Clinicopathological and molecular characterization of resected lung adenocarcinoma: Correlations with histopathological grading systems in Chinese patients.

PURPOSE: Driver mutations inform lung adenocarcinoma (LUAD) targeted therapy. Association of histopathological attributes and molecular profiles facilitates clinically viable testing platforms. We assessed correlations between LUAD clinicopathological features, mutational landscapes, and two grading systems among Chinese cases. METHODS: 79 Chinese LUAD patients undergoing resection were subjected to targeted sequencing. 68 were invasive nonmucinous adenocarcinoma (INMA), graded via: predominant histologic pattern-based grading system (P-GS) or novel IASLC grading system (I-GS). Driver mutation distributions were appraised and correlated with clinical and pathological data. RESULTS: Compared to INMA, non-INMA exhibited smaller, well-differentiated tumors with higher mucin content. INMA grade correlated with size, lymph invasion (P-GS), and driver/EGFR mutations. Mutational spectra varied markedly between grades, with EGFR p.L858R and exon 19 deletion mutations predominating in lower grades; while high-grade P-GS tumors often harbored EGFR copy number variants and complex alterations alongside wild-type cases. I-GS upgrade of P-GS grade 2 to grade 3 was underpinned by ≥20 % high-grade regions bearing p.L858R or ALK fusions. Both systems defined tumors of distinctive phenotypic attributes and molecular genotypes. CONCLUSIONS: INMA represent larger, mucin-poor, molecularly heterogeneous LUAD with divergent grade-specific mutation profiles. Stronger predictor of clinicopathological attributes and driver mutations, P-GS stratification offers greater accuracy for molecular testing. A small panel encompassing EGFR and ALK captures the majority of P-GS grade 1/2 mutations whereas expanded panels are optimal for grade 3.

Excellent response of lung adenocarcinoma harboring a rare SLC8A1 downstream intergenic region ALK fusion to ceritinib treatment: A case report.

RATIONALE: Anaplastic lymphoma kinase (ALK) gene fusion, an important driver gene alteration leading to the development of lung cancer, occurs in 5% of nonsmall cell lung cancer (NSCLC) cases in China. In addition to echinoderm microtubule-associated protein-like 4 (EML4)-ALK, which is the most common type of ALK fusion, various fusion partner genes have been identified in recent years. However, ALK intergenic breakpoint fusions confound fusion detection and targeted treatment. PATIENT CONCERNS: A 40-year-old woman presented to our hospital with a 2-month history of a cough. DIAGNOSIS: Based on the right hilar lymph node biopsy and positron emission tomography computed tomography (PET-CT) examination, the patient was diagnosed with "stage IV lung adenocarcinoma" showing metastases in the mediastina, right hilar lymph nodes, and C7 vertebral body. A rare solute carrier family 8 member A1 (SLC8A1) downstream intergenic region ALK fusion was identified in biopsy specimens using next-generation sequencing (NGS). INTERVENTIONS: The patient received first-line molecular-targeted therapy (ceritinib). OUTCOMES: After nearly 9 months, the best evaluation of partial remission (PR) was obtained. LESSONS: This is the first clinical evidence of advanced NSCLC due to a rare SLC8A1 downstream intergenic region ALK fusion that has been effectively treated with ceritinib. Whether this finding represents an inherent property of this fusion protein or its unique clinicopathological characteristics in patients carrying this fusion protein remains to be investigated. Moreover, the patient's durable response to ceritinib and future resistance mechanisms require further follow-up.

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy.

Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo. PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro. Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.

Lung Adenocarcinoma Cells Promote Self-Migration and Self-Invasion by Activating Neutrophils to Upregulate Notch3 Expression of Cancer Cells.

Background: Invasion and migration of cancer cells play a key role in lung cancer progression and metastasis. Tumor-associated neutrophils (TANs) are related to poor prognosis in many types of cancer. However, the role of TANs in lung cancer is controversial. In this study, we investigated the effect of TANs on the invasion and migration of lung adenocarcinoma. Methods: Immunohistochemistry was performed to detect the density of infiltrating TANs and the expression of Notch3 in 100 lung adenocarcinoma tissues. Flow cytometry was used to observe the viability of neutrophils, which were isolated from healthy peripheral blood and then exposed to the supernatant of cultured lung adenocarcinoma cell lines. After treating with tumor-associated neutrophils culture supernatant, NeuCS (supernatant of cultured neutrophils), tumor cells culture supernatant, Medium (serum-free medium), respectively, the migration and invasion of the lung cancer cells before and after transfected by si-Notch3 were detected by transwell assay and wound healing assay. Kaplan-Meier plotter (http://kmplot.com/analysis/index.php?p) was used to analyze the prognostic role of the density of TANs on lung adenocarcinoma and TIMER ((http://cistrome.dfci.harvard.edu/TIMER/) was used to detect the expression of Notch3 on lung adenocarcinoma. Results: The infiltration of TANs was observed in the parenchyma and stroma of the lung adenocarcinoma, the density of TANs was positively related to the TNM stage and negatively related to the differentiation and prognosis. Notch3 expression of cancer cells was negatively related to the tumor differentiation and prognosis. Compared to quiescent neutrophils, the viability of TCCS-activated neutrophils was enhanced. Both migration and invasion of A549 and PC9 cells were significantly promoted by TANs, while after knocking down Notch3, the migration and invasion of the cancer cells were not affected by TANs. Bioinformatics analysis showed that the density of TANs and the expression of Notch3 were related to the poor prognosis. Conclusion: The results indicated that lung adenocarcinoma cells promote self-invasion and self-migration by activating neutrophils to upregulate the Notch3 expression of cancer cells. The density of infiltrating TANs may be a novel marker for the poor prognosis of lung adenocarcinoma. Targeting TANs might be a potential therapeutic strategy for lung cancer treatment.

Effects of reduced platelet count on the prognosis for patients with non-small cell lung cancer treated with EGFR-TKI: a retrospective study.

BACKGROUND: Progressive lung cancer is associated with abnormal coagulation. Platelets play a vital part in evading immune surveillance and angiogenesis in the case of tumor metastasis. The study aimed to analyze the predictive and prognostic effects of platelet count on non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). METHODS: This study retrospectively analyzed the prognostic effects of platelets on 52 NSCLC patients with epidermal growth factor receptor (EGFR) mutant following EGFR-TKI treatment. Related data, together with the progression-free survival (PFS) and overall survival (OS) were collected before and after 2 cycles of treatments (60 days). RESULTS: The anti-EGFR treatment markedly reduced the platelet count in 33 (63.5%) patients after 2 cycles of treatment. Multivariate Cox analysis revealed that, the decreased platelet count was closely correlated with the longer OS (HR = 0.293; 95%CI: 0.107-0.799; p = 0.017). Besides, the median OS was 326 days in the decreased platelet count group and 241 days in the increased platelet count group (HR = 0.311; 95%CI: 0.118-0.818; P = 0.018), as obtained from the independent baseline platelet levels and other clinical features. CONCLUSIONS: The platelet count may predict the prognosis for EGFR-TKI treatment without additional costs. Besides, changes in platelet count may serve as a meaningful parameter to establish the prognostic model for NSCLC patients receiving anti-EGFR targeted therapy.

Surgery on primary tumor shows survival benefit in selected stage IV colon cancer patients: A real-world study based on SEER database.

Objectives: Most patients with stage IV colon cancer did not have the opportunity for curative surgery, only selected patients could benefit from surgery. This study aimed to determine whether surgery on the primary tumor (SPT) should be performed in patients with stage IV colon cancer and how to select patients for SPT. Methods: This study included 48,933 patients with stage IV colon cancer who were identified in the Surveillance, Epidemiology and End Results (SEER) database between 1998 and 2015. Propensity score matching (PSM) analysis was adopted to balance baseline differences between SPT and non-surgery groups. Kaplan-Meier (K-M) curves were utilized to compare the overall survival (OS). Prognostic nomograms were generated to predict survival based on pre- and post-operative risk factors. Patients were divided into low, middle, and high mortality risk subsets for OS by X-tile analyses based on scores derived from above nomograms. Results: Patients with SPT had a significantly longer OS than those without surgery, regardless of the metastatic sites and diagnostic years. Nomograms, according to the pre- and post-operative risk factors, showed moderate discrimination (all C-indexes above 0.7). Based on X-tile analyses, low mortality risk subset (post-operative score ≤ 22.3, preoperative score ≤ 9.7) recommended for SPT, and high mortality risk was not. Conclusions: SPT led to prolonged survival in stage IV colon cancer. Our nomograms would help to select suitable patients for SPT.

Cardiovascular and other competing causes of death among patients with cancer from 2006 to 2015: An Australian population-based study.

BACKGROUND: With improved cancer survivorship, cardiovascular disease (CVD) and other noncancer events compete with cancer as the underlying cause of death, but the risks of mortality in competing-risk settings have not been well characterized. METHODS: The authors identified 21,637 individuals who had a first cancer registered between 2006 and 2013, with follow-up to 2015, in the Australian population-based Tasmanian Cancer Registry. The cumulative incidence of deaths from specific competing events was assessed in competing-risk analyses. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) for deaths from noncancer causes were calculated for comparison with the general population. RESULTS: Overall, 8844 deaths were observed, with 1946 (22%) from competing events. The cumulative incidence of deaths from CVD increased significantly with age at first cancer diagnosis and exceeded other competing events at age ≥65 years. The risk of death from CVD was more common than expected in the first year of follow-up (SMR, 1.44 [95% confidence interval, 1.26-1.64]; AER, 36.8 per 10,000 person-years). The SMR and AER for CVD deaths varied by first cancer site, indicating increased risks after a first diagnosis of lung cancer, hematologic malignancy, and urinary tract cancer. For other noncancer events, the SMRs increased significantly for deaths from infectious disease and respiratory disease and were highest in the first year of follow-up. CONCLUSIONS: CVD was the leading cause of competing mortality among Tasmanian patients with cancer who were diagnosed from 2006 to 2013. The higher than expected occurrence of death from CVD and other noncancer events during the first year after a cancer diagnosis highlights the importance of early preventive interventions.

Specific inhibitor of Notch­3 enhances the sensitivity of NSCLC cells to gemcitabine.

Notch­3 is a receptor of the Notch signaling pathway and plays an important role in regulating self­renewal, differentiation and apoptosis in cancer cells. Overexpression of Notch­3 has been proved to be associated with resistance to gemcitabine (GEM) and poor patient prognosis for various malignant tumors. In the present study, two non­small cell lung cancer (NSCLC) cell lines, H1299 and A549, were induced with GEM for two months and then were treated with various concentrations of a Notch signaling blocker, N­[N­(3,5­difluorophenacetyl)­L­alanyl]­S­phenylglycine t­butyl ester (DAPT), with the goal of reducing expression of Notch intracellular domain 3 (NICD3). Both cell lines were subsequently treated with either DAPT or DAPT combined with GEM and then viability, apoptosis, colony formation and cell count assays were performed. DAPT treatment effectively downregulated the expression of NICD3 in both cell lines. DAPT combined with GEM also significantly reduced the percentage of viable cells in both cell lines, while increasing the percentage of apoptotic cells, compared with GEM alone. In the clonogenicity assays, the combination of DAPT and GEM led to a decrease in clone numbers and significantly greater inhibition of the H1299 and A549 cells compared to treatment with DAPT or GEM alone. Meanwhile, levels of the apoptosis­related proteins, Bcl­2 and Bax, were found to be affected by the various treatments. Thus Notch­3 appears to be a promising target for gene therapy and DAPT is able to mediate a strong antitumor effect in NSCLC cells that overexpress Notch­3. Further studies of a combined treatment regimen with DAPT and GEM are warranted and may provide greater efficacy and safety in the treatment of NSCLC patients.

Temporal trends in competing mortality from second and subsequent primary cancers, 1980-2014: An Australian population-based study.

BACKGROUND: Subsequent primary cancers (SPCs) compete with first cancers and non-cancer events as the primary cause of death among cancer patients. We aimed to assess temporal trends in SPC mortality since 1980 among adult-onset cancer patients in competing risk models. METHODS: Patients registered with a first cancer in the population-based Tasmanian Cancer Registry, Australia, between 1980-2009 were followed up to December 2014. Cumulative incidence function (CIF) was used to estimate the cumulative incidence of cause-specific deaths in the presence of competing risks. The hazard ratios of SPC-specific deaths were assessed in two regression models: subdistribution hazard ratios from competing risk models (SHRs) and hazard ratios from Cox models (CHRs). RESULTS: Overall, 5339 (9.3%) of 57,288 patients developed SPCs and 2494 died from SPCs during the follow-up. While the cumulative incidence of first cancer deaths at 5, 10, 15 and 20-years gradually decreased over periods of first cancer diagnosis, the cumulative incidence of SPC deaths did not. The SHRs for SPC-specific deaths increased from the reference period 1980-1984 to a peak for first cancers diagnosed in 1995-1999 (SHR = 1.18, 95%CI 1.03-1.35), before a decrease in 2005-2009 (SHR = 0.82, 95%CI 0.70-0.95) in competing risk models. However, this pattern was not consistent in CHRs. For individuals with specific first cancers, those with a first prostate cancer in 1995-1999 ha d the greatest SPC mortality risk (SHR = 2.08, 95%CI 1.29-3.36). CONCLUSION: Competing risk models, but not Cox models, demonstrated temporal increases in SPC-specific mortality. Greater detection of non-fatal first prostate cancers appears to have contributed to this trend.

Temporal trends in the risk of second primary cancers among survivors of adult-onset cancers, 1980 through 2013: An Australian population-based study.

BACKGROUND: The authors' systematic review indicated an increasing trend in the risk of second primary cancers (SPCs) from the 1980s to 2000 when considering studies from the United States and Australia. It is uncertain whether this trend has continued to increase since 2000. METHODS: The current study was a population-based study of 51,802 individuals with adult-onset cancers identified in the Tasmanian Cancer Registry. Patients with a first cancer diagnosis made between 1980 and 2009 were followed up to December 2013. SPC risks were quantified using standardized incidence ratios (SIRs) and absolute excess risks (AERs). Trends in SPC risk were assessed using multivariable Poisson models. RESULTS: With a median follow-up of 4.8 years (mean, 6.9 years), a total of 5339 SPCs were observed. The SIRs for any SPC increased from 0.98 (95% confidence interval, 0.90-1.07) after a first cancer diagnosis in 1980 through 1984 to 1.12 (95% confidence interval, 1.05-1.20) in 2005 through 2009. In multivariable Poisson models accounting for patient sex, age at the time of the first cancer diagnosis, follow-up interval, and first cancer type, the trend in SIRs increased significantly from 1980 through 2009 for all SPCs (P for trend <.001) and for specific SPCs of the head and neck, lung, digestive tract, and prostate (all P for trend <.05). From 2000 onward, the AER for specific SPCs after specific first cancers was highest for prostate cancer after first cancers of the urinary tract (AER, 54.3 per 10,000 person-years). CONCLUSIONS: In Tasmania, the risk of SPCs among survivors of adult-onset cancers has increased with periods of first cancer diagnosis from 1980 through 2009. Increased cancer screening and improved medical imaging may have contributed to the greater risk in recent years. Cancer 2018;124:1808-18. © 2018 American Cancer Society.

Temporal trends in the risk of developing multiple primary cancers: a systematic review.

BACKGROUND: Cancer survivors are at risk of developing second and subsequent primary cancers, referred to as multiple primary cancers (MPCs). It is not clear whether the risk of MPCs has increased over recent decades, but increasing use of radiological imaging and potentially harmful effects of certain cancer treatments raise this possibility. A systematic review was undertaken to assess whether there has been a temporal change in the risk of developing MPCs. METHODS: A systematic search to identify population-based studies of MPCs was performed in Medline/PubMed and Embase databases from inception to August 2016. Included studies were those reporting risk of MPCs for all sites combined following a first cancer at any site or a specific site, using standard incidence ratios (SIRs) or equivalent, and with analysis stratified by calendar years. RESULTS: We identified 28 articles eligible for inclusion, comprising 26 population-based studies and two monographs. MPC incidence was reported in nearly 6.5 million cancer survivors. For all first cancer sites combined, a higher rate of MPCs was reported in more recent than earlier calendar periods in four of the six relevant studies. The SIRs ranged from 1.14 for a first cancer diagnosis in the early 1980s to 1.21-1.46 in the late 1990s in the USA and Australia. Two studies from Italy and France showed no significant difference in SIRs across time periods 1978-2010 and 1989-2004. The remaining 22 studies reported various temporal trends in the risk of developing MPCs after a first cancer at a specific site, but most showed little change. CONCLUSION: Overall, the risk of developing MPCs appears to have increased since the 1980s when considering studies of all primary cancer sites combined from the USA and Australia but not from Europe. With the introduction of more routine nuclear medical imaging over the last 15 years, more studies are needed to confirm recent trends of MPC risk in adult cancer survivors.

Notch signaling molecules as prognostic biomarkers for non-small cell lung cancer.

Notch family proteins have been reported to be associated with the initiation and development of various types of tumors. The present study used a prospective design to investigate the role of Notch proteins as novel biomarkers that are capable of predicting the survival outcome for patients with non-small cell lung cancer (NSCLC). The protein expression of Notch 1, Notch 3 and their ligands, Jagged 1 and Delta-like 4, was examined using immunohistochemistry in NSCLC tissues and adjacent non-cancerous lung tissues from 101 patients who underwent surgical treatment. The expression was also correlated with clinicopathological parameters and overall survival (OS). High Notch 1 protein expression was observed in 55.4% (56/101) of NSCLC samples and high Notch 3 expression was observed in 53.5% (54/101). The nuclear expression of Notch 3 was significantly associated with the lymph node status (P=0.0026) and tumor-node-metastasis (TNM) stage (P<0.0001), while the coexpression of Notch 1 plus Notch 3 was associated with lymph node status (P=0.0056), TNM stage (P=0.0001) and the histological grading (P=0.0359). In the survival analyses, the high expression of Notch 1 and Notch 3 exhibited an additive effect toward a poorer OS compared with a subtype with low coexpression for the two proteins (P<0.001), with high nuclear Notch 3 expression in the NSCLC patients maintaining independent prognostic significance for the outcome on multivariate analysis. These data further demonstrate a central role for Notch signaling in NSCLC and the significance of Notch 3 as a prognostic indicator of a poorer survival for patients with resected NSCLC.

Notch3 overexpression associates with poor prognosis in human non-small-cell lung cancer.

Notch3 receptor is one of the mammalian Notch family receptors (Notch1-4) which plays an important role in the regulation of cellular proliferation, differentiation, and apoptosis. Overexpression of Notch3 is associated with tumorigenesis. In order to assess the expression of Notch3 in Chinese non-small-cell lung cancer (NSCLC) patients and determine its association with prognosis, we designed a prospective study with five years of follow-up to evaluate Notch3 expression in NSCLC tissues and adjacent non-cancerous normal lung tissues from 131 patients undergoing surgical treatment by immunohistochemistry and western blot analysis. Notch3 had high expression in 67 of 131 cases of NSCLC (51.1 %), which was significantly higher than in adjacent noncancerous lung tissues. Moreover, Notch3 overexpression was significantly correlated with TNM stage (P = 5.41e-07 in squamous cell carcinoma, P = 5.338e-07 in adenocarcinoma) and lymph node metastasis (P = 0.00764 in squamous cell carcinoma, P = 0.01491 in adenocarcinoma). Kaplan-Meier survival analysis showed that the overall survival times in patients expressing Notch3 in NSCLC were shorter. Multivariate analysis further demonstrated that Notch3 was an independent prognostic factor for patients with NSCLC. Therefore, Notch3 might be a useful biomarker to predict the prognosis of patients with NSCLC.