Molecular subtyping of small-cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies.

Small-cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non-small-cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole-exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker-directed drug development and targeted therapies in clinical trials. Our study would provide an in-depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype-specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.

Non-small-cell lung cancer patients harboring TP53/KRAS co-mutation could benefit from a PD-L1 inhibitor.

Aim: To explore the association between TP53 mutation and atezolizumab in non-small-cell lung cancer (NSCLC) patients. Materials & methods: Patients with NSCLC from the POPLAR and OAK studies were included. Kaplan-Meier analysis was performed to detect progression-free survival (PFS) and overall survival (OS). PFS and OS were compared using multivariate Cox regression analysis. Results: OS was significantly longer with atezolizumab compared with docetaxel among TP53/KRAS co-mutant NSCLC patients (hazard ratio [HR]: 0.014; 95% CI: 0.000-0.721). There is no significant OS difference between atezolizumab versus docetaxel for TP53-mutant NSCLC patients (HR: 0.831; 95% CI: 0.473-1.458). There is no significant OS difference between atezolizumab versus docetaxel for KRAS-mutant NSCLC patients (HR: 1.354; 95% CI: 0.528-3.472). Conclusion: PD-L1 inhibitors may bring OS benefits for patients with NSCLC harbored TP53/KRAS co-mutation.

Mutations in TP53 have been reported to be the most frequent oncogenic mutations in non-small-cell lung cancer (NSCLC), but there are no favorable targeted therapies. The association between TP53 mutation and atezolizumab in NSCLC patients was explored in this study. Patients with NSCLC from the POPLAR and OAK studies were included. Longer overall survival (OS) was found in TP53-wildtype NSCLC patients treated with atezolizumab compared with those treated with docetaxel. OS benefit of atezolizumab over docetaxel was detected for NSCLC patients only with co-occurrence of TP53 and KRAS mutations. For patients with NSCLC harboring TP53 mutation detected by fluid biopsy, this study provides insights and perspectives into anti-PD-L1 treatment.

Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress.

Long-term poorly controlled myocardial hypertrophy often leads to heart failure and sudden death. Activation of ras-related C3 botulinum toxin substrate 1 (RAC1) by angiotensin II (Ang II) plays a pivotal role in myocardial hypertrophy. Previous studies have demonstrated that scoparone (SCO) has beneficial effects on hypertension and extracellular matrix remodelling. However, the function of SCO on Ang II-mediated myocardial hypertrophy remains unknown. In our study, a mouse model of myocardial hypertrophy was established by Ang II infusion (2 mg/kg/day) for 4 weeks, and SCO (60 mg/kg bodyweight) was administered by gavage daily. In vitro experiments were also performed. Our results showed that SCO could alleviate Ang II infusion-induced cardiac hypertrophy and fibrosis in mice. In vitro, SCO treatment blocks Ang II-induced cardiomyocyte hypertrophy, cardiac fibroblast collagen synthesis and differentiation to myofibroblasts. Meanwhile, we found that SCO treatment blocked Ang II-induced oxidative stress in cardiomyocytes and cardiac fibroblasts by inhibiting RAC1-GTP and total RAC1 in vivo and in vitro. Furthermore, reactive oxygen species (ROS) burst by overexpression of RAC1 completely abolished SCO-mediated protection in cardiomyocytes and cardiac fibroblasts in vitro. In conclusion, SCO, an antioxidant, may attenuate Ang II-induced myocardial hypertrophy by suppressing of RAC1 mediated oxidative stress.

Comprehensive analysis of multiple parameters associated with tumor immune microenvironment in ARID1A mutant cancers.

Aim: To verify the relationship between ARID1A and tumor immune microenvironment thus immune checkpoint inhibitors (ICIs) response. Material & methods: Several public databases were used to characterize the association between ARID1A gene alteration and tumor immunity. Results: The gene mutation frequency was 8.2% in all cancer types. The ARID1A-mutated cancers have higher scores of mutation count, tumor mutational burden, neoantigen load (p < 0.001) and T cell repertoire, B cell repertoire diversity (p < 0.05). The gene mutation has tight association with multiple-activated immune cells. Survival analysis suggested that patients with ARID1A mutant cancers benefit more from ICIs treatment (p = 0.013). Conclusion: The ARID1A gene mutation was correlated with higher tumor immunogenicity and activated antitumor immune microenvironment, resulting in superior cohort that respond well to ICIs.

A hypothesized TNM staging system based on the number and location of positive lymph nodes may better reflect the prognosis for patients with NSCLC.

BACKGROUND: This study aimed to evaluate the feasibility and prognostic accuracy of incorporating the number of positive lymph nodes (PLN) into the TNM staging system for non-small cell lung cancer (NSCLC) patients. METHODS: We screened a total of 9539 patients with resected stage IA-IIIB non-small cell cancer between 2010 and 2015 from SEER database. The chi-square test was used to compare patient baseline characteristics and the X-tile model was applied to determine cut-off values for the number of PLN (nN). The X-tile model was used to screen three different cut-off values including nN = 0, nN1-3 and nN4-. Univariate and multivariate Cox proportional hazards regression models were used to analyze the influence of different variables on overall survival (OS). Kaplan-Meier and log-rank test were used to compare survival differences. RESULTS: Based on the nN cutoffs, we conducted the univariate and multivariate Cox proportional hazards regression. The result showed that nN stage was a significant prognostic factor affecting patients' OS (all P <  0.001). We reclassified the seventh edition TNM stages of the enrolled patients with stage IA-IIIB NSCLC according to the 5-year OS rate. Hypothesized TNM substage based on the location and the number of PLN was further calculated. Then we drew survival curves for each substage, including for the current TNM stage and the hypothesized TNM stage. From the comparison of survival curves, we found that the survival curve of each substage of the hypothesized TNM classification was proportional and well distributed compared with the current TNM classification (P <  0.001). CONCLUSION: Revised TNM staging integrating locational pN stage and numerical nN stage was a more accurate prognostic determinant in patients with NSCLC.

Poor survival of non-small-cell lung cancer patients with main bronchus tumor: a large population-based study.

Aim: In this study, we evaluated the association between tumor location and prognosis in non-small-cell lung cancer patients. Patients & methods: The SEER database was used to screen for suitable patients using our inclusion criteria. The χ2 test was used to compare baseline patient characteristics and the Kaplan-Meier method as well as the log-rank test were used to compare survival differences. At last, univariate and multivariate Cox proportional hazards regression models were used to analyze the influence of different variables on overall survival. Results: The results found no significant difference in overall survival between patients in laterality (p = 0.071). However, patients with main bronchial tumors had worse prognosis than tumors at other locations (p < 0.001). Our results also showed that tumor location including main bronchus, upper lobe, middle lobe, lower lobe and overlapping lesion was a significant factor affecting survival (p < 0.001). Subgroup analysis revealed that regardless of histology or M stage, patients with main bronchial tumors had a worse survival compared with other tumor locations (all; p < 0.001). Interestingly, we found that patients with tumor main bronchial tumors were more likely to be squamous carcinoma and terminal Tumor, Node, Metastasis stage (all; p < 0.001). Conclusion: Non-small-cell lung cancer patients' prognosis was related to the tumor location. And patients with tumors located in main bronchus had worse outcomes than those located in other locations. Tumor primary site should be considered in treatment management and prognosis assessment.

Circular RNA Hsa_Circ_0091579 Serves as a Diagnostic and Prognostic Marker for Hepatocellular Carcinoma.

BACKGROUND/AIMS: An increasing number of studies have suggested that circular RNAs (circRNAs) have vital roles in carcinogenesis and tumor progression. However, the function of circRNAs in hepatocellular carcinoma (HCC) remains poorly characterized. METHODS: We investigated the levels of circRNAs in patients with HCC to identify potential diagnostic biomarkers. We examined circRNA expression profiles in liver tumors and paired non-cancerous liver tissues from three HCC patients with cancer thrombus using a circRNA microarray. Bioinformatics analysis was performed to find circRNAs with significantly altered expression levels between tumors and their paired non-tumor tissues. We confirmed our initial findings by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curves were also applied to identify a candidate circRNA with the optimal specificity and sensitivity. Finally, X-tile software was adopted to calculate the most efficient cut-off value for hsa_circ_0091579 expression. RESULTS: Microarray analysis identified 20 unique circRNAs that were differentially expressed between tumor and non-tumor tissues (P < 0.05). The expression of these 20 circRNAs was verified by qRT-PCR. The expression of hsa_circ_16245-1 and hsa_circ_0091579 mRNA was consistent with their levels as tested by the microarray. The ROC curves showed that both hsa_circ_16245-1 and hsa_circ_0091579 had favorable specificity and sensitivity. We further confirmed that hsa_circ_0091579 was significantly upregulated in HCC and its high expression was intimately associated with a worse overall survival in patients with HCC. CONCLUSION: Hsa_circ_0091579 may play a critical role in HCC progression and serve as a potential biomarker for the prognosis of patients with HCC.

The prognostic analysis of different metastatic patterns in extensive-stage small-cell lung cancer patients: a large population-based study.

AIM: To analyze the metastasis patterns and prognosis differences for extensive-stage small-cell lung cancer patients. METHODS: Log-rank tests were used to calculate and compare survival estimates. Cox regression analyses were used to evaluate the prognosis factors. RESULTS: The liver was the most common metastatic site, and lung was the least common. In two metastatic sites, liver and bone metastases were the most common combination of sites. An isolated liver metastasis had the worst overall survival (OS) and cancer-specific survival (CSS) among metastatic sites (both p < 0.001). Liver and lung metastases were associated with worse CSS (p < 0.039) and OS (p < 0.015). However, for patients with three metastatic sites showed no statistical differences in their CSS and OS (all, p > 0.05). CONCLUSION: Extensive-stage small-cell lung cancer patients with metastasis to the liver alone or in combination with other organs appear to have worse outcomes.

Male patients with resected IIIA-N2 non-small-cell lung cancer may benefit from postoperative radiotherapy: a population-based survival analysis.

AIM: Our analysis was performed to assess the efficacy of postoperative radiotherapy (PORT) on the survival for pathologic IIIA-N2 Non-small-cell lung cancer patients. PATIENTS & METHODS: We identified 2949 patients from 2004 to 2013 in the SEER database. Propensity score-matching was used to reduce the selection bias. Overall survival (OS), cancer-specific survival (CSS) and the factors associated with survival prognosis were evaluated. RESULTS: There was no significant difference in OS and CSS between PORT and non-PORT groups. However, subgroup analysis revealed an OS (p = 0.007) and CSS (p = 0.006) detrimental for male patients not receiving PORT. Multivariate analysis showed that old age, male sex, high pathologic grade, squamous carcinoma, bigger tumor size and larger number of positive lymph nodes had a negative impact on survival. CONCLUSION: PORT could improve OS and CSS in male patients with resected IIIA-N2 non-small-cell lung cancer.

Postmastectomy radiation therapy for breast cancer patients with one to three positive lymph nodes: a propensity score matching analysis.

AIM: Conducting postmastectomy radiation therapy (PMRT) for breast cancer patients with one to three positive lymph nodes is still controversial. METHODS: Propensity score matching analysis was applied to balance the clinical baseline characteristics of patients. Cox proportional hazard analysis was used to analyze the survival prognosis factors and perform subgroup analysis. RESULTS: There was no statistical difference in overall survival and cancer-specific survival rates (all, p > 0.05) between the PMRT and non-PMRT groups. However, for subgroup patients with tumor size ≥5 cm and the number of positive lymph nodes = 3, PMRT showed a significant survival benefit. CONCLUSION: PMRT can improve overall survival and cancer-specific survival only in breast cancer patients whose tumor size is larger than 5 cm and with three positive lymph nodes.

[Qangxin Granule Intervened Chronic Heart Failure Rats with Xin-qi Deficiency Complicated Blood Stasis and Edema Syndrome: an Experimental Study].

OBJECTIVE: To study and evaluate the curative effect and mechanism of Qiangxin Granule (QXG) in intervening chronic heart failure (CHF) rats with Xin-qi deficiency complicated blood stasis and edema syndrome (XQD-BS-ES). METHODS: Totally 72 SD rats of clean grade were randomly divided to the normal control group (n =10) and the model group (n = 62). The XQD-BS-ES rat model was established by adriamycin plus propylthiouracil method. Survived modeled rats were then randomly divided to 5 groups i.e., the model group (n = 11, administered with normal saline by gastrogavage), the Western medicine (WM) group (n =11 , administered with perindopril and hydrochlorothiazide by gastrogavage), the low dose QXG (QXG(L)) group (n = 11, administered with 9.26 g/kg QXG by gastrogavage), the middle dose QXG (QXG(M)) group (n = 11, administered with 18.52 g/kg QXG by gastrogavage), the high dose QXG (QXG(H)) group (n = 11, administered with 37.04 g/kg QXG by gastrogavage). After 4 weeks of treatment, left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), brain natriuretic peptide (BNP), heart rate (HR), respiratory rate (RR), urine output, ear temperature, exhaustive swimming test (EST), tri-iodothyronine (T3), tetra-iodothyronine (T4), thyroid stimulating hormone (TSH), as well as heart, lung, liver weight index and their pathological sections, and high sensitivity C-reactive protein (HS-CRP), angiotensin II (Ang II), carbohydrate antigen 125 (CA125) were detected and compared. RESULTS: Compared with the normal control group, LVEF, LVFS, BNP, HR, RR, urine output, ear temperature, EST, T3, T4, TSH, HS-CRP, Ang II, and CA125 changed significantly in the model group (P < 0.01). Compared with the model group after treatment, LVEF, LVFS, BNP, urine output, EST, T4, heart and liver weight index, HS-CRP, Ang II, CA125 were significantly improved in each QXG group (P < 0.05, P < 0.01). Moreover, TSH was improved in the QXGL and QXG(M) groups (P < 0.05); ear temperature and T3 in the QXG(M) were also improved (P < 0.05); the lung weight index decreased in the QXG(M) and QXG(H) groups (P < 0.01). Compared with the WM group, T4 and CA125 were obviously improved in all QXG groups (P < 0.01); BNP and ear temperature were obviously improved in QXG(L) and QXG(M) groups (P < 0.05, P < 0.01); LVEF, LVFS and TSH were obviously improved in the QXG(M) group (P < 0.05, P < 0.01). And as far as each treatment group, LVEF, LVFS, urine output increased significantly after treatment (P < 0.01); EST obviously increased in QXG(M) and QXG(H) groups (P < 0.01); ear temperature increased in all QXG groups (P < 0.05, P < 0.01). Moreover, compared with the model group, pathological changes of heart, lung, and liver were improved to some degree in each treatment group, especially in the QXG(M) group. CONCLUSIONS: Good curative effect was shown in each QXG group. QXG could improve LVEF, LVFS and BNP of CHF rats of XQD-BS-ES, as well as T3, T4, TSH, EST, urine output, and ear temperature. Moreover, QXG showed superiority than WM group in this respect.

[Establishment of chronic heart failure rat model of Xin-qi deficiency complicated blood stasis and edema syndrome and judgment of diagnosis information integration].

OBJECTIVE: To establish and evaluate chronic heart failure (CHF) rat model of Xin-qi deficiency complicated blood stasis and edema syndrome (XQD-BSES). METHODS: Totally 40 SD rats were randomly divided into the normal control group (Control), the propylthiouracil (PTU) group, the adriamycin (ADR), and the ADR + PTU group. Normal saline was used as equivalent solvent of each group. Rats in the Control group were intragastrically and intraperitoneally injected with normal saline. Rats in the PTU group were intragastrically injected with PTU suspension and intraperitoneally injected with normal saline. Rats in the ADR group were intragastrically injected with ADR solution and intraperitoneally injected with normal saline. And rats in the ADR + PTU group were intragastrically injected with PTU suspension and intraperitoneally injected with ADR solution. The dose of PTU was 0.2% of daily forage weight, once daily. The dose of ADR was 3.5 mg/kg, once per week. The modeling lasted for 6 weeks. Left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), brain natriuretic peptide (BNP), heart rate (HR), respiratory rate (RR), urine output, ear temperature, exhaustive swimming test (EST), Tri-iodothyronine (T3), tetra-iodothyronine(T4), thyroid stimulating hormone (TSH) as well as heart, lung, liver weight indices and their pathological sections were integrated and compared. RESULTS: Compared with the Control group, LVEF, LVFS, BNP, HR, RR, heart, lung, liver weight indices, urine output, ear temperature, EST, and T3, T4, and TSH changed significantly in the ADR group, the PTU group, and the ADR + PTU group with statistical significance (P < 0.05), and pathological changes of heart failure occurred in pathological sections of heart, lung, and liver. Compared with the ADR group, LVEF, LVFS, BNP, and lung, liver weight indices, urine output, ear temperature, T3, T4, and TSH changed significantly in the ADR + PTU group with statistical significance (P < 0.05), and pathological changes of heart failure were more serious in pathological sections of heart, lung, and liver. Compared with the PTU group, LVEF, LVFS, BNP, HR, RR, urine output, EST, T4, heart and lung weight indices changed significantly in the ADR + PTU group with statistical significance (P < 0.05), and pathological changes of heart failure were quite serious in pathological sections of heart, lung, and liver. CONCLUSION: ADR + PTU was an appropriate method to establish CHF rat model of XQD-BSES.

Osimertinib inhibits brain metastases and improves long-term survival in a patient with advanced squamous cell lung cancer: a case report and literatures review.

Background: Squamous cell carcinoma (SCC) is one of the most common subtypes of non-small cell lung cancer, but its treatment options remain limited. Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have limited efficacy in the treatment of lung SCC. Here, we report an SCC patient who developed EGFR-T790M mutation and showed gefitinib resistance achieved an extremely long survival by taking Osimertinib alternatively. Case summary: A patient, 66-year-old non-smoking and drinking male with advanced SCC who was deemed inoperable at the time of diagnosis. The first genetic testing showed deletion mutation of exon 19 of EGFR. The patient was then treated with gefitinib with no significant efficacy. EGFR-T790M mutation was found in the second genetic test. The treatment regimen was changed to radiotherapy with Osimertinib, and the patient's primary lesion and the brain metastases were well controlled. Conclusion: This typical case highlights the important role of Osimertinib in patients with SCC carrying EGFR mutations.

[Study on the metabolin difference of hypertension patients of gan-yang hyperactivity syndrome and yin-yang deficiency syndrome].

OBJECTIVE: To observe the metabolin difference between hypertension patients of Gan-yang hyperactivity syndrome (GYHS) and those of yin-yang deficiency syndrome (YYDS). METHODS: Totally 26 hypertension patients at the Base for Chinese Medicine Clinical Research of Hypertension from June 2009 to May 2010 were assigned to two groups, the GYHS group (12 cases) and the YYDS group (14 cases). Besides, 14 healthy volunteers from the affiliated community were recruited as the control group. Their blood plasmas and principle component analysis (PCA) were analyzed by high performance liquid chromatography-time of flight mass spectrometry (HPLC-TOFMS) technology. The correlated metabolin and their metabolic pathways were identified using Metlin Database. RESULTS: The PCA chart showed that the dispersion was larger in the control group than in the other two groups. The data of the GYHS group and the YYDS group showed gathering tendency. Further PCA results showed good spatial separation between the two groups, with significant difference between them. Totally 6 metabolins were detected. Of them, estrodiol, leucotriene, ceramide, and glucose-ceramide increased more in the GYHS group, while triglyceride and diacylglycerol increased more significantly in the YYDS group. CONCLUSIONS: HPLC-TOFMS is capable of primarily identifying and clarifying different metabolic modes of the GYHS and the YYDS. Different contents of estrodiol, leucotriene, ceramide, glucose-ceramide, triglyceride, and diacylglycerol might probably become the differential points for identifying the two syndrome types.

Clinical significance of tumoral PD-L1 expression in Wilms tumors.

BACKGROUND: Although cure rate for Wilms tumor (WT) is high recent years, there is still small fraction of patients suffering from tumor relapse or metastases. It is urgent to identify more valuable biomarkers associated with disease progression. Previous studies have shown that PD-L1 was abnormally expressed in various type of cancers and acted as predictor for poor prognosis for those cancers. PD-1/PD-L1 inhibitors have achieved great success in various malignancies with correlation between PD-L1 expression and responses. We conducted this retrospective study to better understand the role of PD-L1 in WT development. OBJECTIVE: The aim of this study was to evaluate the expression rate of tumoral PD-L1 in WT and investigate the association of PD-L1 with tumor invasion and metastasis. STUDY DESIGN: Seventy-seven patients with WT, including 20 cases of primary WTs with corresponding resected invasive/lymph node metastatic tumors were enrolled in the research. Immunohistochemistry was used to examine tumoral PD-L1 expression. Kaplan-Meier analysis with regard to the relationship between the expression of tumoral PD-L1 and follow-up information was performed. RESULTS: Positive expression rate of tumoral PD-L1 was 28.6% in primary WT tissues, while 35% in associated invasive/metastatic ones. The tumoral PD-L1 expression in primary WTs were correlated with late stage and unfavorable histology (P = 0.007; P = 0.002). The expression rate of tumoral PD-L1 was higher in the progression group than that without distant metastasis or relapse (P = 0.038). The expression rate of PD-L1 between primary WTs and matched invasive/metastatic tissues was concordant (P = 0.435). Tumoral PD-L1 expression was associated with disease-free survival (DFS) and overall survival (OS) (P = 0.02; P = 0.03). Tumor PD-L1 expression was associated with DFS and OS in univariable analyses but not in multivariable Cox regression, adjusting for histology and tumor stage. DISCUSSION: We found that PD-L1 expression was associated with the late-stage of WT and unfavorable histology, which were tightly associated with disease relapse and progression, predicting poor prognosis. The subsequent survival analysis also showed that PD-L1 expression was linked to both shorter DFS and OS. After adjustment for WT stage and histology, PD-L1 expression was no longer an independent predictor of DFS/OS. The value of PD-L1 as predictor for prognosis and potential therapeutic target in WT still need to be validated in large cohort in future. CONCLUSION: Although PD-L1 expression correlated with established prognostic factors in our dataset, its value as a prognostic marker and therapeutic target, if any, remains to be shown in future.

Genomic Variations and Immune-Related Features of TMB, PD-L1 Expression and CD8+ T Cell Infiltration in Chinese Pulmonary Sarcomatoid Carcinoma.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare and distinct subtype of lung cancer characterized by its aggressiveness and dismal prognosis. However, genomic landscape and immune contexture have not been fully elucidated among PSC patients. Methods: In the present study, whole-exome-sequencing (WES) analyses were performed to depict genomic landscape of 38 independent PSC samples. Tumor mutation burden (TMB) was calculated with the total number of non-synonymous SNVs and indel variants per megabase of coding regions. PD-L1 expression and CD8+ T cell density were evaluated by immunohistochemistry in PSC samples. Their associations with genomic mutation were further assessed in genes with most frequent mutation. Overall survival (OS) of PSC patients with top mutated genes and high and low TMB, PD-L1 and CD8+ TIL expressions were further compared. Subgroup analyses of OS stratified by morphology and pathological type were conducted. Their correlation with TMB, PD-L1 and CD8+ T cell were further assessed. Results: We identified a cohort of genomic and somatic mutation in PSC patients. Subgroup patients with distinct clinicopathological features were found to harbor different genomic mutations and immunologic features. Besides, genomic profiles influenced outcomes, with SARS mutation associated with worsened prognosis. Conclusion: Through the mapping of genetic and immunologic landscape, we find the heterogeneity among the subgroups of PSC. Our findings may provide opportunities for therapeutic susceptibility among Chinese PSC patients.

Whole exome sequencing in Chinese mucinous pulmonary adenocarcinoma uncovers specific genetic variations different from lung adenocarcinoma.

Background: As a rare subtype of primary lung adenocarcinoma (LUAD), mucinous pulmonary adenocarcinoma (MPA) was considered a distinctive entity with unfavorable outcomes. Therefore, there is a great need for a better understanding of the genomic and immunological landscape of this rare tumor type, which would inform improved therapeutic strategies. Methods: A total of 96 patients histologically confirmed with MPA were recruited from Shandong Cancer Hospital and Institute (SCH). Single nucleotide variation (SNV), copy number variation (CNV), genomic instability, and immunological landscape insights into 96 MPA patients were identified using WES. Results: We demonstrated that MPAs had marked different genomic alterations and were more complex in genomic profiles than LUADs. Mutations in Tumor Protein 53 (TP53) and CYP7A Promoter-Binding Factor (CPF) pathways significantly shortened survival whereas mutations in Notch and Wnt pathways significantly prolonged survival in MPA. Besides, we demonstrated that mutations in immune-related genes influenced outcomes, with mutations in TP53, Ataxia Telangiectasia Mutated (ATM), Polymerase (DNA) Delta 1 (POLD1), and Epidermal Growth Factor Receptor (EGFR) correlated with worsened survival. Conclusions: We not only depicted the genetic and immunologic landscape of Chinese MPA but also reveal its distinction from LUAD in genomic and immune context. Our findings may provide opportunities for therapeutic susceptibility among Chinese MPA patients.

Clinicopathological Difference and Survival Impact of Patients with c-SCLC and SCLC.

BACKGROUND: Combined small cell lung cancer (c-SCLC) distinguishes itself from small cell lung cancer (SCLC) due to its inclusion of both SCLC and non-small cell lung cancer (NSCLC) components. Few studies have compared clinicopathological characteristics, prognosis and factors affecting survival. We therefore addressed the issues in this study. PATIENTS AND METHODS: A total of 400 c-SCLC and 20,841 SCLC patients were enrolled using SEER database. Difference in clinicopathological characteristics of SCLC and c-SCLC patients was analyzed using chi-square. Kaplan-Meier was applied to compare their survival before and after propensity score matching (PSM). Cox regression model was adopted to assess the impact of different clinical variables on survival. Logistic regression was applied to identify risk factors for c-SCLC and SCLC patients. RESULTS: Differences in race, sex, T stage, N stage, surgery, bone, brain and liver metastasis were detected between c-SCLC and SCLC patients. c-SCLC patients had better overall survival (OS) than SCLC patients before PSM. Age, race, sex, T stage, N stage, surgery, bone, brain, liver and lung metastasis were prognostic factors affecting OS for c-SCLC and SCLC (P < 0.05). However, a significant OS benefit was not observed in c-SCLC after adjusting for clinicopathological variables (HR, 0.950; 95% CI, 0.842-1.073; P=0.411). No significant OS difference was found between c-SCLC and SCLC patients after PSM (P = 0.789). c-SCLC patients had lower risk of lymph node (OR: 0.555; 95% CI: 0.439-0.703; P < 0.001) and liver metastasis (OR: 0.591; 95% CI: 0.448-0.779; P < 0.001), whereas had no significant differences in bone and brain metastasis risks (P > 0.05) compared with SCLC patients. CONCLUSION: The prognosis of c-SCLC did not significantly differ from that of SCLC if clinicopathological characteristics are controlled. Better prognosis for c-SCLC patients over SCLC patients may be ascribed to fewer liver and lymph node metastases upon diagnosis.

A 5-Genomic Mutation Signature Can Predict the Survival for Patients With NSCLC Receiving Atezolizumab.

Background: At present, there is a lack of studies focusing on the survival prediction of patients with non-small cell lung cancer (NSCLC) receiving atezolizumab in light of gene mutation characteristic. Methods: Patients with NSCLC receiving atezolizumab from the OAK study were defined as the training group. LASSO Cox regressions were applied to establish the gene mutation signature model to predict the overall survival (OS) rate of the training group. NSCLC patients receiving atezolizumab from the POPLAR study were defined as the testing group to validate the gene mutation signature model. In addition, we compared the OS rate between patients receiving atezolizumab and docetaxel classified according to their risk score based on our gene mutation signature model. Results: We successfully established a 5-genomic mutation signature that included CREBBP, KEAP1, RAF1, STK11 and TP53 mutations. We found it was superior to the blood tumor mutation burden (bTMB) score and programmed death ligand 1 (PDL1) expression in the prediction of the OS rate for patients receiving atezolizumab. High-risk patients receiving atezolizumab had a worse OS rate compared with low-risk patients in the training (P = 0.0004) and testing (P = 0.0001) groups. In addition, low-risk patients using atezolizumab had a better OS rate compared with those in use of docetaxel for the training (P <0.0001) and testing groups (P = 0.0095). High-risk patients of the training group (P = 0.0265) using atezolizumab had a better OS rate compared with those using docetaxel. However, the OS difference between atezolizumab and docetaxel was not found in high-risk patients from the testing group (P = 0.6403). Multivariate Cox regression analysis showed that the risk model in light of 5-genomic mutation signature was an independent prognostic factor on OS for patients receiving atezolizumab (P <0.0001). In addition, significant OS benefit could only be found in low-risk patients receiving atezolizumab compared with docetaxel (P <0.0001). Conclusions: The 5-genomic mutation signature could predict OS benefit for patients with NSCLC receiving atezolizumab. Therefore, the establishment of the 5-genomic mutation panel will guide clinicians to identify optimal patients who could benefit from atezolizumab treatment.

Survival analysis for non-squamous NSCLC patients harbored STK11 or KEAP1 mutation receiving atezolizumab.

OBJECTIVE: To analyze the prognostic effect for patients with non-squamous non-small cell lung cancer (NSCLC) harbored STK11 or KEAP1 (STK11/KEAP1) mutations receiving atezolizumab and docetaxel. METHODS: Data from OAK and POPLAR clinical trials was firstly applied to analyze genomic alteration frequency and the correlation between STK11/KEAP1 mutations and blood-based tumor mutational burden (bTMB)/PD-L1 expression. Univariate and multivariate Cox regression hazard models were preformed to analyze the influence of prognostic factors on survival. Survival difference was compared by Kaplan-Meier and log-rank test. RESULTS: Most STK11/KEAP1 mutations (7.33 %/10.76 %) were found in non-squamous NSCLC compared with squamous lung cancer. Interestingly, only 1.56 % STK11 mutation or 3.13 % KEAP1 mutation occurred in EGFR mutant non-squamous NSCLC. Compared with wild type, patients with STK11/KEAP1 mutations had higher bTMB (both, P < 0.001). Moreover, compared with wild type, patients harbored KEAP1 mutation had higher PD-L1 expression (TC3/IC3: 25.00 % vs. 14.54 %), while patients harbored STK11 mutation had lower PD-L1 expression (TC3/IC3: 7.89 % vs. 15.90 %). Univariate and multivariate analyses revealed that STK11/KEAP1 mutations were independent and significant prognostic factors on overall survival (OS) (both, P < 0.05) and progression-free survival (PFS) (both, P < 0.05). Importantly, patients harbored STK11/KEAP1 mutations had a relatively worse OS than wild type both in those receiving atezolizumab and docetaxel (all, P < 0.05). In addition, for STK11 mutant subset, atezolizumab did not improve OS compared with docetaxel (HR = 0.669; 95 %CI: 0.380-1.179; P = 0.669); while cox-regression analysis showed the improved survival of patients with KEAP1 mutation who receiving atezolizumab compared with docetaxel (HR = 0.610; 95 %CI: 0.384-0.969; P = 0.036). CONCLUSION: Compared with wild type, non-squamous NSCLC patients with STK11/KEAP1 mutations may not benefit more from both atezolizumab and docetaxel. However, patients with mere KEAP1 mutations and without STK11 mutations may have a better response to atezolizumab than docetaxel.