Easily applicable predictive score for MPR based on parameters before neoadjuvant chemoimmunotherapy in operable NSCLC: a single-center, ambispective, observational study.

BACKGROUND: Neoadjuvant chemoimmunotherapy (NACI) is promising for resectable nonsmall cell lung cancer (NSCLC), but predictive biomarkers are still lacking. The authors aimed to develop a model based on pretreatment parameters to predict major pathological response (MPR) for such an approach. METHODS: The authors enrolled operable NSCLC treated with NACI between March 2020 and May 2023 and then collected baseline clinical-pathology data and routine laboratory examinations before treatment. The efficacy and safety data of this cohort was reported and variables were screened by Logistic and Lasso regression and nomogram was developed. In addition, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to assess its power. Finally, internal cross-validation and external validation was performed to assess the power of the model. RESULTS: In total, 206 eligible patients were recruited in this study and 53.4% (110/206) patients achieved MPR. Using multivariate analysis, the predictive model was constructed by seven variables, prothrombin time (PT), neutrophil percentage (NEUT%), large platelet ratio (P-LCR), eosinophil percentage (EOS%), smoking, pathological type, and programmed death ligand-1 (PD-L1) expression finally. The model had good discrimination, with area under the receiver operating characteristic curve (AUC) of 0.775, 0.746, and 0.835 for all datasets, cross-validation, and external validation, respectively. The calibration curves showed good consistency, and decision curve analysis indicated its potential value in clinical practice. CONCLUSION: This real world study revealed favorable efficacy in operable NSCLC treated with NACI. The proposed model based on multiple clinically accessible parameters could effectively predict MPR probability and could be a powerful tool in personalized medication.

Plasma hepatocyte growth factor as a noninvasive biomarker in small cell lung cancer.

BACKGROUND: Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine, which is overexpressed and/or activated in multiple malignancies and is reported to be associated with tumor development and inferior survival. At present, the role of HGF in small cell lung cancer (SCLC) has not been fully explored yet. MATERIALS AND METHODS: The expression of HGF and its value in predicting survival in SCLC were explored from GEO database and in pan-cancer analysis. Furthermore, we detected the expression of HGF using tumor tissue and paired plasma samples from a validation cohort of 71 SCLC patients at our institute. Correlation between tumor and plasma HGF expression and the prognostic values were analyzed. RESULTS: GEO database analysis revealed that tumor tissue had lower HGF expression than paired normal tissue in SCLC. At our institute, immunohistochemical staining showed negative expression of HGF in tumor tissue of SCLC at our institute (47/47, 100%). The average baseline plasma HGF was 1.28 (range,0.42-4.35) ng/ml. However, plasma HGF was higher in SCLC patients with patients with N3, M1, liver metastasis (LM) and bone metastasis (BM) disease compared with those N0 - 2 (1.25 vs. 1.75 ng/mL, P = 0.000), M0 (1.26 vs. 1.63 ng/mL, P = 0.003), non-LM (1.32 vs. 2.06 ng/mL, P = 0.009), and non-BM (1.35 vs. 1.77 ng/mL, P = 0.047), respectively. Multivariate analysis revealed plasma HGF was an independent predictor for LM and prognostic factor of OS. CONCLUSION: Our results revealed that plasma HGF rather than tumor HGF exhibited a potential role in predicting metastasis and survival in SCLC. Plasma HGF might be used as a non-invasive detecting and monitoring tool for SCLC.

Mutation status analysis of 58 patients with advanced ALK fusion gene positive non small cell lung cancer.

PURPOSE: To analyze the characteristics and prognostic values of Anaplastic Lymphoma Kinase (ALK) fusion gene partner, gene subtype and abundance in tumor tissues of advanced Non Small Cell Lung Cancer (NSCLC) patients with positive ALK fusion gene and to explore the best treatment mode of ALK-Tyrosine Kinase Inhibitors(TKIs). METHODS: Cases of advanced NSCLC patients with ALK positive confirmed by both Next Generation Sequencing (NGS) and immunohistochemistry were retrospectively collected. The relationships of Overall Survival (OS)/Progression Free Survival (PFS) between different mutation subtypes, mutation abundance, clinicopathological features were analyzed. OS/PFS between different treatment mode of ALK inhibitors were compared. RESULTS: Fifty-eight patients were enrolled. There were diverse fusion partners. Five subtypes of Echinoderm Microtubule-associated protein-Like 4 gene (EML4)-ALK fusion mutation were detected: V1,V2,V3,V5 and V7. The mutation abundance ranged from 0.13 to 27.77%, with a median of 5.34%. The abundance of V2 and V5 was higher than V1 and V3 respectively. There was no difference in OS between the low abundance group(≤ 5.34%) and the high abundance group(>5.34%) (P = 0.434). PFS of second-generation ALK inhibitors as first-line treatment was longer than that of Crizotinib as first-line (P<0.001). Never smokers had longer OS than current smokers(P = 0.001). CONCLUSIONS: There are differences in abundance between different fusion partners and subtypes in advanced NSCLC with positive ALK. OS is not associated with subtypes, mutation abundance and first line treatment option of either generation of ALK inhibitors. Smoking is a poor prognostic factor.

Longitudinal detection of subcategorized CD44v6+ CTCs and circulating tumor endothelial cells (CTECs) enables novel clinical stratification and improves prognostic prediction of small cell lung cancer: A prospective, multi-center study.

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.

Post-therapeutic circulating tumor cell-associated white blood cell clusters predict poor survival in patients with advanced driver gene-negative non-small cell lung cancer.

PURPOSE: This study aimed to investigate the clinical utility of diverse aneuploid circulating tumor cell (CTC) subtypes and particularly CTC-associated white blood cell (CTC-WBC) clusters in predicting treatment response, prognosis and real-time monitoring disease progression in advanced driver gene-negative non-small lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 74 eligible patients were prospectively enrolled and serial blood samples were collected at pre-treatment(t0), after two cycles of therapy (t1) and at post-four-to-six treatment cycles (t2). Co-detection of diverse subtypes of aneuploid CTCs and CTC-WBC clusters was conducted in advanced NSCLC patients receiving first-line treatment. RESULTS: At baseline, CTCs were detected in 69 (93.24%) patients and CTC-WBC clusters were detected in 23 (31.08%) patients. Patients with CTCs < 5/6ml or with CTC-WBC clusters undetectable exhibited a better treatment response than patients with pre-therapeutic aneuploid CTCs ≥ 5/6ml or harboring CTC-WBC clusters (p = 0.034 and p = 0.012, respectively). Before treatment, patients bearing tetraploid CTCs ≥ 1/6ml showed significantly inferior progression-free survival (PFS) [hazard ratio (HR):2.420, 95% confidence interval (CI): 1.426-4.106; p = 0.001] and overall survival (OS) compared to patients with tetraploid CTCs < 1/6ml (HR:1.907, 95%CI: 1.119-3.251; p = 0.018). A longitudinal study demonstrated that post-therapeutic patients harboring CTC-WBC clusters displayed the reduced PFS and OS compared with those without CTC-WBC clusters, and subgroup analysis showed that the presence of CTC-WBC clusters indicated a worse prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. After adjusting for multiple significant factors, post-therapeutic CTC-WBC clusters were the only independent predictor of both PFS (HR:2.872, 95% CI: 1.539-5.368; p = 0.001) and OS (HR:2.162, 95% CI: 1.168-4.003; p = 0.014). CONCLUSIONS: In addition to CTCs, longitudinal detection of CTC-WBC clusters provided a feasible tool to indicate initial treatment response, dynamically monitor disease progression and predict survival in driver gene-negative advanced NSCLC patients.

Interpretable deep learning survival predictive tool for small cell lung cancer.

Background: Small cell lung cancer (SCLC) is an aggressive and almost universally lethal neoplasm. There is no accurate predictive method for its prognosis. Artificial intelligence deep learning may bring new hope. Methods: By searching the Surveillance, Epidemiology, and End Results database (SEER), 21,093 patients' clinical data were eventually included. Data were then divided into two groups (train dataset/test dataset). The train dataset (diagnosed in 2010-2014, N = 17,296) was utilized to conduct a deep learning survival model, validated by itself and the test dataset (diagnosed in 2015, N = 3,797) in parallel. According to clinical experience, age, sex, tumor site, T, N, M stage (7th American Joint Committee on Cancer TNM stage), tumor size, surgery, chemotherapy, radiotherapy, and history of malignancy were chosen as predictive clinical features. The C-index was the main indicator to evaluate model performance. Results: The predictive model had a 0.7181 C-index (95% confidence intervals, CIs, 0.7174-0.7187) in the train dataset and a 0.7208 C-index (95% CIs, 0.7202-0.7215) in the test dataset. These indicated that it had a reliable predictive value on OS for SCLC, so it was then packaged as a Windows software which is free for doctors, researchers, and patients to use. Conclusion: The interpretable deep learning survival predictive tool for small cell lung cancer developed by this study had a reliable predictive value on their overall survival. More biomarkers may help improve the prognostic predictive performance of small cell lung cancer.

Mechanism of OTUD5 in non-small cell lung cancer cell proliferation, invasion, and migration.

Ovarian tumor protease deubiquitinase 5 (OTUD5) has been discussed as a regulator of cancer development. Herein, the current study set out to explore the molecular mechanism of OTUD5 in non-small cell lung cancer (NSCLC) cell proliferation, invasion, and migration. Firstly, the expression patterns of OTUD5, phosphatase and tensin homolog (PTEN), as well as microRNA (miR)-652-3p in cells were detected by qRT-PCR and Western blot. Cell viability, migration, and invasion were assessed with the help of cell-counting kit-8 and Transwell assays, in addition to the measurement of the ubiquitination and protein levels of PTEN. The binding relations between OTUD5 and PTEN, and miR-652-3p and OTUD5 were testified by co-immunoprecipitation or dual-luciferase assays. Cells were further treated with GSK2643943A (inhibitor of deubiquitinase) or miR-652-3p-inhibitor to explore the role of PTEN ubiquitination and miR-652-3p in NSCLC cells. OTUD5 and PTEN were both poorly-expressed, and miR-652-3p was highly-expressed in NSCLC cells. On the other hand, over-expression of OTUD5 suppressed NSCLC cell proliferation, invasion, and migration. OTUD5 deubiquitinated and stabilized PTEN, and miR-652-3p targeted and inhibited OTUD5 expression. Augmenting the ubiquitination levels of PTEN promoted NSCLC cell growth, whereas miR-652-3p inhibition promoted the tumor-suppressing effects of the OTUD5/ PTEN axis in NSCLC. Altogether, our findings highlighted that miR-652-3p restrained the role of OTUD5 in deubiquitinating PTEN to improve PTEN protein level, thereby promoting NSCLC cell proliferation, invasion, and migration.

[A Single Center Analysis of Advanced Non-small Cell Lung Cancer Patients Treated with Immunotherapy in Real-world Practice].

BACKGROUND: In recent years, a number of clinical trials have shown that immunocheckpoint inhibitors (ICI) have brought survival benefits to patients with advanced non-small cell lung cancer (NSCLC), however, such clinical trials comprise cohorts selected based on strict and complex entry and exclusion criteria, and the results cannot fully reflect the real world situation. The purpose of this study was to investigate the clinical efficacy and safety of immunotherapy in the real world, as well as possible prognostic factors. METHODS: Patients with advanced NSCLC receiving immunotherapy in Beijing Chest Hospital from January 2017 to July 2019 were retrospectively collected, and the following information were collected: curative effect, progression-free surival (PFS) and adverse reactions. The occurrence of adverse reactions and clinical curative effect and prognosis factors that may be relevant were explored. RESULTS: 34 patients were enrolled in this study, median PFS was 5.66 months (95%CI: 4.48-6.84), grade 1-2 and 3-4 incidence of adverse events was 61.71% (22/34) and 14.71% (5/34), there were 3 patients (8.82%) experienced fatal immune related adverse events (irAE), 2 cases were immune associated pneumonia, 1 case was immune related myocarditis. Univariate analysis showed that tumor-node-metastasis (TNM) stage and metastatic site were correlated with median PFS (P<0.05), and multivariate analysis showed that patients with extrapulmonary metastasis (OR=6.42, P=0.029) and pleural metastasis (OR=14.14, P=0.006) had shorter median PFS. CONCLUSIONS: In the real world, immunotherapy has good efficacy in patients with advanced NSCLC, but the incidence of severe irAE is also higher. Distant metastasis and pleural metastasis are poor prognostic factors for advanced NSCLC patients receiving immunotherapy.

Well-differentiated fetal adenocarcinoma of the lung: clinicopathologic features of 45 cases in China.

OBJECTIVE: Well-differentiated fetal adenocarcinoma (WDFA) is a rare pulmonary carcinoma with low malignancy and favorable prognosis. All cases were collected, analyzed and summarized to better understand this disease. METHODS: We used the keywords "fetal adenocarcinoma" and "epithelial pulmonary blastoma (EPB)" to search WANFANG MED ONLINE, CNKI and NCBI PUBMED for cases reported by Chinese authors from 1987 to July 2015. RESULTS: A total of 64 cases reported in China were reviewed, and the details of the clinicopathological features of 45 cases were summarized. Among these 45 patients, 23 (23/45, 51.1%) patients were male and 22 (22/45, 48.9%) patients were female. The mean age at diagnosis was 35 ± 15 years old (range, 6-72 years old) with a bimodal peak in the second and third decades. Furthermore, 24 tumors (24/31, 77.4%) were found to have progressed past stage I, while only three (3/45, 6.7%) tumors had lymph nodes metastases. These tumor cells were 100% reactive for keratin, ß-catenin, Napsin A and PDGFRα when stained by these antibodies. Better survival could be obtained if the metastatic tumor is removed in some patients with metastases. Four (4/31, 12.9%) patients died due to their tumors. CONCLUSIONS: WDFA is very different to conventional adenocarcinoma in clinicopathology. It prefers to occur in the second and third decades. Lymph node metastasis is infrequent. Beta-catenin may be a potential marker for disease. Surgery is the best therapy method if the technology is feasible.

[Serum CYFRA21-1 is Correlated with the Efficacy of Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor in Non-small Cell Lung Cancer Patients Harboring EGFR Mutations].

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment regimen for EGFR mutated non-small cell lung cancer (NSCLC) patients. However, the efficacy of EGFR-TKIs widely varies. The aim of this study is to determine whether the pretreatment serum cytokeratin-19 fragments (CYFRA21-1) and carcinoembryonic antigen (CEA) are associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients. METHODS: We retrospectively enrolled 194 NSCLC patients harboring EGFR mutations who received EGFR-TKIs. Clinical characteristics were collected, and the relation between the efficacy of EGFR-TKIs and pretreatment serum CYFRA21-1 and CEA was analyzed. RESULTS: In all cases, progression-free survival (PFS) in patients with high CYFRA21-1 level was significantly shorter than PFS in patients with normal CYFRA21-1 (7.0 vs 11.9 months, P<0.001). Overall survival (OS) in patients with high CYFRA21-1 was significantly shorter than in the normal-CYFRA21-1 group (12.6 vs 28.0 months, P<0.001). In adenocarcinoma patients, PFS in the high-CYFRA21-1 level group was significantly shorter than in patients with normal CYFRA21-1 (7.0 vs 12.0 months, P<0.001). OS in patients with high CYFRA21-1 was significantly shorter than that in the normal-CYFRA21-1 group (13.1 vs 28.1 months, P<0.001). Among squamous carcinoma patients, CYFRA21-1 level did not affect survival. No significant difference in PFS and OS was observed between patients with high CEA and patients with normal CEA. CONCLUSIONS: EGFR-mutated patients with high CYFRA21-1 had significantly shorter PFS and OS than patients with normal CYFRA21-1 after receiving EGFR-TKIs. Pretreatment serum CYFR21-1 level was a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.
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Topoisomerase I expression is associated with prognosis in postoperative non-small cell lung cancer patients.

BACKGROUND: Biomarkers may help to improve non-small cell lung cancer (NSCLC) prognosis. However, the prognostic effect of topoisomerase I (Topo I) on NSCLC is unknown. We evaluated the clinicopathologic and prognostic significance of tumor Topo I and thymidylate synthase (TS) protein expression in postoperative NSCLC patients. METHODS: One hundred and fifteen patients with postoperative NSCLC were enrolled. Topo I and TS protein were detected in removed tumors by immunohistochemistry. The correlations between Topo I/TS protein expression and clinicopathologic characters and outcomes of patients were analyzed. RESULTS: Increased expression of Topo I was found in 57 (49.6%) tumors. The largest diameter of the tumor was significantly different between patients with high and low Topo I expression (P = 0.035). TS staining showed that 35 (30.4%) carcinomas were TS positive. The level of TS expression was correlated with tumor differentiation (P = 0.037). Patients with low Topo I expression had significantly longer overall survival (OS) than those with high expression (P = 0.004). The correlation between Topo I expression and OS was demonstrated among patients with squamous cell carcinoma (P = 0.030) and patients in pathological tumor node metastasis stage I (P = 0.027). Topo I expression was positively correlated with TS expression in tumor tissue (R = 0.251, P = 0.007). CONCLUSIONS: Low Topo I expression is an independent favorable prognostic factor for longer OS in postoperative NSCLC patients, especially in squamous cell carcinoma. There is a correlation between the expression of TS and Topo I in removed tumor tissue.

High levels of Phosphatase and Tensin Homolog Expression Predict Favorable Prognosis in Patients with Non-small Cell Lung Cancer.

The prognostic role of phosphatase and tensin homolog (PTEN) in non-small cell lung cancer (NSCLC) has been controversial. In this study, levels of PTEN expression were investigated in NSCLC patients and their prognostic value in NSCLC was assessed. PTEN expression in tumor tissues from 68 NSCLC patients was analyzed using immunohistochemistry and confocal microscopy. Survival analysis was performed using the log-rank test and Cox proportional hazards regression analysis. NSCLC patients classified as expressers of high levels of PTEN (n = 46) had better prognoses than those classified as expressers of low levels (mean survival 17.1 vs. 12.9 months, log rank P = 0.038). In patients with adenocarcinoma (AC), high PTEN expression (n = 9) was associated with significantly longer survival than low PTEN expression (mean survival 23.50 vs. 15.54 months, log rank P = 0.043). High levels of PTEN expression resulted in 43 % reduction in risk for all NSCLC patients (HR 0.57, 95 % CI 0.33-0.98, P = 0.041). PTEN expression and clinical stage remained significantly associated with survival after adjustment for age, sex, and tumor type (HR 0.56, 95 % CI 0.32-0.99; P = 0.048; HR 0.54, 95 % CI 0.36-0.97; P = 0.045). No significant difference in continuous PTEN expression levels was observed among groups with different clinical or pathological characteristics (P > 0.17). When levels of PTEN expression were binarized using the optimal cut-point, higher levels of PTEN expression were observed in patients with T1/T2 than in those with T3/T4 (80 and 58 %, respectively, P = 0.049) and in patients with AC than in those with squamous-cell carcinoma (78 and 58 %, respectively, P = 0.08). No significant difference in binarized PTEN expression levels was found among groups with any other clinical/pathologic characteristic (P > 0.28). Our results suggest that high levels of PTEN expression may be favorable prognostic markers in NSCLC patients.

Antioxidant and SGC-7901 cell inhibition activities of Rhizoma Dioscoreae bulbiferae. ethanol extracts.

The objective of this research was to study the pharmacology of Dioscorea bulbifera L. on antioxidant and anticancer activity. Alcohol extracts of Dioscorea bulbifera L. were made out by different concentration alcohol; they were tested by Hydroxyl radical scavenging test, reducing capacity test and total antioxidant capacity test. In the anticancer test, MTT test was used to study the inhibition rate. The results told that 70% ethanol extracts could scavenge most DPPH· at 2 mg/ml. The rate was 55.2%; 80% ethanol extract could clear the most ·OH. The clearance rate was 51.2%. 80% ethanol crude extracts possessed the strongest reducing ability per gram of the extract equal to 49.3 µmol Fe(2 +). Different concentrations of the extracts could inhibit the proliferation of line SGC-7901, and with the concentration increased, the inhibition rate was gradually increased.

5-Hydroxytryptamine enhances L-type calcium current in norepinephrine-induced hypertrophic ventricular myocytes.

AIM: To study the effects of 5-hydroxytryptamine (5-HT) on L-type calcium current (ICa) in norepinephrine (NE)-induced hypertrophic ventricular myocytes. METHODS: Left ventricular hypertrophy was induced by injecting NE intraperitoneally in rats. The single myocytes were isolated enzymatically from left ventricle. ICa was recorded with the whole-cell configuration of the patch-cl amp technique. RESULTS: (1) The ratio of left heart weight to body weight (LHW/BW) was higher (P < 0.01) in the NE-treated rats compared with the control rats on d 15. LHW/BW was increased 31.8 % in NE-treated rats. (2) ICa was larger in hypertrophic cells than that in normal cells (4.5 p A/pF +/- 0.5 pA/pF vs 3.5 pA/pF +/- 0.3 pA/pF, respectively, at testing potential of 0 mV; P < 0.01). (3) 5-HT (1, 10 micromol/L) increased ICa and decreased the peak current potential from 0 mV to -10 mV in both myocytes. The augmentation of ICa induced by 5-HT was larger in hypertrophic ones. (4) 5-HT did not markedly influence the steady-state activation kinetics. However, 5-HT shifted steady-state inactivation curve with half inactivation voltage V 1/2 changing from -39.5 mV +/- 1.8 mV to -27.8 mV +/- 1.7 m V (P < 0.05), while not changing the voltage responsiveness of calcium channel (slope factor k was not changed markedly). CONCLUSION: 5 -HT increased ICa in ventricular myocytes by changing the kinetics of steady-st ate inactivation. A larger alteration of ICa induced by 5-HT i n hypertrophic ventricular myocytes suggests that 5-HT be more prone to induce arrhythmia in hypertrophic heart than in normal one.