Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer (RATICAL): a nationwide multicenter retrospective study.

BACKGROUND: Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement. This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC. METHODS: In this real-world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)-VENTANA-D5F3. The positive ALK gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well. RESULTS: The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC-VENTANA-D5F3 revealed an intra-hospital consistency rate of 98.2% (879/895) and an inter-hospital consistency rate of 99.2% (646/651). IHC-VENTANA-D5F3 was used in 53.6%, real-time polymerase chain reaction (RT-PCR) in 25.4%, next-generation sequencing (NGS) in 18.3%, and fluorescence in-situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT-PCR. The overall ALK gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of > 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all P < 0.05). CONCLUSIONS: This study highlights the real-world variability and challenges of ALK test in advanced NSCLC, demonstrating a predominant use of IHC-VENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.

Injectable hydrogel with doxorubicin-loaded ZIF-8 nanoparticles for tumor postoperative treatments and wound repair.

The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments.

Two case reports: EML4-ALK rearrangement large cell neuroendocrine carcinoma and literature review.

Anaplastic lymphoma kinase gene (ALK) rearrangement is present in only approximately 5% of non-small cell lung cancers (NSCLCs) and is scarce in LCNEC patients. The conventional first-line treatment options are chemotherapy combined with immunotherapy or chemotherapy followed by palliative radiotherapy. In this report, we present two cases of metastatic LCNEC with EML4-ALK fusion that were treated with ALK-TKI inhibitors and demonstrated a rapid therapeutic response. Both patients were nonsmoking women who declined cytotoxic chemotherapy, underwent Next-Generation Sequencing (NGS), and confirmed EML4-ALK fusion. They were treated with alectinib as first-line therapy, and the tumors showed significant shrinkage after two months, achieving a PR (defined as a more than 30% decrease in the sum of maximal dimensions). The PFS was 22 months and 32 months, respectively, until the last follow-up. A systematic review of all previously reported cases of LCNEC with ALK mutations identified only 21 cases. These cases were characterized by being female (71.4%), nonsmoking (85.7%), diagnosed at a relatively young age (median age 51.1), and stage IV (89.5%), with an overall response rate (ORR) of 90.5%. PFS and OS were significantly longer than those treated with conventional chemotherapy/immunotherapy. Based on the clinical characteristics and the effective therapeutic outcomes with ALK inhibitors in LCNEC patients with ALK fusion, we recommend routine ALK IHC (economical, affordable, and convenient, but with higher false positives) as a screening method in advanced LCNEC patients, particularly nonsmoking females or those who are not candidates for or unwilling to undergo cytotoxic chemotherapy. Further molecular profiling is necessary to confirm these potential beneficiaries. We suggest TKI inhibitors as the first-line treatment for metastatic LCNEC with ALK fusion. Additional studies on larger cohorts are required to assess the prevalence of ALK gene fusions and their sensitivity to various ALK inhibitors.

CT-based radiomics model to predict spread through air space in resectable lung cancer.

BACKGROUND: Spread through air space (STAS) has been identified as a pathological pattern associated with lung cancer progression. Patients with STAS were related to a worse prognosis compared with patients without STAS. The objective of this study was to establish a radiomics model capable of forecasting STAS before surgery, which can assist surgeons in selecting the most appropriate operation type for patients with STAS. METHOD: There were 537 eligible patients retrospectively included in this study. ROI segmentation was performed manually on all CT images to identify the region of interest. From each segmented lesion, a total of 1688 features were extracted. The tumor size, maximum tumor diameters, and tumor type were also recorded. Using Spearman's correlation coefficient to calculate the correlation and redundancy of elements, and redundant features less than 0.80 were removed. In order to reduce the level of overfitting and avoid statistical biases, a dimension reduction process of the dataset was conducted to decrease the number of features. Finally, a radiomics model included 44 features was established to predict STAS. To evaluate the performance of the model, the receiver operating characteristic (ROC) curve was used, and the area under the curve (AUC) was calculated, and the accuracy of the model was verified by 10-fold cross-validation. RESULTS: The incidence of STAS was 38.2% (205/537). The tumor type, maximum tumor diameters, and consolidation tumor ratio were significantly different between STAS group and non-STAS group. The training group included 430 patients, while the test group was consisted with 107. The training group achieved an AUC of 0.825 (sensitivity, 0.875; specificity, 0.621; and accuracy, 0.749) and the test group had an AUC of 0.802 (sensitivity, 0.797; specificity,0.688; and accuracy, 0.748). The 10-fold cross-validation had an AUC of 0.834. CONCLUSION: CT-based radiomic model can predict STAS effectively, which is of great importance to guide the selection of operation types before surgery.

[Study on the Biological Function of Abemecilib in Inhibiting the Proliferation, Invasion and
Migration of Small Cell Lung Cancer with High c-Myc Expression].

BACKGROUND: Small cell lung cancer (SCLC) with high c-Myc expression is prone to relapse and metastasis, leading to extremely low survival rate. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib plays a key role in the treatment of tumors, but the effects and mechanisms on SCLC remain unclear. This study was to analyze the effect and molecular mechanism of Abemaciclib in inhibiting proliferation, migration and invasion of SCLC with high c-Myc expression, with a view to expanding a new direction for reducing the recurrence and metastasis. METHODS: Proteins interacting with CDK4/6 were predicted using the STRING database. The expressions of CDK4/6 and c-Myc in 31 cases of SCLC cancer tissues and paired adjacent normal tissues were analyzed by immunohistochemistry. The effects of Abemaciclib on the proliferation, invasion and migration of SCLC were detected by CCK-8, colony formation assay, Transwell and migration assay. Western blot was used to detect the expressions of CDK4/6 and related transcription factors. Flow cytometry was used to analyze the effects of Abemaciclib on the cell cycle and checkpoint of SCLC. RESULTS: The expression of CDK4/6 was associated with c-Myc by STRING protein interaction network. c-Myc can directly modalize achaete-scute complex homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1) and Yes-associated protein 1 (YAP1). Moreover, CDK4 and c-Myc regulate the expression of programmed cell death ligand 1 (PD-L1). Immunohistochemistry showed that the expressions of CDK4/6 and c-Myc in cancer tissues were higher than those in adjacent tissues(P<0.0001). CCK-8, colony formation assay, Transwell and migration assay verified that Abemaciclib could effectively inhibit the proliferation, invasion and migration of SBC-2 and H446OE(P<0.0001). Western blot analysis further showed that Abemaciclib not only inhibited CDK4 (P<0.05) and CDK6 (P<0.05), but also affected c-Myc (P<0.05), ASCL1 (P<0.05), NEUROD1 (P<0.05) and YAP1 (P<0.05), which are related to SCLC invasion and metastasis. Flow cytometry showed that Abemaciclib not only inhibited the cell cycle progression of SCLC cells (P<0.0001), but also significantly increased PD-L1 expression on SBC-2 (P<0.01) and H446OE (P<0.001). CONCLUSIONS: Abemaciclib significantly inhibits the proliferation, invasion, migration and cell cycle progression of SCLC by inhibiting the expressions of CDK4/6, c-Myc, ASCL1, YAP1 and NEUROD1. Abemaciclib can also increase the expression of PD-L1 in SCLC.

Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) usually contains heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of the MIP subtype responsible for its malignant behaviors are substantially unknown. In this study, eight FFPE samples from LUAD patients were micro-dissected to isolate MIP and LEP components, then sequenced by whole-exome sequencing. More comprehensive analyses involving our samples and public validation cohorts on the two subtypes were performed to better decipher the key biological and evolutionary mechanisms. As expected, the LEP and MIP subtypes exhibited the largest disease-free survival (DFS) differences in our patients. EGFR was found with the highest mutation frequency. Additionally, shared mutations were observed between paired LEP and MIP components from single patients, and recurrent mutations were verified in the Lung-Broad, Lung-OncoSG, and TCGA-LUAD cohorts. Distinct biological processes or pathways were involved in the evolution of the two components. Besides, analyses of copy number variation (CNV) and intratumor heterogeneity (ITH) further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level, ITH, and the pervasive DNA damage response and WNT pathway gene alternations in the MIP component. Phylogenetic analysis of five pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analyses combining our samples and public cohorts, PTP4A3, NAPRT, and RECQL4 were identified to be co-amplified. Multi-omics data also demonstrated the immunosuppression prevalence in the MIP component. Our results uncovered the evolutionary pattern of the concomitant LEP and MIP components from the same patient that they were derived from the same initiation cells and the pathway-specific mutations acquired after EGFR clonal mutation could shape the subtype-specificity. We also confirmed the immunosuppression prevalence in the MIP subtype by multi-omics data analyses, which may have resulted in its unfavorable prognosis.

METTL3-induced DLGAP1-AS2 promotes non-small cell lung cancer tumorigenesis through m6A/c-Myc-dependent aerobic glycolysis.

The critical roles of N6-methyladenosine (m6A) modification have been demonstrated by more and more evidence. However, the cross talk of m6A and long noncoding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC) tumorigenesis is still unclear. Here, this work focused on the functions and molecular mechanism of m6A-modified lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) in NSCLC. Microarray analysis found that lncRNA DLGAP1-AS2 is upregulated in NSCLC cells. Clinical data showed that DLGAP1-AS2 high-expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 overexpression promoted the aerobic glycolysis and DLGAP1-AS2 knockdown suppressed the tumor growth of NSCLC cells. Mechanistically, m6A methyltransferase METTL3 enhanced the stability of DLGAP1-AS2 via m6A site binding. Moreover, DLGAP1-AS2 interacted with YTHDF1 to enhance the stability of c-Myc mRNA through DLGAP1-AS2/YTHDF1/m6A/c-Myc mRNA. In conclusion, our work indicates the functions of m6A-modified DLGAP1-AS2 in the NSCLC aerobic glycolysis, disclosing a potential m6A-dependent manner for NSCLC treatment.

Case Report: Sarcoid-Like Reactions and Tertiary Lymphoid Structures Following Dual Checkpoint Inhibition in a Patient with Early-Stage Lung Adenocarcinoma.

Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples. TP53 R181C, KRAS G12C and SMAD4 R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3+ regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures.

Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer.

Tertiary lymphoid structures (TLS) existence is correlated with favorable prognosis in many types of cancer including non-small cell lung cancer (NSCLC). However, TLS formation and its relationship with treatment response remains unknown in NSCLC who received anti-PD-1 antibody plus chemotherapy as the neoadjuvant treatment (neoadjuvant chemoimmunotherapy). Here, we investigate TLS maturation and abundance in resectable NSCLC receiving neoadjuvant treatments. We retrospectively collected formalin-fixed paraffin embedded (FFPE) tissues from patients with resectable NSCLC (stage II-IIIA) from three cohorts based on treatment: naïve (N=40), neoadjuvant chemoimmunotherapy (N=40), and neoadjuvant chemotherapy (N=41). The TLS in tumor tissues was detected by immunohistochemical staining, and the differences in TLS maturation and abundance among different treatment groups were analyzed, as well as the relationship with pathological response and prognosis of patients. Multiplex immunofluorescence staining was used to explore the features of immune microenvironment. Higher major pathological response (MPR) rate and pathological complete response (pCR) rate were in the neoadjuvant chemoimmunotherapy group than in the neoadjuvant chemotherapy group (MPR: 45.0% vs 17.1%; pCR: 35.0% vs 4.9%). Among the three cohorts, neoadjuvant chemoimmunotherapy-treated NSCLCs displayed highest TLS maturation and abundance. Both the maturation and abundance of TLS were significantly correlated with MPR in both the neoadjuvant chemoimmunotherapy and the chemotherapy group. Patients with high maturation and abundance of TLS exhibited better disease-free survival (DFS) in all the three cohorts. TLS maturation was also an independent predictor for DFS in the neoadjuvant chemoimmunotherapy and treatment naïve group. Multiplex immunohistochemistry analysis using paired biopsy-surgery samples showed increased infiltration of CD8+T cell and decreased infiltration of M1 and M2 macrophages after neoadjuvant chemoimmunotherapy treatment in patients achieving MPR. There were no significant differences in features of immune cell infiltration for those with mature TLS achieving MPR when cross-compared across the three cohorts. These results demonstrate that TLS maturation is associated with MPR and an independent predictor for DFS in resectable neoadjuvant chemoimmunotherapy-treated NSCLC. The induction of TLS maturation may be a potential mechanism of action of neoadjuvant chemoimmunotherapy in resectable NSCLC.

Effectiveness of alectinib and osimertinib in a brain metastasized lung adenocarcinoma patient with concurrent EGFR mutations and DCTN1-ALK fusion.

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions after she acquired osimertinib resistance. Furthermore, we summarize 22 published cases of patients with lung adenocarcinoma with concurrent EGFR mutation and ALK rearrangement, including details of clinical characteristics, natural history, and pertinent therapy of this uncommon tumor subtype. This literature review shows that EGFR inhibition was an indispensable aspect of the treatment of patients with EGFR/ALK co-alterations in the pre-alectinib era and that ALK inhibition with crizotinib did not show more eye-catching therapeutic results. Considering the effectiveness achieved by alectinib, this case study provides a new perspective for the treatment of lung cancer brain metastasis patients with concurrent EGFR/ALK mutations.

A nomogram-based immune-serum scoring system predicts overall survival in patients with lung adenocarcinoma.

OBJECTIVE: The immunoscore, which is used to quantify immune infiltrates, has greater relative prognostic value than tumor, node, and metastasis (TNM) stage and might serve as a new system for classification of colorectal cancer. However, a comparable immunoscore for predicting lung adenocarcinoma (LUAD) prognosis is currently lacking. METHODS: We analyzed the expression of 18 immune features by immunohistochemistry in 171 specimens. The relationship of immune marker expression and clinicopathologic factors to the overall survival (OS) was analyzed with the Kaplan-Meier method. A nomogram was developed by using the optimal features selected by least absolute shrinkage and selection operator (LASSO) regression in the training cohort (n = 111) and evaluated in the validation cohort (n = 60). RESULTS: The indicators integrated in the nomogram were TNM stage, neuron-specific enolase, carcino-embryonic antigen, CD8center of tumor (CT), CD8invasive margin (IM), FoxP3CT, and CD45ROCT. The calibration curve showed prominent agreement between the observed 2- and 5-year OS and that predicted by the nomogram. To simplify the nomogram, we developed a new immune-serum scoring system (I-SSS) based on the points awarded for each factor in the nomogram. Our I-SSS was able to stratify same-stage patients into different risk subgroups. The combination of I-SSS and TNM stage had better prognostic value than the TNM stage alone. CONCLUSIONS: Our new I-SSS can accurately and individually predict LUAD prognosis and may be used to supplement prognostication based on the TNM stage.

A Case of Simultaneously Diagnosed Lung Adenocarcinoma and Endobronchial Inflammatory Myofibroblastic Tumor with Two Distinct Types of ALK Translocation.

A 61-year-old male patient was simultaneously diagnosed with lung adenocarcinoma and inflammatory myofibroblastic tumor (IMT). The lung adenocarcinoma and IMT harbored two distinct types of ALK translocation, LOC101927285-ALK, and TPM3-ALK, respectively. The ALK Ventana showed strong positivity on both lesions. The patient was therefore given an endobronchial cryotherapy and ALK inhibitor crizotinib. The tumors showed durable response however the left lung adenocarcinoma relapsed at 17th month post-crizotinib treatment. Tissue re-biopsy on the resistant tumor revealed an ALK exon 23 C1156Y missense mutation in addition to LOC101927285-ALK mutation. Further RNA-based sequence uncovered that the noncoding region rearrangement is the fusion mutation of EML4-ALK. The patient was therefore received alectinib, and the tumor exhibited partly response. Overall, it is very rare that two types of pulmonary tumors exist in one patient driven by two distinct ALK fusions, which emphasizes the necessity of gene sequencing in clinical decision-making and individualized therapy.

A study of ALK-positive pulmonary squamous-cell carcinoma: From diagnostic methodologies to clinical efficacy.

BACKGROUND: High concordance has been observed between Ventana D5F3 ALK immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) in lung adenocarcinoma (LADC). However, whether a similar conclusion can be applied to lung squamous-cell carcinoma (LSCC) has remained unclear. We therefore evaluated the ALK (anaplastic lymphoma kinase) status and the therapeutic effect of an ALK tyrosine kinase inhibitor (TKI) in IHC- or FISH-positive LSCC. MATERIALS AND METHODS: A total of 2403 LSCC patients from three institutions were screened for ALK aberration by IHC. All IHC-positive cases were subjected to FISH (with an approximately equal number of negative cases as a control group) and next-generation sequencing (NGS). Clinical efficacy was evaluated for the patients who received TKI therapy. RESULTS: In 2403 cases of LSCC, 37 cases were identified as ALK-positive by IHC. After quality control, 28 cases were succeeded by FISH (six with insufficient tissue, three with lack of signals) and 13 by NGS (24 failed due to insufficient samples or poor DNA quality); the percentage of non-diagnostic tests was 24.3% (9/37) and 64.9% (24/37), respectively. Four cases (4/2394, 0.17%) analyzed by FISH were determined as ALK-positive. For the control group (40 ALK IHC), FISH demonstrated no samples with ALK gene fusion. The concordance between ALK IHC- and ALK FISH-positive results was 14.3% (4/28). In the 13 cases studied by NGS, two cases showed ALK-EML4 fusion (consistent with two FISH-positive results), and two cases were interpreted as harboring an ALK-association gene mutation. Among four patients (two FISH-positive and two IHC-positive only cases) receiving TKI therapy, two patients had stable disease and the other two had progressive disease. CONCLUSIONS: The positive concordance rate of ALK IHC and FISH in LSCC is far less than that reported for LADC. Therefore, ALK IHC detection in LSCC cannot be used as a diagnostic method for ALK rearrangement.

A combination of tumor and molecular markers predicts a poor prognosis in lung adenocarcinoma.

PURPOSE: Whether patients with stage IA-IIA lung adenocarcinoma require conventional chemotherapy is still a controversy. An ideal metastasis risk prediction model in lung adenocarcinoma is valuable for determining the prognosis and giving timely, individualized treatment. RESULTS: Analyzing the clinical cases of 153 lung adenocarcinoma patients using an χ2 test, Kaplan-Meier survival curves, and a multivariate logistic regression analysis, we selected the most valuable factors for determining metastasis and constructed metastasis prediction models. We confirmed the importance of the tumor markers (CEA, NSE) and a molecular marker (CAMKII) as independent prognostic factors in lung adenocarcinoma. The result of a five-year survival status was significantly associated with CAMKII and CEA (P < 0.05). A nomogram was created using CEA, NSE, CYFRA 21-1, and CAMKII to estimate the metastasis probability for individuals, specifically, 78 stage I lung adenocarcinoma patients were used to verify the effectiveness of the nomogram. Using machine learning, LASSO selected the subset of variables that minimized the predictive error of the outcome, including CEA, NSE, CYFRA 21-1, CAMKII, tumor size, histologic type, lymph node status, smoking, and age. A ten-fold cross-validation showed the average accuracy of this model was 86.208%, with an area under the curve of 0.857, a sensitivity value of 0.840, and a specificity value of 0.873. CONCLUSION: Using both complementary methods, the predictive models illustrated that the combination of tumor markers and a key molecule to predict the prognosis of lung adenocarcinoma patients in early stages is valuable. The postoperative transfer rate of stage I patients can be effectively predicted by these complementary methods.

Clinical Significance of 4L Lymph Node Dissection in Left Lung Cancer.

PURPOSE: To investigate the prognostic impact of 4L lymph node (LN) dissection in left lung cancer and to analyze the relative risk factors for 4L LN metastasis. PATIENTS AND METHODS: We retrospectively collected data from 657 patients with primary left lung cancer who underwent surgical pulmonary resection from January 2005 to December 2009. One hundred thirty-nine patients underwent 4L LN dissection (4LD+ group); the other 518 patients did not receive 4L LN dissection (4LD- group). Propensity score weighting was applied to reduce the effects of observed confounding between the two groups. Study end points were disease-free survival (DFS) and overall survival (OS). RESULTS: The metastasis rate of station 4L was 20.9%, which was significantly higher than those of station 7 (14.0%; P = .048) and station 9 (9.8%; P < .001). Station 4L metastasis was associated with most other LN station metastases in univariate analysis, but only station 10 LN metastasis was an independent risk factor for 4L LN metastasis (odds ratio, 0.253; 95% CI, 0.109 to 0.588; P = .001) in multivariate logistic analysis. The 4LD+ group had a significantly better survival than the 4LD- group (5-year DFS, 54.8% v 42.7%; P = .0376; 5-year OS, 58.9% v 47.2%; P = .0200). After allowing potential confounders in multivariate survival analysis, dissection of 4L LN retained its independent favorable effect on DFS (hazard ratio, 1.502; 95% CI, 1.159 to 1.947; P = .002) and OS (hazard ratio, 1.585; 95% CI, 1.222 to 2.057; P = .001). Propensity score weighting further confirmed that the 4LD+ group had a more favorable DFS ( P = .0014) and OS ( P < .001) than the 4LD- group. CONCLUSION: Station 4L LN involvement is not rare in left lung cancer, and dissection of the 4L LN station seems to be associated with a more favorable prognosis as compared with those who did not undergo this dissection.

Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.

One of the major obstacles hindering the treatment of lung cancer (LC) is chemoresistance; however, its mechanism remains unclear. The overexpression of the metastasis-associated in colon cancer 1 (MACC1) gene has been demonstrated to reverse chemoresistance. In the current study, the expression of MACC1 in LC cells with cisplatin resistance (Cis-Re) was investigated. Cisplatin-resistant cell sublines (A549/CR and H446/CR) were induced by stepwise escalation of cisplatin exposure. MTS and flow cytometry assays were performed to measure cell proliferation and apoptosis, respectively. Western blot analysis and qRT-PCR assays were performed to determine the changes in signaling pathway-related protein and mRNA levels, respectively. A nude mouse xenograft model was used for in vivo experiments. Our results showed that MACC1 expression was increased in the cisplatin-resistant A549/CR and H446/CR cell lines, and the resistance was reversed with a decrease of MACC1 expression. MACC1 overexpression triggered an increase of Cis-Re, which was contrary to the effect of MACC1 down-regulation. In addition, the effect of MACC1 on Cis-Re was blocked by the inhibition of the PI3K/AKT pathway, and treatment with both cisplatin and a PI3K/AKT inhibitor effectively inhibited tumor growth in xenografts with MACC1 overexpression. In conclusion, our results revealed that MACC1 increased Cis-Re partially via the PI3K/AKT signaling pathway, suggesting that MACC1 could serve as a potential target to overcome Cis-Re. Furthermore, combination therapy could alleviate Cis-Re resulted from MACC1 overexpression in patients with LC.

MicroRNA-130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/ß-catenin pathway.

More and more studies indicate the relevance of miRNAs in inducing certain drug resistance. Our study aimed to investigate whether microRNA-130b-3p (miR-130b) mediates the chemoresistance as well as proliferation of lung cancer (LC) cells. MTS assay and apoptosis analysis were conducted to determine cell proliferation and apoptosis, respectively. Binding sites were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT-PCR and immunoblot, respectively. Mouse xenograft model was used to evaluate the role of miR-130b in cisplatin resistance in vivo. The rising level of miR-130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. We identified PTEN as miR-130b's major target and inversely correlated with miR-130b expression in LC. Moreover, excessive miR-130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. Suppression of miR-130b enhanced drug cytotoxicity and reduced proliferation of A549/CR cells both internally and externally. Particularly, miR-130b mediated Wnt/ß-catenin signalling pathway activities, chemoresistance and proliferation in LC cell, which was partially blocked following knockdown of PTEN. These findings suggest that miR-130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/ß-catenin pathway. The rising level of miR-130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. Moreover, excessive miR-130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. These findings suggest that miR-130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/ß-catenin pathway.

Clinical significance of the monocyte-to-lymphocyte ratio in peripheral blood of patients with pulmonary sarcomatoid carcinoma / 中国肿瘤生物治疗杂志

@# Objective: To explore the relationship between monocyte-to-lymphocyte ratio (MLR) in peripheral blood of patients with pulmonary sarcomatoid carcinoma (PSC) and their clinicopathological features and prognosis, and to investigate its clinical significance. Methods: A retrospective analysis was carried out to analyze the complete case data of 80 patients with PSC from October 2010 to April 2017 in Tianjin Cancer Hospital (monocyte and lymphocyte counts of peripheral blood, clinicopathological features, and survival follow-up). The receiver operating curve (ROC) was used to determine the best cut-off value of MLR for the prediction of overall survival time (OS). The patients were divided into high MLR group and low MLR group. Kaplan-Meier method was used to calculate OS and draw survival curves. The Log-Rank test was used to compare the difference in OS between the two groups. The variables with statistical significance in univariate analysis were included into the COX risk regression model to verify and calculate thehazard ratio (HR)and 95% confidence interval (95%CI). Results: The absolute median values of monocytes and lymphocytes were 0.63×109/L and 1.84×109/L, respectively. The best cut-off value of MLR is 0.44. Univariate analysis shows that MLR≥0.44 (P<0.01), no radical surgery (P<0.01), clinical stage Ⅲ+Ⅳ (P<0.01), tumor maximal diameter > 3 cm (P<0.01), and LDH>247 U /L (P<0.01) are the poor prognostic factors affecting overall survival. Multivariate analysis shows that MLR≥0.44（HR=3.554; 95%CI=1.671-6.125; P<0.01), and clinical stage Ⅲ+Ⅳ（HR=3.275; 95%CI=2.047-9.399; P<0.01) are the independent risk factors for the overall survival of PSC, and radical surgery is an independent protective factor affecting the overall survival of PSC（HR=0.360; 95%CI=0.195-0.848; P<0.01). Conclusion: High MLR is an independent risk factor for poor prognosis in patients with PSC.

Is MPP a good prognostic factor in stage III lung adenocarcinoma with EGFR exon 19 mutation?

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein encoded by a gene located in the short arm of chromosome 7. This study aimed to investigate the clinicopathologic characteristics of classic EGFR exon mutation in Chinese patients with TMN stage III lung adenocarcinoma who received radical surgery. A total of 1,801 lung adenocarcinomas were analyzed for mutations in EGFR; 35% exhibited mutation of classic EGFR exons. Clinical and pathologic characteristics of patients with EGFR exon 19 mutation were compared with those who harbored EGFR exon 21 mutation. Patients with EGFR exon 19 mutation had a higher overall survival (OS, p=0.023) than those harboring EGFR exon 21 mutation. Our results demonstrated that patients with a micropapillary pattern (MPP) pathologic type in EGFR exon 19 mutation had a higher OS (p=0.022), and patients with exon 19 mutation were more sensitive to EGFR-tyrosine kinase inhibitors (p=0.032). The results of the current study can be used in decision-making regarding the treatment of patients with classic EGFR exon mutations.

Platelet-lymphocyte ratio is an independent prognostic factor in patients with ALK-positive non-small-cell lung cancer.

AIM: As the prognostic value of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) is unclear in patients with ALK-positive non-small-cell lung cancer (NSCLC), this study assessed the importance of these factors was in this patient subset. PATIENTS & METHODS: In 173 patients with primary ALK-positive NSCLC at pathological stages I-IV, neutrophil, platelet, lymphocyte, D-dimer and eosinophil levels were recorded before starting treatment. RESULTS: The patients' median NLR and PLR values were 2.10 and 127.69, respectively. Univariate analyses showed that NLR and PLR values, the D-dimer level and the eosinophil count were all associated with survival. Although multivariate analysis showed PLR to be an independent prognostic factor for overall survival (p = 0.018), NLR was not. CONCLUSION: PLR is an independent prognostic factor in ALK-positive NSCLC.