Thromboembolic Events Associated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Pharmacovigilance Analysis of the US FDA Adverse Event Reporting System (FAERS) Database.

BACKGROUND AND OBJECTIVES: Although thromboembolic events (TEEs) have been reported with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), their association remains largely unknown. In this study, we aimed to provide a comprehensive review of TEEs associated with EGFR-TKIs. METHODS: We collected EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib) adverse reaction reports from 2015 Q1 to 2023 Q1 from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to identify thromboembolic adverse events associated with EGFR-TKIs by comparing them with the overall FAERS database according to the reporting odds ratio (ROR). Associated factors were explored using univariate logistic regression. RESULTS: We identified 1068 reports of TEEs associated with EGFR-TKIs (1.24% accounts for all TEEs). Affected patients were females (49.72%) and those older than 65 years (41.20%). The reported TEE case fatality was 30.24%. The median time to onset (TTO) of all cases was 39 days [interquartile range (IQR) 11-161], and the median TTO of fatalities [31 days (IQR 10-116)] was significantly shorter than that of non-fatal cases [46 days (IQR 12-186)]. CONCLUSION: This study yielded three key findings. Firstly, EGFR-TKIs seem to exhibit prothrombotic effects, elevating the risk of TEEs. Secondly, the clinical outcomes of TEEs associated with EGFR-TKIs were poor. Thirdly, most TEEs occurred within the initial 3 months, and fatal cases occurred earlier than non-fatal cases.

A novel image deep learning-based sub-centimeter pulmonary nodule management algorithm to expedite resection of the malignant and avoid over-diagnosis of the benign.

OBJECTIVES: With the popularization of chest computed tomography (CT) screening, there are more sub-centimeter (≤ 1 cm) pulmonary nodules (SCPNs) requiring further diagnostic workup. This area represents an important opportunity to optimize the SCPN management algorithm avoiding "one-size fits all" approach. One critical problem is how to learn the discriminative multi-view characteristics and the unique context of each SCPN. METHODS: Here, we propose a multi-view coupled self-attention module (MVCS) to capture the global spatial context of the CT image through modeling the association order of space and dimension. Compared with existing self-attention methods, MVCS uses less memory consumption and computational complexity, unearths dimension correlations that previous methods have not found, and is easy to integrate with other frameworks. RESULTS: In total, a public dataset LUNA16 from LIDC-IDRI, 1319 SCPNs from 1069 patients presenting to a major referral center, and 160 SCPNs from 137 patients from three other major centers were analyzed to pre-train, train, and validate the model. Experimental results showed that performance outperforms the state-of-the-art models in terms of accuracy and stability and is comparable to that of human experts in classifying precancerous lesions and invasive adenocarcinoma. We also provide a fusion MVCS network (MVCSN) by combining the CT image with the clinical characteristics and radiographic features of patients. CONCLUSION: This tool may ultimately aid in expediting resection of the malignant SCPNs and avoid over-diagnosis of the benign ones, resulting in improved management outcomes. CLINICAL RELEVANCE STATEMENT: In the diagnosis of sub-centimeter lung adenocarcinoma, fusion MVCSN can help doctors improve work efficiency and guide their treatment decisions to a certain extent. KEY POINTS: • Advances in computed tomography (CT) not only increase the number of nodules detected, but also the nodules that are identified are smaller, such as sub-centimeter pulmonary nodules (SCPNs). • We propose a multi-view coupled self-attention module (MVCS), which could model spatial and dimensional correlations sequentially for learning global spatial contexts, which is better than other attention mechanisms. • MVCS uses fewer huge memory consumption and computational complexity than the existing self-attention methods when dealing with 3D medical image data. Additionally, it reaches promising accuracy for SCPNs' malignancy evaluation and has lower training cost than other models.

Lack of incremental value of three-dimensional measurement in assessing invasiveness for lung cancer.

OBJECTIVES: The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS: A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS: A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P = 0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P < 0.000 vs P < 0.000) and overall survival (P = 0.003 vs P = 0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P = 0.189). CONCLUSIONS: Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional.

Dynamic monitoring of serum tumor markers as prognostic factors in patients with advanced non-small-cell lung cancer treated with first-line immunotherapy: a multicenter retrospective study.

Background: To date, no specific studies have reported the use of dynamic serum tumor markers (STMs) as prognostic factors in patients with advanced non-small-cell lung cancer (NSCLC) who receive first-line immunotherapy. Therefore, it is unclear whether STMs can be used as a prognostic factor for first-line immunotherapy in advanced NSCLC. Objectives: To elucidate the role of STMs in monitoring immunotherapy response in advanced NSCLC. Patients were treated with first-line programmed cell death-1/programmed cell death ligand-1 inhibitors at four Chinese centers. Design: This was a multicenter retrospective study. Methods: Blood samples were collected at baseline and after 6-8 weeks of treatment. Computed tomography scans were used to evaluate treatment efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Post-treatment drops in STMs [Serum carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125)] were decreased ⩾20% (Group C) over baseline was used as cutoff level for defining a marker response. If STMs were increased by ⩾20% after treatment, the therapeutic effect was limited (Group A). Patients with STM changes between a 20% increase or decrease were enrolled in Group B. In univariate and multivariate stepwise Cox regression analyses, STMs and RECIST responses were analyzed for their impact on progression-free survival (PFS) and overall survival (OS). Results: The analysis included 716 patients. By multivariate analysis, CEA, NSE, CYFRA21-1, CA19-9, and CA125 (Group A versus Group B and Group A versus Group C) were associated with significant differences in PFS. Similar results were observed in the OS analysis. Similar results were observed in the adenocarcinoma subgroup analyses. In squamous cell carcinoma subgroup analyses, there was no statistical difference in PFS (p = 0.147) or OS (p = 0.068) between Group A and Group B for CA125. Conclusion: The increase and decrease in serum levels of STMs might be reliable prognostic factors for immunotherapy efficacy in NSCLC patients.

Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

PURPOSE: This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. PATIENTS AND METHODS: Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. RESULTS: A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1-49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). CONCLUSIONS: PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation.

Comparison of first-line immunotherapy efficacy between advanced lung squamous cell carcinoma and pulmonary lymphoepithelioma-like carcinoma: A propensity score matching multicenter study.

Background: Compared with other lung squamous cell carcinomas (LUSC), pulmonary lymphoepithelioma-like carcinoma (pLELC) is closely associated with Epstein-Barr virus (EBV) infections with a unique molecular profile and immune microenvironment. This study was thus established to compare the treatment response and effectiveness of immunotherapy between pLELC and LUSC. Material and Methods: We enrolled 31 patients with pLELC and 116 with LUSC receiving first-line immunotherapy at three centers in China and compared the treatment response and effectiveness of immunotherapy. Propensity score matching (PSM) was used to balance the differences in baseline data between the two groups. Results: Before PSM, progression-free survival and overall survival were longer in the pLELC group than in the LUSC group (progression-free survival: hazard ratio (HR), 1.67, 95% CI: 1.05-2.63, P = 0.028; overall survival: HR, 1.90, 95% CI: 1.06-3.40, P = 0.028). This remained unchanged after PSM (progression-free survival: HR, 1.79, 95% CI: 1.02-3.15, P = 0.044; overall survival: HR, 2.20; 95% CI: 1.10-4.37, P = 0.022). Conclusion: pLELC showed a clinically meaningful survival benefit compared with traditional LUSC following immunotherapy. Subsequent studies should consider the role of the EBV in the tumor immune microenvironment of pLELC.

Baseline serum tumor markers predict the survival of patients with advanced non-small cell lung cancer receiving first-line immunotherapy: a multicenter retrospective study.

BACKGROUND: This study aimed to investigate the association between baseline serum tumor markers (STMs) (carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], cytokeratin-19 fragment [CYFRA21-1], carbohydrate antigen 19-9 [CA19-9], and carbohydrate antigen 125 [CA125]) and the efficacy of first-line immunotherapy in patients with advanced non-small cell lung cancer. METHODS: This multicenter retrospective study evaluated patients who received first-line immunotherapy between July 2017 and July 2022. The endpoints were progression-free survival (PFS) and overall survival (OS), as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. We divided the patients into three groups based on STM levels: Group A ≥ threefold upper limit of normal, threefold upper limit of normal > Group B > upper limit of normal, and Group C ≤ upper limit of normal. RESULTS: In total, 716 patients were included in this study. In Cox proportional hazards analyses, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung adenocarcinoma (LUAD). Except for CA19-9 level, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung squamous carcinoma (LUSC). Except for CEA and CA19-9 levels, the levels in Group A were independently associated with inferior PFS and OS in patients with LUAD and LUSC. CONCLUSIONS: Serum CEA, NSE, CYFRA21-1, and CA125 levels can predict PFS and OS in patients with LUAD and LUSC, and serum CA19-9 levels can predict PFS and OS in patients with LUAD. The higher the serum NSE, CYFRA21-1, and CA125 levels, the worse the PFS and OS in patients with LUAD and LUSC. In addition, the higher the serum CA19-9 level, the worse the OS in patients with LUAD.

Sublobectomy for stage IA1-2 invasive lung adenocarcinoma with consolidation tumor ratio ≤ 0.25.

BACKGROUND: Sublobectomy for early-stage non-small cell lung cancer (NSCLC) remains a matter of debate. This study aimed to discuss the feasibility of sublobectomy in patients with pathological-stage IA1-2 confirmed as pathologically invasive but radiologically noninvasive adenocarcinoma. METHODS: From 2011 to 2019, we screened clinical stage IA1-IA2 lung cancer patients who underwent surgery at the Guangdong Provincial People's Hospital (GDPH). Inclusion criteria were maximum tumor diameter of 2.0 cm or less, consolidation tumor ratio (CTR) ≤ 0.25, and pathologically confirmed invasive adenocarcinoma. Sublobectomy (segmentectomy and wedge resection) and lobectomy groups were created, and propensity scores were computed. The primary endpoints were lung cancer-specific overall survival (LCSS) and LCS- relapse-free survival (LCS-RFS) after adjusting propensity scores. RESULTS: A total of 1731 patients were screened, and 100 patients were enrolled. The lobectomy group had 51 patients and the limited resection group had 49. No cases relapsed, and two patients died from nontumor causes. For the entire cohort, the 5-year LCSS and 5-year LCS-RFS were 100% in the lobectomy and limited resection groups. When propensity scores matched, there were no differences in LCSS and LCS-RFS between the two groups (LCSS:100%, LCS-RFS 100% in lobectomy and limited resection, respectively). DISCUSSION: Sublobectomy may be curative for pathologically invasive but radiologically noninvasive adenocarcinoma at pathological stage IA1-2.

Comparison of Immunotherapy, Chemotherapy, and Chemoimmunotherapy in Advanced Pulmonary Lymphoepithelioma-Like Carcinoma： A Retrospective Study.

Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare subtype of lung cancer that is associated with the Epstein-Barr virus in Asia. Due to the lack of prospective studies, the best first-line treatment and survival outcomes remain unclear. Herein, This study investigated the efficacy and safety of different treatment regimens for advanced pLELC. This retrospective study included 68 patients with advanced pLELC from two centers in China. Patients were divided into three groups according to different first-line treatments: chemotherapy (n=49, 72.1%), immunotherapy (n=7, 10.3%), and chemoimmunotherapy (n=12,17.6%). The primary endpoint of this study was the 2-year progression-free survival (PFS) of each group. The results show that the median PFS was 6.9 months (range, 2.3-not estimable) in the chemotherapy group, 11.0 months (range, 2-not estimable) in the immunotherapy group, and 11.8 months (range, 6-not estimable) in the chemoimmunotherapy group. There was a significant difference in 2-year PFS between the chemoimmunotherapy group and the chemotherapy group (hazard ratio, 0.38, 95% confidence interval: 0.18-0.78, log-rank P=0.007). The most frequent grade 3-4 adverse event in the chemotherapy and chemoimmunotherapy groups was myelosuppression (10/49 [22.4%] and 4/12 [33.3%], respectively). The most frequent grade 3-4 adverse events in the immunotherapy group were diarrhea (1/7, 14.8%) and hepatotoxicity (1/7, 14.8%). Chemoimmunotherapy had the highest 2-year PFS as a first-line treatment for advanced pLELC compared to chemotherapy and immunotherapy. This study suggests that chemoimmunotherapy may be the best first-line treatment for patients with advanced pLELC.

Survival rates of patients with tumors originating in different segments of the left upper lung in stage I to III non-small cell lung cancer.

BACKGROUND: The aim of this research was to evaluate the effect of spatial location of tumors on the prognosis of patients with left upper lung non-small cell lung cancer (NSCLC), with a focus on the S1+2+3 and lingual segment. METHODS: A total of 486 patients who underwent lobectomy and systematic lymph node dissection were collected retrospectively in this study (354 S1+2+3 and 132 lingual segment patients). Factors impacting survival were assessed via univariate analyses, multivariate analyses, and log-rank tests. RESULTS: Compared with tumor location in S1+2+3, lingual segment tumor location of stage II to III left upper lung NSCLC patients was significantly associated with a better 5-year disease-free survival (DFS) (P=0.041). Multivariate analysis results showed that tumor location in the lingual segment was a good independent prognostic factor of stage II to III left upper lung NSCLC patients [hazard ratio (HR) =0.602, 95% confidence interval (CI): 0.149-0.865, P=0.006). However, in stage I left upper lung NSCLC, tumor location (HR =1.069, 95% CI: 0.571-2.000, P=0.835) was not an independent prognostic factor, and only T2 (HR =2.422, 95% CI: 1.271-4.620, P=0.007) was an independent worse prognosis factor. CONCLUSIONS: Tumor location in the lingual segment of left upper lung stage II to stage III NSCLC is a good independent prognostic factor compared with S1+2+3. Nevertheless, tumor location does not impact the prognosis of patients with stage I NSCLC in the left upper lung.

A New Prognostic Index Combines the Metabolic Response and RECIST 1.1 to Evaluate the Therapeutic Response in Patients With Non-Small Cell Lung Cancer.

Aim: Response Evaluation Criteria in Solid Tumors (RECIST) is occasionally insufficient for evaluation. We proposed a new prognostic index (NPI) that combines the standardized uptake value (SUV), metabolic tumor volume (MTV), and RECIST. Methods: In total, 116 patients with lung cancer who underwent consecutive positron emission tomography-computed tomography prior to and after the initial treatment were included. We formulated the NPI by estimating the hazard ratios of overall survival for ΔMTV, ΔSUVmax, and ΔD (tumor size based on RECIST). Progression-free survival (PFS) and overall survival (OS) were compared between RECIST and the NPI. Results: ROC curve analysis identified two cutoff values based on the NPI (≤ -49.3% and ≥43.4%) to discriminate partial remission (NPR), stable disease (NSD) and progressive disease (NPD). Based on RECIST, survival analysis did not discriminate significantly on either PFS or OS between the PR, SD, and PD groups. However, according to the NPI, PFS and OS differed significantly between the NPR, NSD, and NPD groups (training set: PFS, p = 0.048; OS, p = 0.026; validation set: PFS, p = 0.004; OS, p = 0.023). Moreover, therapeutic response based on NPI was independent prognostic factor for both PFS [NPR as reference, NSD: hazard ratio (HR) 2.04; 95% confidence interval (95% CI) 1.35-3.08; p = 0.001; NPD: HR 6.87; 95% CI 3.03-15.57; p < 0.001] and OS (NPR as reference, NSD: HR 1.64; 95% CI 1.05-2.57; p = 0.031; NPD: HR 3.56; 95% CI 1.59-7.95; p = 0.002). Conclusion: The NPI showed superiority for evaluation of the therapeutic response and survival for patients with non-small cell lung cancer, overcoming the limitations of RECIST.

Risk of Gastrointestinal Events During Lapatinib Therapy: A Meta-Analysis From 12,402 Patients With Cancer.

Lapatinib, a tyrosine kinase inhibitor used as an anticancer therapeutic agent, has adverse events associated with treatment resulting in noncompliance and withdrawal from the therapy. Here, we performed meta-analysis of published clinical trials to determine relative risk (RR) and incidence of gastrointestinal events during lapatinib therapy in patients with cancer. A comprehensive literature search was performed and summary incidence, RR, and 95% confidence intervals (CI) were calculated using fixed-effects or random-effects models, depending on the heterogeneity of trials. Thirty-six trials with 12,402 patients were included; summary incidences of all-grade gastrointestinal events in patients with cancer were diarrhea 57.8%, nausea 30.8%, and vomiting 19.6%. Lapatinib combination with chemotherapy or any anti-HER2 mAbs were associated with significant risk of all-grade diarrhea [(RR 3.64, 95% CI, 2.96-4.49), (RR 2.89, 95% CI, 2.21-3.79), respectively] and high-grade diarrhea [(RR 11.25, 95% CI, 7.31-17.33), (RR 9.96, 95% CI, 7.23-13.72), respectively], and lapatinib combination with chemotherapy group showed a significantly increased risk of all-grade nausea (RR 1.54, 95% CI, 1.25-1.89). Lapatinib combination with chemotherapy or any anti-HER2 mAbs were associated with significant risk of all-grade vomiting [(RR 1.47, 95% CI, 1.12-1.93), (RR 1.30, 95% CI, 1.11-1.52), respectively]. Lapatinib combination with any anti-HER2 mAbs was associated with a significant risk of high-grade vomiting (RR 2.25, 95% CI, 1.41-3.61). This study revealed a significantly increased risk of diarrhea, nausea, and vomiting in patients with cancer receiving lapatinib, suggesting that appropriate clinical intervention and gastrointestianal protective agents should be emphasized.

Different Doses of Clazosentan for Aneurismal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials.

Clazosentan therapy has been found to be effective in reducing the incidence of vasospasm after aneurismal subarachnoid hemorrhage (aSAH). The objective of this meta-analysis was to determine whether different doses of clazosentan treatment significantly reduced the incidence of delayed ischemic neurological deficits (DINDs) and new cerebral infarction (NCI). We systematically searched PubMed, Embase, Cochrane library and Medline from inception until October, 2015. All randomized controlled trials related to the functions of clazosentan in aSAH were included. Analyses were performed following the method guideline of Cochrane Back Review Group. Four randomized placebo-controlled trials met eligibility criteria and enrolled a total of 2159 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk, 0.49 and 95% CI, 0.33-0.73) and NCI (relative risk, 0.42 and 95% CI, 0.25-0.71) in patients treated with a high dose of clazosentan (15 mg/h) after aSAH. In addition, a high dose of clazosentan (15 mg/h) had no more effect on the incidence of adverse events than that of a low dose (1-5 mg/h). The results of the present meta-analysis show that a high dose of clazosentan significantly reduced the incidence of the vasospasm-related DINDs and NCI. Further study is required to fully understand the potential usefulness of clazosentan in patients with aSAH.

Risk of Gastrointestinal Events During Vandetanib Therapy in Patients With Cancer: A Systematic Review and Meta-analysis of Clinical Trials.

Vandetanib, a tyrosine kinase inhibitor used as an anticancer therapeutic agent, has adverse events associated with treatment resulting in noncompliance and withdrawal from the therapy. Here, we performed meta-analysis of published clinical trials to determine relative risk (RR) and incidence of gastrointestinal events during vandetanib therapy in patients with cancer. A comprehensive literature search was performed and summary incidence, RR, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models, depending on the heterogeneity of trials. Twenty-two trials with 6382 patients were included summary incidences of all-grade gastrointestinal events in patients with cancer were anorexia 24% (95% CI, 20%-28%), constipation 17% (95% CI, 13%-20%), diarrhea 46% (95% CI, 40%-53%), nausea 29% (95% CI, 25%-33%), and vomiting 17% (95% CI, 14%-21%). Incidences of vandetanib-associated gastrointestinal events stratified by tumor histology were statistically insignificant. Vandetanib was associated with a significant risk of all-grade diarrhea (RR 1.75, 95% CI, 1.42-2.16) and high-grade diarrhea (RR 1.94, 95% CI, 1.43-2.64) and significantly decreased risk of all-grade constipation (RR 0.80, 95% CI, 0.71-0.91). Summary RR showed a significant risk of vandetanib-associated constipation (RR 0.82, 95% CI, 0.72-0.93) and diarrhea (all-grade: RR 1.68, 95% CI, 1.31-2.14 and high-grade: RR 1.57, 95% CI, 1.14-2.17) in patients with non-small-cell lung cancer. This study revealed a significantly increased risk of diarrhea and a reduced risk of constipation in patients with cancer receiving vandetanib, suggesting that appropriate and frequent clinical monitoring should be emphasized.

Risk of Hypertension With Sorafenib Use in Patients With Cancer: A Meta-Analysis From 20,494 Patients.

Sorafenib is a new multikinase inhibitor; the incidence of hypertension (HTN) with sorafenib has been reported to vary substantially among clinical trials. We searched multiple databases to investigate the risk of sorafenib-induced HTN in patients with cancer. A total of 93 trials involving 20,494 patients were selected for this meta-analysis. The relative risks (RRs) of all-grade and high-grade HTN associated with sorafenib were 3.06 (P < 0.001) and 3.33 (P < 0.001). There are no significantly RRs of all-grade, 0.81 (P = 0.047), and high-grade HTN, 0.64 (P = 0.075), in sorafenib monotherapy versus other multitargeted antiangiogenic tyrosine kinase inhibitors. The incidence of sorafenib-associated all-grade and high-grade HTN was 21.3% (P < 0.001) and 5.9% (P < 0.001), respectively. The patients with renal cell carcinoma (RCC) and thyroid cancer have high incidence (≥20%) of sorafenib-associated all-grade HTN and high incidence (≥5%) of sorafenib-associated high-grade HTN. The trials with median treatment duration ≥ 4, 5, and 7 months were 21.0% (P < 0.001), 25.4% (P < 0.001), and 27.6% (P < 0.001); progression-free survival ≥ 6, 9, and 12 months were 24.5% (P < 0.001), 26.8% (P < 0.001), and 32.8% (P < 0.001); and overall survival ≥ 12, 18, and 24 months were 18.5% (P < 0.001), 22.5% (P < 0.001), and 25.9% (P < 0.001), respectively. There is a significantly high risk of sorafenib-induced HTN. In comparison between sorafenib and other multitargeted antiangiogenic tyrosine kinase inhibitors, RRs had no significance. The patients with RCC and thyroid cancer have significantly higher incidence of HTN. With prolonged treatment duration, progression-free survival, and overall survival, the incidence of all-grade HTN may increase.

MicroRNA-212 functions as an epigenetic-silenced tumor suppressor involving in tumor metastasis and invasion of gastric cancer through down-regulating PXN expression.

Altered expression of paxillin (PXN) is closely linked to the pathogenesis progression, metastasis and prognosis of different malignancies including gastric cancer (GC). Epigenetic silencing of tumor-suppressive microRNAs (miRNAs) is a crucial component of the mechanism underlying activation of oncogenes in tumor. To screen for epigenetically silenced miRNAs which target PXN in GC, we performed bioinformatics algorithms and real-time PCR analysis, and identified miR-212 as the optimum candidate gene. A luciferase reporter gene assay validated that miR-212 directly targets the 3'UTR region of PXN. Importantly, miR-212 levels were inversely correlated with PXN expression in GC cell lines and clinical tumor tissues. The use of miR-212 minics decrease PXN mRNA and protein level in GC cell lines. Moreover, low expression of miR-212 and its promoter hypermethylation were causally related and were associated with aggressive tumor phenotype and adverse prognosis in GC. Restoring mir-212 expression by exogenous mirprecursor molecules transfection or reexpression of endogenous miR-212 treated by 5-aza-2'-deoxycytidine (5-aza) can exert similar effect that reduce GC cells invasion and metastasis abilities in vitro by interacting PXN gene. In addition, 5-aza-induced PXN reduction could be partically blocked by miR-212 inhibitor, resulting in a reversal of weankening cell migration and invasion ability of 5-aza. A rescue experiment and a loss-of-function experiment in vitro and vivo showed that PXN restoration rescues migration and invasion phenotype in miR-212 overexpressed GC cell lines and PXN knockdown blocks GC cells migration and invasion in the presence miR-212 inhibitors. Taken together, our results clearly show that overexpression of PXN induced by methylationsuppressed miR-212 promotes tumor metastasis and invasion, and regulation of miR-212 expression may be a novel therapeutic strategy for gastric cancer.

Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials : Risk of sorafenib-associated death.

BACKGROUND: Sorafenib is a relatively new multi-kinase inhibitor used to treat a wide range of cancers. As fatal adverse events from sorafenib therapy are rare, their investigation requires a meta-analysis. Aim of the review To provide a meta-analysis of sorafenib-associated fatal adverse events with the most expansive and current data. METHOD: We searched Medline, EMBASE, Web of Science and Cochrane Library databases. We also searched abstracts from a number of conferences. Twenty trials of sorafenib were found in 9434 cancer patients, tested against placebos and against other drugs. We calculated relative risks and incidences for sorafenib-associated mortality. RESULTS: Overall incidence of sorafenib-associated mortality was 3.3 %. Patients with renal cell carcinoma (RCC) and thyroid cancer had treatment-related mortality ≥5 %. Patients treated with sorafenib had a significantly greater risk of mortality than those in placebo/control groups, with an RR of 1.75. Subgroup analyses also showed significant differences in sorafenib versus placebo (RR 1.87, 95 % CI 1.23-2.86; I (2) = 0.0 %, P = 0.865); and sorafenib + platinum-based chemotherapy (RR 2.03, 95 % CI 1.15-3.59; I (2) = 0.0 %, P = 0.654). However, sorafenib had lower risk than other multi-targeted antiangiogenic tyrosine kinase inhibitors. Patients with RCC and non-small-cell lung carcinoma were significantly more vulnerable. CONCLUSION: Sorafenib presents a significant risk of fatal adverse events (FAEs) in patients with cancer, especially for RCC or non-small-cell lung carcinoma, and in patients treated with sorafenib + platinum-based chemotherapy. However, compared with other multi-targeted antiangiogenic tyrosine kinase inhibitors, sorafenib has a lower risk of FAEs.

The efficacy and safety of EGFR inhibitor monotherapy in non-small cell lung cancer: a systematic review.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but what it is still unclear is the efficacy of (EFGR-TKIs: gefitinib or erlotinib) monotherapy in previously treated non-small-cell lung cancer (NSCLC). In December 2013, we performed a search in the PubMed, EMBASE, Cochrane library databases and Web of Science for randomized trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through strict inclusion and exclusion criteria, fourteen trials (three front-line, two second-line, nine maintenance, n = 8970 patients) were eligible. EGFR-TKIs significantly increased overall survival (OS) [hazard ratio (HR) 0.88, 95%confidence interval (CI) 0.82-0.96, I (2) = 50.5%] and progression-free survival (PFS) (HR 0.71, 95% CI 0.63-0.81, I (2) = 81.2%] compared with placebo or best support care (BSC). Patients with clinical features such as never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced OS and PFS benefit. The main adverse reactions were diarrhea, rashes, anorexia and anemia, [odds ratio (OR) = 3.635, 95% confidence interval (CI) = (2.377 to 5.557)], [OR = 15.664, 95%CI = (8.869 to 27.665)], [OR = 1.555, 95%CI = (1.060 to 2.283)], [OR = 1.481, 95%CI = (1.114 to 1.969)], respectively. The results show that monotherapy therapy with EFGR-TKIs produce a significant OS and PFS benefit for patients with NSCLC compared with placebo or BSC, especially for the patients who had adenocarcinomas, non-smokers and patients with EGFR gene mutations.