Fully automated hybrid approach on conventional MRI for triaging clinically significant liver fibrosis: A multi-center cohort study.

Establishing reliable noninvasive tools to precisely diagnose clinically significant liver fibrosis (SF, ≥F2) remains an unmet need. We aimed to build a combined radiomics-clinic (CoRC) model for triaging SF and explore the additive value of the CoRC model to transient elastography-based liver stiffness measurement (FibroScan, TE-LSM). This retrospective study recruited 595 patients with biopsy-proven liver fibrosis at two centers between January 2015 and December 2021. At Center 1, the patients before December 2018 were randomly split into training (276) and internal test (118) sets, the remaining were time-independent as a temporal test set (96). Another data set (105) from Center 2 was collected for external testing. Radiomics scores were built with selected features from Deep learning-based (ResUNet) automated whole liver segmentations on MRI (T2FS and delayed enhanced-T1WI). The CoRC model incorporated radiomics scores and relevant clinical variables with logistic regression, comparing routine approaches. Diagnostic performance was evaluated by the area under the receiver operating characteristic curve (AUC). The additive value of the CoRC model to TE-LSM was investigated, considering necroinflammation. The CoRC model achieved AUCs of 0.79 (0.70, 0.86), 0.82 (0.73, 0.89), and 0.81 (0.72-0.91), outperformed FIB-4, APRI (all p < 0.05) in the internal, temporal, and external test sets and maintained the discriminatory power in G0-1 subgroups (AUCs range, 0.85-0.86; all p < 0.05). The AUCs of joint CoRC-LSM model were 0.86 (0.79-0.94), and 0.81 (0.72-0.90) in the internal and temporal sets (p = 0.01). The CoRC model was useful for triaging SF, and may add value to TE-LSM.

Visible-Light-Mediated Catalyst-Free [2+2] Cycloaddition Reaction for Dihydrocyclobuta[b]naphthalene-3,8-diones Synthesis under Mild Conditions.

A facile and efficient visible-light-mediated method for directly converting 1,4-naphthoquinones into dihydrocyclo-buta[b]naphthalene-3,8-diones (DHCBNDOs) under mild and clean conditions without using any photocatalysts is reported. This approach exhibited favorable compatibility with functional groups and afforded a series of DHCBNDOs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

Beyond collaterals: brain frailty additionally improves prediction of clinical outcome in acute ischemic stroke.

OBJECTIVES: We aimed to investigate the additional significance of cerebral small vessel disease (SVD) beyond collaterals in determining the clinical outcome after acute ischemic stroke (AIS). METHODS: We retrospectively reviewed large vessel-involved stroke patients who had baseline CTA within 24 h after symptom onset and had an MRI scan 5 days after admission from October 1, 2018, to October 31, 2021. Collaterals and SVD markers (including atrophy, leukoaraiosis, lacunes, and perivascular space) were graded on CT angiography and MR images, respectively. Modified Rankin Scale (mRS) score at 90 days was recorded, and mRS ≤ 2 was regarded as a good clinical outcome. The associations between SVD markers, collaterals, and mRS were analyzed using logistic and causal mediation regression. RESULTS: We finally enrolled 119 patients (70 ± 13 years). The multivariable regression showed atrophy (evidence: OR 0.05 [95% CI 0.01-0.31], p = 0.002; severe: OR 0.08 [95% CI 0.01-0.44], p = 0.007) and evidence of lacune (OR 0.30 [95% CI 0.08-0.96], p = 0.049) were associated with poor clinical outcomes after correcting covariables. Collaterals mediated 25.74% of the effect of atrophy on poor clinical outcomes (p < 0.001), while lacune impacted clinical outcomes without collaterals' mediation effect (p = 0.54). The classification model with atrophy and lacune had a significantly higher AUC than without markers to distinguish good and poor outcomes (p = 0.036). CONCLUSIONS: Beyond collaterals, brain frailty, specifically assessed by atrophy and lacune, was essential in evaluating stroke patients and could additionally improve the stroke outcome prediction. KEY POINTS: • Beyond collaterals, brain frailty, specifically assessed by brain atrophy and lacune, was still an independent risk factor of unfavorable clinical outcomes after AIS. • Adding brain atrophy and lacune into the model has an extra benefit in predicting stroke outcomes. • The effect of atrophy on stroke outcomes was proportionally mediated through collaterals, but about three-quarters of the effect of brain atrophy and the total effect of lacune directly impacted stroke outcomes without a mediation effect of collaterals.

Comparison of MRI and CT for the Prediction of Microvascular Invasion in Solitary Hepatocellular Carcinoma Based on a Non-Radiomics and Radiomics Method: Which Imaging Modality Is Better?

BACKGROUND: Computed tomography (CT) and magnetic resonance imaging (MRI) are both capable of predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). However, which modality is better is unknown. PURPOSE: To intraindividually compare CT and MRI for predicting MVI in solitary HCC and investigate the added value of radiomics analyses. STUDY TYPE: Retrospective. SUBJECTS: Included were 402 consecutive patients with HCC (training set:validation set = 300:102). FIELD STRENGTH/SEQUENCE: T2-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging MRI at 3.0T and contrast-enhanced CT. ASSESSMENT: CT- and MR-based radiomics signatures (RS) were constructed using the least absolute shrinkage and selection operator regression. CT- and MR-based radiologic (R) and radiologic-radiomics (RR) models were developed by univariate and multivariate logistic regression. The performance of the RS/models was compared between two modalities. To investigate the added value of RS, the performance of the R models was compared with the RR models in HCC of all sizes and 2-5 cm in size. STATISTICAL TESTS: Model performance was quantified by the area under the receiver operating characteristic curve (AUC) and compared using the Delong test. RESULTS: Histopathologic MVI was identified in 161 patients (training set:validation set = 130:31). MRI-based RS/models tended to have a marginally higher AUC than CT-based RS/models (AUCs of CT vs. MRI, P: RS, 0.801 vs. 0.804, 0.96; R model, 0.809 vs. 0.832, 0.09; RR model, 0.835 vs. 0.872, 0.54). The improvement of RR models over R models in all sizes was not significant (P = 0.21 at CT and 0.09 at MRI), whereas the improvement in 2-5 cm was significant at MRI (P < 0.05) but not at CT (P = 0.16). DATA CONCLUSION: CT and MRI had a comparable predictive performance for MVI in solitary HCC. The RS of MRI only had significant added value for predicting MVI in HCC of 2-5 cm. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Renal Functional MRI and Its Application.

Renal function varies according to the nature and stage of diseases. Renal functional magnetic resonance imaging (fMRI), a technique considered superior to the most common method used to estimate the glomerular filtration rate, allows for noninvasive, accurate measurements of renal structures and functions in both animals and humans. It has become increasingly prevalent in research and clinical applications. In recent years, renal fMRI has developed rapidly with progress in MRI hardware and emerging postprocessing algorithms. Function-related imaging markers can be acquired via renal fMRI, encompassing water molecular diffusion, perfusion, and oxygenation. This review focuses on the progression and challenges of the main renal fMRI methods, including dynamic contrast-enhanced MRI, blood oxygen level-dependent MRI, diffusion-weighted imaging, diffusion tensor imaging, arterial spin labeling, fat fraction imaging, and their recent clinical applications. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:863-881.

Fe-doped carbon dots: a novel fluorescent nanoprobe for cellular hypochlorous acid imaging.

Real-time monitoring of hypochlorous acid (HClO) in biological systems is of great significance for exploring and regulating its pathological functions because abnormal production of HClO is closely related with many diseases, such as atherosclerosis, rheumatoid arthritis, and cancer. Herein, we developed a reliable fluorescent Fe-doped carbon dots (Fe-CDs) for the sensitive and selective detection of biological HClO using ferrocenecarboxylic acid and m-phenylenediamine as precursors through a one-step solvothermal procedure. The Fe-CDs exhibited excellent a wide HClO detection range from 20 nmol/L to 1000 nmol/L with corresponding limits of detection at 7.8 nmol/L. The sensing mechanism is based on the chemical oxidation of the hydroxyl groups on the surface of Fe-CDs by HClO. In addition, Fe-CDs also displayed high photoluminescence yield, excitation-independence emission, as well as good biocompatibility, enabling the successful imaging of endogenous and exogenous HClO in HeLa cells. These results revealed that Fe-CDs holds great promise as a robust fluorescent probe for investigating HClO-mediated biological events.

Electrical stimulation induced pre-vascularization of engineered dental pulp tissue.

Vascularization is a key step to achieve pulp tissue regeneration and in vitro pre-vascularized dental pulp tissue could be applied as a graft substitute for dental pulp tissue repair. In this study, human dental pulp stem cells (DPSCs) and human umbilical vein endothelial cells (hUVECs) were co-cultured in 3D Matrigel and 150 mV/mm electric fields (EFs) were used to promote the construction of pre-vascularized dental pulp tissue. After optimizing co-cultured ratio of two cell types, immunofluorescence staining, and live/dead detection were used to investigate the effect of EFs on cell survival, differentiation and vessel formation in 3D engineered dental pulp tissue. RNA sequencing was used to investigate the potential molecular mechanisms by which EF regulates vessel formation in 3D engineered dental pulp tissue. Here we identified that EF-induced pre-vascularized engineered dental pulp tissue not only had odontoblasts, but also had a rich vascular network, and smooth muscle-like cells appeared around the blood vessels. The GO enrichment analysis showed that these genes were significantly enriched in regulation of angiogenesis, cell migration and motility. The most significant term of the KEGG pathway analysis were NOTCH signaling pathway and Calcium signaling pathway etc. The PPI network revealed that NOTCH1 and IL-6 were central hub genes. Our study indicated that EFs significantly promoted the maturation and stable of blood vessel in 3D engineered pulp tissue and provided an experimental basis for the application of EF in dental pulp angiogenesis and regeneration.

Tandem Vinylogous Aldol and Intramolecular [2 + 2] Cycloaddition toward Benzocyclobutenes by UV Light Photocatalysis.

A facile and efficient radical tandem vinylogous aldol and intramolecular [2 + 2] cycloaddition reaction for direct synthesis of cyclobutane-containing benzocyclobutenes (BCBs) under extremely mild conditions without using any photocatalysts is reported. This approach exhibited definite compatibility with functional groups and afforded new BCBs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost, and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

A multidimensional model incorporating radiomics score and liquid biopsy for the prediction of malignant and benign pulmonary nodules.

Background: As the lesions in pulmonary nodules (PNs) are small and the clinical manifestations lack specificity, the etiology of PNs is complex, predisposing them to misdiagnoses missed diagnoses. Thus, the diagnosis and treatment of PNs remains challenging and an important clinical problem. Methods: This study prospectively enrolled 156 patients with computed tomography (CT)-diagnosed PNs who underwent circulating genetically abnormal cell (CAC) testing between January 2020 and December 2021. We collected data on clinical features closely related to the nature of PNs, such as age, smoking history, and type of nodule. All internal regions of interest (ROIs) of PNs in this study were segmented. Radiomic feature extraction was performed on the ROIs, and a radiomics model was constructed using least absolute shrinkage and selection operator (LASSO) regression to obtain a radiomics score (Rad-score). A comprehensive model combining clinical features, Rad-score, and liquid biopsy was constructed using logistic regression analysis. The diagnostic performance of the model was evaluated using receiver operating characteristic (ROC) curves. Results: In this study, 5 radiomics features were screened for model construction. The area under the ROC curve (AUC) of the radiomics model was 0.844 [95% confidence interval (CI): 0.766-0.915] in the training set. The Rad-score, clinical features, and CAC were further combined to construct a multidimensional analysis model. The AUC of the synthesized model was 0.943 (95% CI: 0.881-0.978) in the training set. Conclusions: A multidimensional model is an effective tool for the noninvasive diagnosis of malignant PNs. The validation and combination of multiple diagnostic methods is a productive avenue of research trend for the identification of malignant PNs.

Prediction of unfavourable response to checkpoint blockade in lung cancer patients through an integrated tumour-immune expression score.

BACKGROUND: Treatment by immune checkpoint blockade (ICB) provides a remarkable survival benefit for multiple cancer types. However, disease aggravation occurs in a proportion of patients after the first couple of treatment cycles. METHODS: RNA sequencing data was retrospectively collected. 6 tumour-immune related features were extracted and combined to build a lung cancer-specific predictive model to distinguish responses as progression disease (PD) or non-PD. This model was trained by 3 public pan-cancer datasets and a lung cancer cohort from our institute, and generated a lung cancer-specific integrated gene expression score, which we call LITES. It was finally tested in another lung cancer dataset. RESULTS: LITES is a promising predictor for checkpoint blockade (area under the curve [AUC]=0.86), superior to traditional biomarkers. It is independent of PD-L1 expression and tumour mutation burden. The sensitivity and specificity of LITES was 85.7% and 70.6%, respectively. Progression free survival (PFS) was longer in high-score group than in low-score group (median PFS: 6.0 vs. 2.4 months, hazard ratio=0.45, P=0.01). The mean AUC of 6 features was 0.70 (range=0.61-0.75), lower than in LITES, indicating that the combination of features had synergistic effects. Among the genes identified in the features, patients with high expression of NRAS and PDPK1 tended to have a PD response (P=0.001 and 0.01, respectively). Our model also functioned well for patients with advanced melanoma and was specific for ICB therapy. CONCLUSIONS: LITES is a promising biomarker for predicting an impaired response in lung cancer patients and for clarifying the biological mechanism underlying ICB therapy.

Ru(II)-modified TiO2 nanoparticles for hypoxia-adaptive photo-immunotherapy of oral squamous cell carcinoma.

The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4+ and CD8+ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.

Intratumoral genetic and immune microenvironmental heterogeneity in T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers.

BACKGROUND: Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls. RESULTS: In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division-related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles. CONCLUSIONS: Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability.

Comprehensive Characterization of Immune Landscape Based on Epithelial-Mesenchymal Transition Signature in OSCC: Implication for Prognosis and Immunotherapy.

Current anatomic TNM stage classification fails to capture the immune heterogeneity of oral squamous cell carcinoma (OSCC). Increasing evidence indicates the strong association between epithelial-mesenchymal transition (EMT) and tumor immune response. In this study, we employed an EMT signature to classify OSCC patients into epithelial- (E-) and mesenchymal- (M-) phenotypes using TCGA and GSE41613 transcriptome data. The ESTIMATE and CIRBERSORT analyses implied that the EMT signature genes originated from the stroma of the bulk tissue. The M-subtype tumors were characterized as "immune-hot" with more immune cell infiltration than the E-subtype ones. The low infiltration of active immune cells, the high infiltration of inactive immune cells, and the high expressions of immune checkpoints demonstrated an immunosuppressive characteristic of the M-subtype tumors. Moreover, we developed and validated a novel prognostic classifier based on the EMT score, the expressions of seven immune checkpoints, and the TNM stages, which could improve the prediction efficiency of the current clinical parameter. Together, our findings provide a better understanding of the tumor immune heterogeneity and may aid guiding immunotherapy in OSCC.

MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors.

BACKGROUND: MET amplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method for MET amplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS in MET amplification remains uncertain. METHODS: Forty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment. MET amplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number (CN) > 5. MET amplification by NGS was defined as gene copy number (GCN) ≥ 5. RESULTS: The concordance rate among FISH and NGS was 62.5% (25/40). MET amplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 with MET amplification) vs. 6.7% (1/15 without MET amplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P < 0.001). MET amplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, with MET GCN ≥ 5) vs. 40.0% (12/30, with MET GCN < 5); the median PFS was 4.8 months vs. 2.2 months (P = 0.357). The PR rate was 68.8% (11/16) and the median PFS was 4.8 months in patients with focal amplification by NGS. CONCLUSIONS: MET amplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

Safety of EGFR-TKIs for EGFR mutation-positive non-small cell lung cancer.

Introduction: Lung cancer is the most prevalent malignant tumors worldwide. Over the past decade, the emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has ushered in a new era of lung cancer treatment. Therefore, clinical trials investigating the efficacy and safety of these drugs are important.Areas covered: This review provides an overview on the safety of three classes of EGFR-TKIs and discusses the adverse events (AEs) and reactions reported in the literature.Expert opinion: EGFR-TKIs significantly improve progression-free survival and overall survival in non-small cell lung cancer (NSCLC) patients with an activating mutation of EGFR. However, EGFR-TKIs also block the EGFR-regulating pathways in the skin and gastrointestinal tract and cause AEs, including diarrhea, liver toxicity, skin disease, stomatitis, interstitial lung disease, and ocular toxicity, which have detrimental effects on quality of life and drug compliance. Clinicians should understand how to prevent and control these adverse reactions, which can often be achieved by dose reduction, discontinuation of treatment, or switching to another drug.

A new Atrococcus species (Hemiptera, Coccomorpha, Pseudococcidae) from China, with a key to Chinese species.

A new mealybug species Atrococcus rushuiensis Zhang, sp. nov., collected under the leaf sheath of Sporobolus fertilis (Poaceae) in Fuzhou City, Jiangxi Province, China, is described and illustrated. A new combination is introduced, transferring Allotrionymus shanxiensis Wu to the genus Atrococcus as A. shanxiensis (Wu), comb. nov. A key is presented for the species of Atrococcus recorded from China.

Localized amyloidosis affecting the lacrimal sac managed by endoscopic surgery: A case report.

BACKGROUND: Here we present a rare case of localized amyloidosis involving the nasolacrimal duct and lacrimal sac which was managed by endoscopic surgery. CASE SUMMARY: A 50-year-old man whose medical history included bilateral ventricular fold and vocal cord amyloidosis complained of bilateral epiphora. Magnetic resonance imaging revealed a neoplasm within the nasolacrimal sac. Characteristic positivity for Congo red staining and birefringence under a polarized microscope proved the diagnosis of amyloidosis. Dacryocystorhinostomy via an endoscope obtained a favorable result. A one-year follow-up found no recurrence. CONCLUSION: There are few reports on amyloidosis involving the lacrimal outflow system, and management and outcome are not clear. Endoscopic dacryocystorhinostomy can be a choice to relieve symptoms. Regular follow-up and monitoring of systemic diseases are highly recommended.

Association between APOBEC3H-Mediated Demethylation and Immune Landscape in Head and Neck Squamous Carcinoma.

Immunotherapy has been demonstrated as a promising strategy in controlling head and neck squamous cell carcinoma (HNSC). The AID/APOBEC family is well characterized as DNA mutator and considered to play critical roles in immune responses in HNSC. However, the expression pattern and deamination-dependent demethylation roles of AID/APOBECs in HNSC are unclear. In this study, the RNA-seq and DNA methylation profiles of HNSC from TCGA database and cell-based experiments were applied to analyze the relationships between AID/APOBEC expression levels, patients' clinical outcomes, methylation alterations, and immune responses. Here, we found that APOBEC3H was abnormally upregulated in HNSC patients. HPV+ patients tended to have higher APOBEC3H levels than HPV- patients. Remarkably, patients with high APOBEC3H levels showed a favorable overall survival. Furthermore, tumors with high APOBEC3H levels exhibited a genome-wide DNA hypomethylation pattern. APOBEC3H was identified to demethylate and upregulate CXCL10 and improve CD8+ T cell tumor infiltration in the tumor microenvironment. Collectively, APOBEC3H plays critical roles in CD8+ T cell immune infiltration and activation in HNSC, which may be a potential biomarker for oncoimmunotherapy in HNSC.

Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients.

BACKGROUND: The KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, the KRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of the KRAS G12C mutation in Chinese NSCLC patients are rarely reported. METHODS: Next-generation sequencing was used to confirm the KRAS mutation status in 40,804 NSCLC patients from multiple centers (mCohort). Survival data were collected retrospectively from 1456 patients at one of the centers, the Guangdong Lung Cancer Institute (iCohort). RESULTS: In the mCohort, 3998 patients (9.8%) were confirmed to harbor a KRAS mutation, of whom 1179 (29.5%) had the G12C subtype. In the iCohort, 130 NSCLC patients (8.9%) had a KRAS mutation and 42 (32.3%) had the G12C subtype. The G12C subgroup included more male patients (85.2% vs 67.4%, P < 0.0001) and more smokers (76.2% vs 53.4%, P = 0.02) than did the non-G12C subgroup. Both the KRAS mutation group and KRAS G12C mutation subgroup were associated with a shorter median overall survival (OS) than wildtype tumors (15.1 vs 26.7 months, hazard ratio [HR] KRAS = 1.50, P = 0.002; 18.3 vs 26.7 months, HR G12C = 1.66, P = 0.007). In Cox regression analysis, smoking (HR = 1.39, P = 0.05) and stage IV disease (HR = 2.72, P < 0.001) remained as independent predictors of shorter OS. Both the KRAS mutation (HR = 1.30, P = 0.07) and KRAS G12C mutation (HR = 1.47, P = 0.07) reached borderline significance. CONCLUSIONS: In the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients had KRAS mutations. Of these, nearly 30% harbored the KRAS G12C mutation subtype, which was most common in male smokers. The KRAS G12C mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by G12C-specific inhibitors in the future.(296 words).

Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma.

BACKGROUND: Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. METHODS: An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. FINDINGS: The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. INTERPRETATION: Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. FUNDING: The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).