12 other types of mutations. Of 110 patients with concomitant EGFR mutations and MET overexpression, 61 (59.8%) patients had 19_del mutations, 44 (46.8%) patients had L858R mutations and five (41.7%) patients had others. Patients with MET overexpression had a markedly shorter PFS and OS than patients with MET H-score < 200 in the EGFR L858R mutation subgroup (median PFS: 12 versus 26 months, p = 0.001; median OS: 24 versus 32 months, p = 0.038), whereas no significant difference was observed in 19_del mutation subgroup. Multivariate Cox analysis showed that MET overexpression was an independent poor prognostic factor for PFS and OS in patients with the L858R mutations (HR = 3.064, 95% CI 1.705-5.507, p < 0.001; HR = 2.043, 95% CI 1.000-4.172; p = 0.049), rather than 19_del. CONCLUSIONS: MET overexpression is a poor prognostic factor for advanced ADC patients with the EGFR L858R mutation.

T Cell-Mediated Tumor Killing-Related Classification of the Immune Microenvironment and Prognosis Prediction of Lung Adenocarcinoma.

BACKGROUND: Although immune checkpoint inhibitors (ICI) are a promising therapeutic strategy for lung adenocarcinoma (LUAD), individual subgroups that might benefit from them are yet to be identified. As T cell-mediated tumor killing (TTK) is an underlying mechanism of ICI, we identified subtypes based on genes associated with TTK sensitivity and assessed their predictive significance for LUAD immunotherapies. METHODS: Using high-throughput screening techniques, genes regulating the sensitivity of T cell-mediated tumor killing (GSTTK) with differential expression and associations with prognosis were discovered in LUAD. Furthermore, patients with LUAD were divided into subgroups using unsupervised clustering based on GSTTK. Significant differences were observed in the tumor immune microenvironment (TIME), genetic mutation and immunotherapy response across subgroups. Finally, the prognostic significance of a scoring algorithm based on GSTTK was assessed. RESULTS: A total of 6 out of 641 GSTTK exhibited differential expression in LUAD and were associated with prognosis. Patients were grouped into two categories based on the expression of the six GSTTK, which represented different TTK immune microenvironments in LUAD. Immune cell infiltration, survival difference, somatic mutation, functional enrichment and immunotherapy responses also varied between the two categories. Additionally, a scoring algorithm accurately distinguished overall survival rates across populations. CONCLUSIONS: TTK had a crucial influence on the development of the varying TIME. Evaluation of the varied TTK modes of different tumors enhanced our understanding of TIME characteristics, wherein the changes in T cell activity in LUAD are reflected. Thus, this study guides the development of more effective therapeutic methods.

Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans.

"On-target off-tumor" toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid tumors, and would therefore appear to be a suitable antigen target. To understand the risk of toxicity to different organs on anti-mesothelin CAR T cell therapy, single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems were analyzed in this study, including the respiratory, cardiovascular, digestive, and urinary systems. According to scRNA-seq datasets, the organs were stratified into high or low risk based on the level of mesothelin expression. We report that the proportion of mesothelin-positive cells was 7.71%, 2.40% and 2.20% of myocardial cells, pulmonary cells and stomach cells, respectively, indicating that these organs could be at high risk of "on-target off-tumor" toxicity on anti-mesothelin CAR T cell therapy. By contrast, esophagus, ileum, liver, kidney and bladder exhibited low mesothelin expression (<1%). Therefore, these organs could be regarded as at low risk. Thus, the risk of toxicity to different organs and tissues in anti-mesothelin CAR T cell therapy may be predicted by these scRNA-seq data.

Anti-PD-1 sintilimab-induced bilateral optic neuropathy in non-small cell lung cancer: A case report and literature review.

Anti-PD-1/PD-L1 immunotherapy reactivates T-cell activity to boost the antitumor effect and may trigger autoimmune toxicity in various organ systems involving eyeball and periocular structures at the same time. The rarity of ocular immune-related adverse events should not prevent us from paying attention to this issue because of the bad consequences of visual impairment. This is the first case report of anti-PD-1 sintilimab-induced bilateral optic neuropathy in a 76-year-old man with squamous non-small cell lung cancer (NSCLC). The patient presented with sudden vision blurring without pain in both eyes after three therapeutic cycles of sintilimab plus chemotherapy. Based on the ophthalmic examination, laboratory, and radiological results, our patient was diagnosed with optic neuropathy complication secondary to anti-PD-1 sintilimab treatment. Consequently, sintilimab was held and systemic steroids were administered. The follow-up review showed that the vision recovered and the size of the primary tumor continued to decrease with the response assessment as the partial response. In conclusion, this case report suggested that patients with NSCLC undergoing anti-PD-1/PD-L1 therapy should be closely monitored for ophthalmic assessment and alert to the occurrence of sintilimab-induced optic neuropathy.

EGFR Mutation Status and Subtypes Predicted by CT-Based 3D Radiomic Features in Lung Adenocarcinoma.

Objective: In this study, we aim to establish a non-invasive tool to predict epidermal growth factor receptor (EGFR) mutation status and subtypes based on radiomic features of computed tomography (CT). Methods: A total of 233 lung adenocarcinoma patients were investigated and randomly divided into the training and test cohorts. In this study, 2300 radiomic features were extracted from original and filtered (Exponential, Laplacian of Gaussian, Logarithm, Gabor, Wavelet) CT images. The radiomic features were divided into four categories, including histogram, volumetric, morphologic, and texture features. An RF-BFE algorithm was developed to select the features for building the prediction models. Clinicopathological features (including age, gender, smoking status, TNM staging, maximum diameter, location, and growth pattern) were combined to establish an integrated model with radiomic features. ROC curve and AUC quantified the effectiveness of the predictor of EGFR mutation status and subtypes. Results: A set of 10 features were selected to predict EGFR mutation status between EGFR mutant and wild type, while 9 selected features were used to predict mutation subtypes between exon 19 deletion and exon 21 L858R mutation. To predict the EGFR mutation status, the AUC of the training cohort was 0.778 and the AUC of the test cohort was 0.765. To predict the EGFR mutation subtypes, the AUC of training cohort was 0.725 and the AUC of test cohort was 0.657. The integrated model showed the most optimal predictive performance with EGFR mutation status (AUC = 0.870 and 0.759) and subtypes (AUC = 0.797 and 0.554) in the training and test cohorts. Conclusion: CT-based radiomic features can extract information on tumor heterogeneity in lung adenocarcinoma. In addition, we have established a radiomic model and an integrated model to non-invasively predict the EGFR mutation status and subtypes of lung adenocarcinoma, which is conducive to saving clinical costs and guiding targeted therapy.