Clinical recommendations for perioperative immunotherapy-induced adverse events in patients with non-small cell lung cancer.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.

A continuous responder algorithm to optimize clinical management of small-cell lung cancer with progastrin-releasing peptide as a simple blood test.

This study aimed to investigate whether changes in progastrin-releasing peptide (ProGRP) levels correlate with treatment response and can be used to optimize clinical management of patients with small-cell lung cancer. Patients with small-cell lung cancer (any stage) receiving chemotherapy were eligible. ProGRP was measured in serum/plasma at baseline and after each chemotherapy cycle using the Elecsys® ProGRP assay (Roche Diagnostics). Treatment response was assessed by computed tomography scan. The primary objective was to examine whether changes in ProGRP levels correlated with computed tomography scan results after two cycles of chemotherapy. The prognostic value of ProGRP among patients receiving first-line chemotherapy was also assessed. Overall, 261 patients from six centers were eligible. Among patients with elevated baseline ProGRP (>100 pg/mL), a ProGRP decline after Cycle 2 was associated with nonprogression (area under the curve: 84%; 95% confidence interval: 72.8-95.1; n = 141). ProGRP changes from baseline to end of Cycle 1 were predictive of response, as determined by computed tomography scan 3 weeks later (area under the curve: 87%; 95% confidence interval: 74.1-99.2; n = 137). This was enhanced by repeat measurements, with a 92% area under the curve (95% confidence interval: 85.3-97.8) among patients with ProGRP data after both Cycles 1 and 2 (n = 123); if a patient experienced a ≥25% decline in ProGRP after Cycle 1, and ProGRP remained stable or decreased after Cycle 2, the probability of finding progression on the interim computed tomography scan at the end of Cycle 2 was almost zero (sensitivity: 100%, specificity: 71%). Both ProGRP levels at baseline and at the end of first-line chemotherapy were prognostic; the latter provided a moderately improved hazard ratio of 2.43 (95% confidence interval: 1.33-4.46; n = 110) versus 1.87 (95% confidence interval: 1.04-3.37; n = 216). In summary, for patients with small-cell lung cancer and elevated baseline ProGRP levels, ProGRP may be a simple, reliable, and repeatable tool for monitoring response to chemotherapy and provide valuable prognostic information.

Icotinib as Adjuvant Treatment for Stage II-IIIA Lung Adenocarcinoma Patients with EGFR Mutation (ICWIP Study): Study Protocol for a Randomised Controlled Trial.

The efficacy and possible role of epidermal growth factor receptor tyrosine kinase inhibitors in treating early-stage non-small-cell lung cancer have yet to be established. Therefore, we aimed to explore the efficacy and safety of icotinib in completely resected EGFR-mutant stage II-IIIA lung adenocarcinoma patients who underwent standard chemotherapy. This is a randomised, double-blinded, placebo-controlled, multicentre, Phase III trial. A total of 124 patients aged 18-75 years who qualified the inclusion criteria were recruited. These patients were randomised (1:1) to receive either icotinib (125 mg 3 times per day) or placebo (the same dosage and frequency) for 36 months, followed by a further 36 months of observational window. The primary endpoint is disease-free survival (DFS), while the secondary endpoints are overall survival, 3-year and 5-year DFS, safety and tolerability of the medication, and health-related quality-of-life. Analyses will be conducted in a full analysis set and a per-protocol set as well. To our knowledge, the present study is the first randomised, double-blinded, placebo-controlled, multicenter trial designed to explore efficacy and safety of icotonib in this population. The results obtained in the near future may provide potential guidance in clinical practice. Trial Registration: This trial was registered on www.ClinicalTrail.gov as NCT02125240.

Macrophage Inhibitory Cytokine-1 as a Novel Diagnostic and Prognostic Biomarker in Stage I and II Nonsmall Cell Lung Cancer.

BACKGROUND: Increased level of serum macrophage inhibitory cytokine-1 (MIC-1), a member of transforming growth factor-µ superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-1 can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer (NSCLC). METHODS: A prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease (BPD) and 105 healthy controls were also included in the study. Serum MIC-1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed. RESULTS: In patients with NSCLC, serum protein levels of MIC-1 were significantly increased compared with healthy controls and BPD patients (all P< 0.001). A threshold of 1000 pg/ml of MIC-1 was found in patients with early-stage (Stage I and II) NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels of MIC-1 were associated with age (P = 0.001), gender (P = 0.030), and T stage (P = 0.022). Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 (≥1465 pg/ml) was lower than that of NSCLC patients with low serum MIC-1 levels (77.6% vs. 94.8%). Multivariate Cox regression survival analysis showed that a high serum level of MIC-1 was an independent risk factor for reduced overall survival (hazard ratio = 3.37, 95% confidential interval: 1.09-10.42, P= 0.035). CONCLUSION: The present study suggested that serum MIC-1 may be a potential diagnostic and prognostic biomarker for patients with early-stage NSCLC.

Increased lung cancer mortality rates in the Chinese population from 1973-1975 to 2004-2005: An adverse health effect from exposure to smoking.

BACKGROUND: Lung cancer incidence and mortality rates have increased substantially in China despite improvements in clinical diagnosis and treatment approaches as well as significant advances in the implementation of tobacco-control policies in recent decades. METHODS: Age-standardized mortality rates and age-specific rates of lung cancer in China were estimated for the periods 1973 to 1975, 1990 to 1992, and 2004 to 2005 using data from 3 National Death Surveys. Among patients with lung cancer who were identified from a hospital-based information system, the percentages of ever-smokers were analyzed according to histologic and demographic variables. RESULTS: Age-standardized mortality from lung cancer in China dramatically increased from 7.30 per 100,000 during 1973 through 1975 to 27.62 per 100,000 during 2004 through 2005. Increases in lung cancer age-standardized mortality were consistent among men and women in urban and rural populations. Among men ages 75 to 79 years, lung cancer mortality increased remarkably to 453.67 per 100,000 in 2004 and 2005 (from 246.78 per 100,000 during 1990-1992 and from 53.65 per 100,000 during 1973-1975). Among 6674 patients with lung cancer who were identified from 2003 to 2007 from a hospital-based database, 82.97% of men were ever-smokers (73.35% of men with adenocarcinoma and 91.8% of men with squamous cell carcinoma), and 11.18% of women were ever-smokers (6% of women with adenosquamous carcinoma and 39.02% of women with squamous cell carcinoma). Differences in the numbers of ever-smokers were observed between age groups but not according to the year of diagnosis. CONCLUSIONS: The consistent and rapid increases in lung cancer mortality rates observed in the Chinese population and the high prevalence of exposure to smoking in China prompt a strong call for the implementation of a comprehensive tobacco-control policy and specific public health educational strategies.

LFC131 peptide-conjugated polymeric nanoparticles for the effective delivery of docetaxel in CXCR4 overexpressed lung cancer cells.

CXCR4 is a chemokine receptor which is over expressed in multiple cancers including lung cancers. LFC131 peptide (d-Tyr-Arg-Arg-2-Nal-Gly), an inhibitor of CXCR4-ligand binding, is a low molecular weight CXCR4 antagonist. In this study, we developed novel LFC131 peptide surface conjugated O-carboxymethyl chitosan nanoparticles (O-CMC NP) to target CXCR4 over expressed A549 lung cancer cells. CXCR4-targeted drug delivery system was characterized for its binding, uptake, targeting specificity, and in vitro antitumour effect. Our main goal was to increase the intracellular concentration of docetaxel (DTX) in the cancer cells via a targeted approach. We have reported a nanosized particle with spherical shape and showed a high loading capacity. The CMC NP showed a controlled release pattern and presence of LFC131 did not influence the release of DTX. The fluorescence analysis showed an enhanced cell uptake for targeted NP via CXCR4-LFC131 biological interactions. The receptor-mediated cellular internalization was further confirmed confocal microscopy. The cytotoxicity assays showed enhanced cancer cell death by targeted NPs due to the selective delivery of DTX. Consistent with the cellular uptake analysis, targeted NPs induced a greater caspase-3 activity in A549 cancer cells. LFC/CMC NP exhibited a remarkable cell apoptosis by inducing apoptotic and necrotic cell death. Together, targeted LFC/CMC NP significantly enhanced cancer cell death than compared to non-targeted and free drugs. This kind of targeted nanoplatform which is based on polymeric nanocarriers could further facilitate a treatment protocol for CXCR4 overexpressing A549 lung cancer cells.

Multicenter evaluation of a new progastrin-releasing peptide (ProGRP) immunoassay across Europe and China.

BACKGROUND: We performed a multicenter evaluation of the Elecsys® progastrin-releasing peptide (ProGRP) immunoassay in Europe and China. METHODS: The assay was evaluated at three European and two Chinese sites by imprecision, stability, method comparison and differentiation potential in lung cancer. RESULTS: Intermediate imprecision across five analyte concentrations ranged from 2.2% to 6.0% coefficient of variation. Good stability for plasma and serum samples was shown for various storage conditions. There was excellent correlation between the Elecsys® and ARCHITECT assays in plasma (slope 1.02, intercept -2.72pg/mL). The Elecsys® assay also showed good correlation between serum and plasma samples (slope 0.93, intercept 2.35pg/mL; correlation coefficient 0.97). ProGRP differentiated small-cell and non-small-cell lung cancer (NSCLC; area under the curve 0.90, 95% CI 0.87-0.93; 78.3% sensitivity, 95% specificity; at 84pg/mL), with no relevant effects of ethnicity, age, gender or smoking. Median ProGRP concentrations were low in benign diseases (38pg/mL), other malignancies (40pg/mL) or NSCLC (39pg/mL), except chronic kidney disease above stage 3 (>100pg/mL). CONCLUSIONS: Increased stability of the Elecsys® ProGRP assay in serum and plasma offers clear benefits over existing assays. This first evaluation of a ProGRP assay in China demonstrated comparable differentiation potential among different ethnicities.

Inhibition of SENP1 induces radiosensitization in lung cancer cells.

Lung cancer is one of the most common and lethal types of malignancy. To date, radiotherapy and chemotherapy have been used as the two major treatment methods. However, radioresistance of lung cancer remains a therapeutic hindrance. The aim of this study was to identify whether small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a marker of radioresistance that may serve as a target for enhancing the efficacy of lung carcinoma radiotherapy. SENP1 was observed to be overexpressed in lung cancer tissues, and the modulation of SENP1 expression was demonstrated to significantly affect the proliferation of lung cancer cells. Moreover, silencing the expression of SENP1 using small interfering RNA (siRNA) significantly sensitized lung cancer cells to radiation. Mechanically, it was demonstrated that SENP1 depletion significantly enhanced ionizing radiation (IR)-induced cell cycle arrest, γ-H2AX expression and apoptosis. Thus, these data suggest that SENP1 may be a desirable drug target for lung carcinoma radiotherapy.

[A comparative study of complete video-assisted thoracoscopic lobectomy and video-assisted mini-thoracotomy in treatment of lung cancer].

OBJECTIVE: To explore the clinical application value of complete video-assisted thoracoscopic (cVATS) lobectomy in the mini-invasive treatment of lung cancer. METHODS: 90 patients with non-small cell lung cancer (NSCLC) who had undergone lobectomy were reviewed. According to surgical approach, complete video-assisted thoracoscopic lobectomy group (cVATS, n = 47) and video-assisted mini-thoracotomy group (VAMT, n = 43) were studied. Numbers of dissected lymph nodes, operation duration, volumes of intraoperative bleeding, duration of postoperative catheter drainage, length of postoperative hospital stay, incidence rates of postoperative complications, postoperative pain scores of patients were compared between the two groups retrospectively. RESULTS: There were no significant differences in numbers of dissected lymph nodes, operation duration, bleeding during operation, incidence rates of postoperative complication between the two groups (P > 0.05). Duration of postoperative catheter drainage and length of postoperative hospital stay of patients in cVATS group were shorter than those in VAMT group (P < 0.05). Pain scores of patients in cVATS group were lower than those at the same time in VAMT group (P < 0.05). CONCLUSION: Complete video-assisted thoracoscopic lobectomy is safe and effective surgical strategy for lung cancer patients with advantage of rapid recovery.

Adenoviral delivery of the EMX2 gene suppresses growth in human gastric cancer.

BACKGROUND: EMX2 is a human orthologue of the Drosophila empty spiracles homeobox gene that has been implicated in embryogenesis. Recent studies suggest possible involvement of EMX2 in human cancers; however, the role of EMX2 in carcinogenesis needs further exploration. RESULTS: In this study, we reported that down-regulation of EMX2 expression was significantly correlated with EMX2 promoter hypermethylation in gastric cancer. Restoring EMX2 expression using an adenovirus delivery system in gastric cancer cell lines lacking endogenous EMX2 expression led to inhibition of cell proliferation and Wnt signaling pathway both in vitro and in a gastric cancer xenograft model in vivo. In addition, we observed that animals treated with the adenoviral EMX2 expression vector had significantly better survival than those treated with empty adenoviral vector. CONCLUSION: Our study suggests that EMX2 is a putative tumor suppressor in human gastric cancer. The adenoviral-EMX2 may have potential as a novel gene therapy for the treatment of patients with gastric cancer.

Triparanol suppresses human tumor growth in vitro and in vivo.

Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma.

Gremlin is a member of the bone morphogenetic protein (BMP) antagonist family and its antagonistic effect is likely through direct binding to BMP proteins. As an antagonist of BMP, Gremlin plays a role in regulating organogenesis, body patterning and tissue differentiation. Recent studies have shown a deregulation of Gremlin in several types of human cancers. However, the role of Gremlin in human malignant mesothelioma (MM) is still unknown. In this study, we investigated the expression of Gremlin in human MM. We found that Gremlin mRNA and protein were both overexpressed in the majority of primary MM tissue samples that we examined. We also observed high level expression of the Gremlin gene in 4 of the 6 MM cell lines. Consistently, we found that the Gremlin promoter activity was significantly elevated in those MM cell lines expressing the Gremlin gene. On the other hand, no activity of the Gremlin promoter was detected in the two MM cell lines lacking Gremlin expression. Moreover, to examine the functional significance of the Gremlin overexpression in MM, we used shRNA to knock down Gremlin expression in MM cell lines expressing Gremlin and found that inhibition of Gremlin expression significantly suppressed proliferation of those MM cells. Taken together, our results suggest that the BMP antagonist Gremlin is overexpressed in MM and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of human MM.

A case of huge esophageal carcinosarcoma.

Carcinosarcoma of the esophagus is a rare malignant neoplasm with both epithelial and mesenchymal (sarcomatous) components. We describe a case of a 72-year-old man with a huge esophageal tumor which could often have been considered inoperable. However, the patient underwent a curative resection and had a good prognosis. In this report, we suggest that carcinosarcomas have a lower tendency of invasion, even late in their course. We therefore recommend aggressive surgical resection of this kind of tumor.