Exosomal miR-133a-3p promotes the growth and metastasis of lung cancer cells following incomplete microwave ablation.

PURPOSE: Exosomal miRNAs play key roles in various biological processes such as cell proliferation, angiogenesis, migration and invasion. We explored whether exosomal miRNAs can promote local recurrence (LR) of lung tumors following incomplete microwave ablation (MWA) therapy. METHODS: Exosomal miRNA profiles before and after incomplete MWA in lung cancer (LC) patients with LR (n = 3) were sequenced and compared. The differentially expressed miRNAs of interest were validated in clinical samples (n = 10) and MWA-treated cells using RT-qPCR analysis. Target genes of the miRNAs were predicted and validated. The biological functions of miRNAs in proliferation, angiogenesis and metastasis of A549 cells were evaluated in vitro and in vivo. RESULTS: A total of 270 miRNAs (243 upregulated and 27 downregulated) were differentially expressed after incomplete MWA in patients with local recurrence. Upregulation of miR-133a-3p after MWA was validated in the cells and clinical samples. Cell functional experiments suggested that miR-133a-3p overexpression derived from serum exosomes increased cell viability, migration and invasion ability, tube formation activity and proliferation of A549 cells. Sirtuin 1 (SIRT1) was identified as a target gene for miR-133a-3p. Moreover, miR-133a-3p delivered by exosomes significantly promoted tumor growth, paralleled by reduced SIRT1 expression in a subcutaneous tumorigenesis animal model and increased the number of lung nodules by tail vein metastasis in vivo. CONCLUSION: Exosomal miR-133a-3p overexpression promoted tumor growth and metastasis following MWA and could be a promising biomarker for LC recurrence after incomplete MWA.

Facilitating combined biopsy and percutaneous microwave ablation of pulmonary ground-glass opacities using lipiodol localisation.

OBJECTIVES: Whether preoperative localisation is necessary and valuable for the microwave ablation (MWA) of small pulmonary lesions with ground-glass opacity (GGO) remains unclear. This study aimed to explore the role of the Chiba needle and lipiodol localisation techniques in facilitating MWA and biopsy. METHODS: This retrospective before-after study included patients with GGOs who underwent conventional MWA and biopsy treatment in our hospital between January 2018 and December 2019 (group A) or who underwent the Chiba needle and lipiodol localisation treatment before MWA and biopsy between January 2020 and December 2020 (group B). The characteristics of each patient and GGO lesion were collected and analysed to evaluate the safety and effectiveness of the localisation technique. RESULTS: A total of 122 patients with 152 GGOs and 131 patients with 156 GGOs underwent MWA and biopsy in groups A and B, respectively. The primary technique efficacy rate of MWA differed significantly between the two groups (A vs. B: 94.1% vs. 99.4%; p = 0.009). The positive biopsy rate in the two groups was determined by the difference (A vs. B: 93.4% vs. 98.1%; p = 0.042). The incidence of complications did not increase in group B. CONCLUSIONS: Compared with the unmarked group, the Chiba needle and lipiodol localisation technique improved the positive rate of biopsy and the initial effective rate of MWA, without significantly increasing the complication rate. KEY POINTS: • The localisation of the Chiba needle and lipiodol could improve the positive biopsy rate and the initial effective rate of MWA. • The localisation of the Chiba needle and lipiodol does not affect the subsequent MWA and biopsy and does not increase the incidence of pneumothorax and haemorrhage.

Hypophysitis: A rare but noteworthy immune-related adverse event secondary to camrelizumab therapy.

The programmed cell death 1 (PD-1) inhibitor - camrelizumab - is a promising agent for the treatment of several malignancies. Secondary hypophysitis has been reported in patients treated with the other PD-1 inhibitors such as nivolumab and pembrolizumab. However, camrelizumab-related hypophysitis has not yet been described. Herein, we report three cases of hypophysitis secondary to camrelizumab therapy. Case 1 was a 60-year-old male patient with non-small-cell lung carcinoma, who was diagnosed with central adrenal insufficiency associated with hypophysitis after 11 cycles of camrelizumab treatment (200 mg every 2 weeks). Glucocorticoid therapy rapidly improved his symptoms. Case 2 was a 68-year-old male patient with hepatocellular carcinoma who received ten cycles of camrelizumab (200 mg every 2 weeks) plus apatinib (250 mg daily), before the diagnosis of hypophysitis. Steroid therapy was also efficacious. Case 3 was a 69-year-old male patient diagnosed with renal carcinoma. After eight cycles of camrelizumab therapy (200 mg every 2 weeks) combined with oral apatinib (250 mg daily), the patient presented with hypophysitis, which responded well to glucocorticoid therapy. These results suggest a caution for hypophysitis in patients treated with camrelizumab.

Synchronous Microwave Ablation Combined With Cisplatin Intratumoral Chemotherapy for Large Non-Small Cell Lung Cancer.

Background: Microwave ablation (MWA) and intratumoral chemotherapy (ITC) are useful for treating tumors in animal models; however, their clinical use in patients with large non-small cell lung cancer (NSCLC) remains unknown. This retrospective study aimed to evaluate preliminary outcomes of MWA + ITC for large NSCLC. Methods: From November 2015 to April 2020, a total of 44 NSCLC patients with a mean lesion diameter of 6.1 ± 1.5 cm were enrolled and underwent synchronous MWA + ITC procedures. The primary endpoint was local progression-free survival (LPFS); secondary endpoints were progression-free survival (PFS), complications, overall survival (OS), and associated prognostic factors. Results: The median follow-up time was 19.0 months. At the 1-month CT scan, complete tumor ablation was observed in 47.7% of cases. Median LPFS was 12.1 months; 1-, 2-, and 3-year LPFS rates were 51.2%, 27.9%, and 13.6%, respectively. A shorter LPFS was significantly associated with large lesions (HR 1.23, 95% CI 1.02-1.49; p = 0.032). Median PFS was 8.1 months; 1-, 2-, and 3-year PFS rates were 29.5%, 18.2%, and 9.1%, respectively. LPFS was significantly superior to PFS (p = 0.046). Median OS was 18.8 months. The 1-, 2-, 3-, and 5-year OS rates were 65.9%, 43.2%, 26.4%, and 10.0%, respectively. In univariate comparisons, high performance status (PS) score, smoking, and larger lesions were significantly correlated with poor survival. In multivariate analysis, advanced age, higher PS score, higher stage, larger lesion, and prior systematic treatment were independent prognostic factors for shorter OS. Adverse events were well tolerated and all patients recovered after appropriate intervention. Conclusions: MWA + ITC is a safe and effective new modality of local treatment for large NSCLC and can significantly prolong LPFS.

A study of microwave ablation for small cell lung cancer.

Purpose: To reveal the survival and safety of percutaneous microwave ablation (MWA) combined with chemoradiotherapy (CRT) in treating small cell lung cancer (SCLC). Materials and Methods: Clinical data of 48 SCLC patients who underwent MWA were retrospectively collected; survival and incidence of major complications were analyzed. Results: Totally, 48 SCLC patients underwent 51 MWA procedures. The median overall survival (OS) for all SCLC was 27.0 months (95% confidence interval 22.4-31.6 months). The OS of limited-stage (LS-SCLC) was longer than the extensive-stage (ES-SCLC) (median 48.0 months vs. 25.0 months, P = 0.022). The OS of SCLC with tumor diameter ≤3.0 cm was longer than that of tumor diameter >3.0 cm (median 48.0 months vs. 27.0 months, P = 0.041). For LS-SCLC, the 1-, 2-, 3-, and 5-year survival rate was 91.67%, 72.22%, 66.67%, and 61.11%, respectively. For ES-SCLC, the 1-, 2-, and 3-year survival rates were 83.33%, 50.0%, and 8.33%. Major complications included pneumothorax needing tube placement (29.4%), rarely arrhythmia (2.0%), empyema (2.0%), pulmonary fungal infection (2.0%), and shingles (2.0%). Conclusion: For SCLC patients, who received MWA combined with CRT, OS of LS-SCLC and tumor diameter ≤3.0 cm was better than that of the ES-SCLC and tumor diameter >3.0 cm. For inoperable SCLC, MWA was safe.

CT-guided microwave ablation in patients with lung metastases from breast cancer.

BACKGROUND: Computed tomography (CT)-guided percutaneous microwave ablation (MWA) is a very common ablation method that shows a good local tumor control rate in primary and secondary lung tumors. At present, few reports have explored the safety and efficacy of MWA for lung metastases from breast cancer. METHODS: From January 2012 to January 2018, 32 breast cancer patients with 46 pulmonary metastases received CT-guided percutaneous MWA. The study was approved by the local institutional review board. The clinical efficacy and complications of MWA were investigated. RESULTS: The median follow-up time was 32 months and the main effective rate was 97.8% (45/46). Five of 46 lesions had local progression (10.9%), with a median progression time of 10 months. The 1-, 3-, and 5-year overall survival (OS) rates were 96.9%, 53.3%, and 17.8%, respectively. The median OS time was 36 months. Among 46 MWA treatments, 11 (23.9%) had massive pneumothorax, two (4.3%) had massive pleural effusion, and two (4.3%) had a pulmonary infection. CONCLUSION: CT-guided percutaneous MWA may be safe and effective for treating lung metastases from breast cancer.

A feasibility and safety study of computed tomography-guided percutaneous microwave ablation: a novel therapy for multiple synchronous ground-glass opacities of the lung.

Purpose: The present study retrospectively evaluated the feasibility, safety, and short-term efficacy of computed tomography (CT)-guided percutaneous microwave ablation (MWA) to treat multiple synchronous ground-glass opacities (GGOs) of the lung.Materials and Methods: From October 2016 to May 2019, 33 patients (9 males and 24 females, mean age: 59.6 ± 10.0 years) with multiple GGOs (103 GGOs with mean size 12.3 ± 6.3 mm) were enrolled in this study. Patients underwent 66 procedures of CT-guided percutaneous MWA. The feasibility, safety, local progression-free survival, and overall survival were evaluated.Results: The technical success and technique efficacy rate were 100% and no MWA procedure-related deaths were reported. The median follow-up period was 18.1 (range: 6.8-37.7) months. Major complications included pneumothorax (11/66, 16.7%), pleural effusion (2/66, 3.0%), pneumonia (3/66, 4.5%), and nerve injury (1/66, 1.5%), which were well controlled by appropriate treatment. Minor complications included pneumothorax (38/66, 57.6%), pleural effusion (43/66, 65.2%), hemoptysis (13/66, 19.7%), subcutaneous emphysema (4/66, 6.1%), and hemothorax (2/66, 3.0%). Currently, all patients are alive without local progression or tumor recurrence, despite the relatively insufficient follow-up time.Conclusion: CT-guided percutaneous MWA for the treatment of multiple synchronous lung GGOs is feasible, safe, and efficacious over short-term follow-up. It may also be employed as an alternative approach for nonsurgical candidates. A longer follow-up is warranted to evaluate the oncologic outcomes.

Radiomics analysis of lung CT image for the early detection of metastases in patients with breast cancer: preliminary findings from a retrospective cohort study.

OBJECTIVES: To investigate whether subtle changes in radiomics features are present in lung CT images prior to the development of CT-detectable lung metastases in patients with breast cancer. METHODS: Thirty-three radiomics features were measured in the metastasis region (MR) and in matched contralateral tissues (non-metastasis region, NMR) of 29 breast cancer patients at the last CT scan, as well as in the corresponding regions of the patients' pre-metastasis scan (pre-MR and pre-NMR). We also compared them with normal lung tissues (control group, CG) from 29 healthy volunteers. Then, 8 patients from the 29 patients with lung metastases and 8 patients who did not develop lung metastases were chosen for further study of the correlation between radiomics parameters and tumor growth. RESULTS: In the MR vs. NMR and MR vs. CG groups, almost all radiomics features were significantly different. Twenty-six parameters showed significant differences between the pre-MRs and pre-NMRs. Linear fitting demonstrated a significant correlation between 5 features and tumor growth in the metastasis group, but not in the non-metastasis group. Among them, run percentage was the most representative feature. The calculated area under curves (AUCs), based on run percentage for the classification of metastasis and pre-metastasis, were 0.954 and 0.852, respectively. CONCLUSIONS: Radiomics features may allow early detection of lung metastases before they become visually detectable, and the feature run percentage may be a promising image surrogate marker for the microinvasion of tumor cells into the lung tissue. KEY POINTS: • The significant differences in radiomics features between pre-MR and pre-NMR are critical for the early detection of lung metastases. • Five radiomics features show a correlation with tumor growth. • The radiomics feature run percentage may be a potential imaging biomarker for the early detection of lung metastases.

Primary tumor-secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway.

Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor-bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO-1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO-1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF-induced hyperpermeability. Further investigations revealed that VEGF-induced occludin phosphorylation at Ser-490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin-proteasome system. In conclusion, primary tumor-secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF-induced vascular hyperpermeability in the lung premetastatic niche.

Proposal of a new nodal classification for operable non-small cell lung cancer based on the number of negative lymph nodes and the anatomical location of metastatic lymph nodes.

Lymph node metastasis is one of the most important prognostic indicators in patients with radically resected non-small cell lung cancer (NSCLC). This retrospective study aimed to compare the predictive value of metastatic lymph nodes (MNs), lymph node ratio (LNR), resected lymph nodes (RNs), and negative lymph nodes (NNs) with the currently used pathologic nodal (pN) staging category.We conducted a retrospective analysis of 1019 consecutive NSCLC patients treated with complete resection in a single institution. Prognostic values of various lymph node factors were evaluated by analysis of univariate and multivariate Cox proportional hazards model, and the results were compared with those using the location-based pN stage classification.The median follow-up duration was 47 months. During this period, 353 cases of cancer recurrence and 337 deaths were reported. Multivariate cox analysis indicated that both pN and NN categories were independent predictors of patient survival. The patients were divided into six groups on the basis of pN and NN categories. The survival rates of the groups were as follows: pN0, NN≥8, 81.4%; pN0, NN<8, 73.8%; pN1, NN≥8, 61.4%; pN1, NN<8, 54.2%; pN2, NN≥8, 48.4%; and pN2>1, NN<8, 35.0%. Comparison of the predictive values of the lymph node factors showed that the new N category was a more valuable prognostic factor in operable NSCLC.The combination of anatomically based pN stage classification and the number of MNs is an accurate prognostic determinant in patients with operable NSCLC which can be equal to 8th N category.

Effects of postoperative non-steroidal anti-inflammatory drugs on long-term survival and recurrence of patients with non-small cell lung cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve postoperative fever, surgery pain, and inflammation. In addition, NSAIDs have anticancer activity and may reduce the risk and mortality of several cancers. However, the association between postoperative NSAIDs and the clinical outcome of non-small cell lung cancer (NSCLC) patients with fever after surgery is not fully understood. We performed a retrospective study of NSCLC patients who underwent surgery between July 2011 and June 2012, aiming to evaluate the effect of postoperative NSAIDs on overall survival (OS) and progression-free survival (PFS). Differences in clinical data between the postoperative NSAIDs group and non-NSAIDs groups were analyzed by Chi-square tests. Kaplan-Meier curves method and Cox regression analysis were conducted for survival analysis. The primary and secondary endpoints were OS and PFS, respectively. This retrospective study included 347 NSCLC patients. There were no significant differences in the clinical characteristics between the NSAIDs group and non-NSAIDs group except for age (P = .024) and differential degree (P = .040). Administration of postoperative NSAIDs was related to longer OS (hazards ratio [HR] 0.528, 95% confidence interval [CI] 0.278-0.884, P = .006) and longer PFS (HR 0.557, 95% CI 0.317-0.841, P = .002) in the multivariate Cox regression model. Subgroup analysis showed statistically significant differences in elderly individuals, male subjects, low smoking index, poor differentiation, and non-adenocarcinoma subgroups, respectively. In conclusion, the administration of postoperative NSAIDs was related to longer OS and PFS in NSCLC patients with postoperative fever.

Optimal managements of stage IIIA (N2) non-small cell lung cancer patients: a population-based survival analysis.

BACKGROUND: This study aimed to investigate the optimal management of stage IIIA (cN2) non-small cell lung cancer (NSCLC) patients and determine potential predictive factors. METHODS: We extracted patients diagnosed as NSCLC stage IIIA (cN2) between 2004 and 2011 from Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients given different clinical managements by Kaplan-Meier method. Other variables such as age, sex and tumor size were analyzed to explore the factors associated with outcomes. RESULTS: A total of 98,700 IIIA-cN2 NSCLC patients were identified from SEER database. Survival of patients treated with surgery was better than that of patients treated by radiotherapy alone (P<0.001). Radiation prior to surgery significantly improved the survival in comparison with surgery alone (P<0.001). In the subgroups of OS analysis, age >65 (P=0.902), adenocarcinoma (P=0.279), tumor size ≤3 cm (P=0.170), well differentiated (P=0.360) patients, preoperative radiotherapy improved survival insignificantly compared with surgery alone. CONCLUSIONS: Preoperative radiation with surgery had the most encouraging survival outcomes in stage IIIA-cN2 NSCLC patients compared with radiation or surgery alone. No significant outcome improvement was shown between postoperative radiotherapy (PORT) and surgery alone.

Long-term outcomes of stage I NSCLC (≤3 cm) patients following segmentectomy are equivalent to lobectomy under analogous extent of lymph node removal: a PSM based analysis.

BACKGROUND: Segmentectomy has the advantage of less complications, but might have less lymph node sampling and higher risk of recurrence. We aimed to compare treatment outcome between two surgical options, and explore the effect of regional lymph node removal on the prognostic difference. METHODS: We retrospectively analyzed data of stage I non-small cell lung cancer (NSCLC) (≤3 cm in size) patients who underwent either segmentectomy, or lobectomy, collected from the Surveillance, Epidemiology and End Results (SEER) database, from 2003 to 2013. The primary endpoints were overall survival (OS) and lung cancer-specific survival (LCSS). We also collected data from Shandong Provincial Hospital as validation. RESULTS: Ultimately 1,156 patients treated by segmentectomy and 17,748 patients treated by lobectomy from SEER database were included in the analysis. Overall, segmentectomy was inferior to lobectomy in terms of OS [hazard ratio (HR): 1.316 (1.186-1.461), P<0.001] and LCSS [HR: 1.310 (1.142-1.504), P<0.001]. When the removal of regional lymph nodes (LN) was taken into consideration, no significant difference was found in OS and LCSS, in any Scope of Regional Lymph Node Surgery layer (0, 1-3, more than 3, and biopsy/sentinel layer, all P>0.05). After propensity score matching (PSM), there was no difference between segmentectomy and lobectomy in OS [HR: 1.081 (0.937-1.248), P=0.286] and LCSS [HR: 1.039 (0.861-1.253), P=0.692]. Only sex, age, histology, summary stage, differentiation, tumor size, and radiation still remained as independent prognostic factors for both OS and LCSS. For validation part, there was no significantly prognostic difference between lobectomy and sublobectomy group in overall (P=0.132) and each regional LN removed layer (0, 1-3, more than 3 layers: all P>0.05). CONCLUSIONS: Segmentectomy with proper lymph node resection or sampling could be a good alternative to lobectomy.

Subcellular localization of ß-arrestin1 and its prognostic value in lung adenocarcinoma.

ß-Arrestins play important roles in cancer progression, and the subcellular localization of ß-arrestin1 has been receiving increasingly more attention. Intriguingly, several studies, including some of our previous work, showed that the effects of ß-arrestin1 on outcomes of cancer patients were controversial.Specimens were obtained from 133 patients with lung adenocarcinoma. Immunohistochemistry was used to detect the expression of ß-arrestin1 and p300 in the collected tissues. The Kaplan-Meier analysis and Cox proportional hazards regression were used to examine the relationship between ß-arrestin1 and patient survival.We found no significant association between ß-arrestin1 and clinicopathological variables. The Kaplan-Meier plot showed that patients with high expression of ß-arrestin1 (especially in the nucleus) had a poorer overall survival (OS) and shorter disease-free survival (DFS) (P = .026, P = .015). Additionally, high p300 expression also resulted in worse OS (P = .039). Following the univariate analysis, high expressions of nuclear ß-arrestin1 and p300 were classed as poor prognostic factors for both OS (P = .016) and DFS (P = .025).The expression of ß-arrestin1 in the nucleus is associated with increased malignant tendency of lung adenocarcinoma, and the predictive value of ß-arrestin1 may be optimized by combining information about the expression of p300 acetyltransferase.

Prognostic effects of preoperative obstructive pneumonitis or atelectasis and comparison with tumor size in non-small cell lung cancer.

BACKGROUND: In the eighth TNM staging system proposal, lung cancer with part or complete obstructive pneumonitis/atelectasis was classified to T2 category, and dividing lines of T category were changed. We conducted this study to search prognostic effect of preoperative obstructive pneumonitis/atelectasis and its comparison with tumor size. METHODS: We collected clinical characteristics, preoperative hematological indicators, follow-up information of 1,313 lung cancer patients. Chi-square test was used to search relationship between obstruction pneumonitis/atelectasis and other factors. Kaplan-Meier (K-M) curves and cox regression methods were used for survival analysis. RESULTS: Preoperative obstructive pneumonitis/atelectasis indicated shorter OS (HR: 1.308; 95% CI: 1.058-1.619) and RFS (HR: 1.276; 95% CI: 1.032-1.579) as an independent factor. In comparison with tumor size, we found patients with obstructive pneumonitis/atelectasis and T1 size tumor had similar prognosis to those with T2 size but without obstructive pneumonitis/atelectasis, and OS, RFS of patients with obstructive pneumonitis/atelectasis and T2 size were significantly shorter than those with T2 tumor size but without obstructive pneumonitis/atelectasis, while similar to patients with T3 tumor size but without obstructive pneumonitis/atelectasis according to division by the eighth edition. We also found obstructive pneumonitis/atelectasis was significantly related to higher neutrophil (P<0.001), platelet (P<0.001), monocyte (P<0.001), NLR (P<0.001), PLR (P=0.002), ESR (P<0.001) and lower LMR (P<0.001). CONCLUSIONS: Preoperative obstructive pneumonitis/atelectasis predicted poor survival independently in non-small cell lung cancer (NSCLC). And we suggested which T staging group the patients with obstructive pneumonitis/atelectasis would be divided to should depend on tumor size in the eighth TNM staging system.

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy.

BACKGROUND: Prognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy. MATERIAL AND METHODS: We searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS). RESULT: 17studies were enrolled. The results was not significant in overall survival (I2=37.1%, P=0.080, HR=1.08, 95% CI=0.97-1.21) and in progression-free survival (I2=0.0%, P=0.637, HR=1.05, 95% CI=0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects. CONCLUSION: So far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.

Diagnostic and prognostic value of blood samples for KRAS mutation identification in lung cancer: a meta-analysis.

Circulating tumor DNA (ctDNA) and tumor cells (CTC) are novel approaches for identifying genomic alterations. Thus, we designed a meta-analysis to evaluate the diagnostic value and prognostic significance of a KRAS proto-oncogene, GTPase (KRAS) mutation for lung cancer patients. All included articles were from PubMed, EMBASE, Web of Science and Cochrane Library. Twelve articles that described 1,131 patients were reviewed. True positives (TP), false positives (FP), true negatives (TN), and false negatives (FN) were used to calculate pooled sensitivity, specificity, the positive likelihood ratio (PLR), the negative likelihood ratio (NLR), a diagnostic odds ratio (DOR), the area under the curve (AUC) and corresponding 95% confidence intervals (95% CI). PLR is calculated as sensitivity/(1-specificity) and NLR is (1- sensitivity)/specificity. DOR is a measured of diagnostic effectiveness (PLR/NLR). A survival analysis subgroup was also designed to evaluate prognostic significance. Pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.79 (95% CI, 0.63-0.89), 0.93 (95% CI, 0.89-0.96), 12.13 (92% CI, 7.11-20.67), 0.22 (95% CI, 0.12-0.41), 54.82 (95% CI, 23.11-130.09), and 0.95 (95% CI, 0.93-0.96), respectively. KRAS mutation and wild-type hazard ratios for overall survival and progression-free survival were 1.37 (95% CI, 1.08-1.66), 1.46 (95% CI, 1.15-1.77) in blood samples, and 1.16 (95% CI, 1.03-1.28), 1.28 (95% CI, 1.09-1.46) in tumor tissue.

Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.

PURPOSE: Gastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma. MATERIALS AND METHODS: Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed. RESULTS: Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001). CONCLUSION: Tumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

ARRB1 enhances the chemosensitivity of lung cancer through the mediation of DNA damage response.

ARRB1 (also known as ß-arrestin-1) serves as a multifunctional adaptor contributing to the regulation of signaling pathways. ARRB1 may be involved in DNA damage accumulation; however the underlying mechanism involved is unclear. In the present study, non-small cell lung cancer (NSCLC) cell lines (H520 and SK-MES-1) were transfected with ARRB1 plasmids or small interfering ribonucleic acid (siRNA) and received treatment with DNA-damaging agents (cisplatin and etoposide). A mouse xenograft model was used to assess the impact of ARRB1 on the efficacy of cisplatin in vivo. A total of 30 surgically resected NSCLC patients were recruited for the present study and qRT-PCR was performed to determine the mRNA levels in cancer tissues compared with para-carcinoma tissues. Our data showed that DNA damage was abrogated in the ARRB1­knockdown cells and enhanced in the ARRB1-overexpressing cells. ATR and Chk1 were more activated in the ARRB1-overexpressing cells compared to the ARRB1-knockdown cells, followed by increased H2AX phosphorylation. DNA damage and apoptosis were increased in the ARRB1-overexpressing cells treated with cisplatin. These data provided strong evidence that ARRB1 contributes to the response of NSCLC to DNA-damaging agents and is essential for DNA damage response (DDR). ARRB1 may enhance the efficacy of DNA-damaging agents in NSCLC.

The Effect of Diabetes Mellitus on Lung Cancer Prognosis: A PRISMA-compliant Meta-analysis of Cohort Studies.

Previous studies suggested that diabetes mellitus (DM) was associated with risk and mortality of cancer, but studies investigating the correlation between DM and lung cancer prognosis remain controversial. Herein, a meta-analysis was performed to derive a more precise estimate of the prognostic role of DM in lung cancer.Medline and Embase were searched for eligible articles from inception to October 25, 2015. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was calculated to evaluate the correlation between DM and lung cancer prognosis. Subgroup meta-analysis was performed based on the histology and the treatment methods.A total of 20 cohort studies from 12 articles were included in the meta-analysis. Also, 16 studies investigated the overall survival (OS) and 4 studies investigated the progression-free survival (PFS). DM was significantly associated with the inferior OS of lung cancer with the pooled HR 1.28 (95% CI: 1.10-1.49, P = 0.001). The association was prominent in the nonsmall cell lung cancer (NSCLC) subgroup (HR 1.35, 95%CI: 1.14-1.60, P = 0.002), whereas the association was not significant in the small cell lung cancer (SCLC) subgroup (HR 1.33, 95% CI: 0.87-2.03, P = 0.18). When NSCLC patients were further stratified by treatment methods, DM had more influence on the surgically treated subgroup than the nonsurgically treated subgroup. There was no obvious evidence for publication bias by Begg's and Egger's test.The results of this meta-analysis exhibit an association of DM with inferior prognosis amongst lung cancer patients, especially the surgically treated NSCLC patients. Given the small number of studies included in this meta-analysis, the present conclusion should be consolidated with more high-quality prospective cohort studies or randomized controlled trials.