Integrated whole-exome and bulk transcriptome sequencing delineates the dynamic evolution from preneoplasia to invasive lung adenocarcinoma featured with ground-glass nodules.

OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.

Ivermectin induces nonprotective autophagy by downregulating PAK1 and apoptosis in lung adenocarcinoma cells.

INTRODUCTION: LUAD (Lung adenocarcinoma), the most common subtype of lung carcinoma and one of the highest incidences and mortality cancers in the world remains still a substantial treatment challenge. Ivermectin, an avermectin derivative, has been traditionally used as an antiparasitic agent in human and veterinary medicine practice during the last few decades. Though ivermectin has been shown to be effective against a variety of cancers, however, there is few available data reporting the antitumor effects of ivermectin in LUAD. METHODS: The effect of ivermectin on cell viability and proliferative ability of LUAD cells was evaluated using CCK-8 and colony formation assay. Apoptosis rate and autophagy flux were detected using flow cytometry based on PI/Annexin V staining and confocal laser scanning microscope based on LC3-GFP/RFP puncta, respectively. Western blotting experiment was conducted to verify the results of changes in apoptosis and autophagy. LUAD-TCGA and GEO databases were used to analyse the expression and predictive value of PAK1 in LUAD patients. Xenograft model and immumohistochemical staining were used for verification of the inhibitor effect of ivermectin in vivo. RESULTS: Ivermectin treatment strikingly impeded the colony formation, and the viability of the cell, along with cell proliferation, and caused the apoptosis and enhanced autophagy flux in LUAD cells. In addition, ivermectin-induced nonprotective autophagy was confirmed by treating LUAD cells with 3-MA, an autophagy inhibitor. Mechanistically, we found that ivermectin inhibited PAK1 protein expression in LUAD cells and we confirmed that overexpression of PAK1 substantially inhibited ivermectin-induced autophagy in LUAD cells. Based on TCGA and GEO databases, PAK1 was highly expressed in LUAD tissues as compared with normal tissues. Furthermore, LUAD patients with high PAK1 level have poor overall survival. Finally, in vivo experiments revealed that ivermectin efficiently suppressed the cellular growth of LUAD among nude mice. CONCLUSION: This study not only revealed the mechanism of ivermectin inhibited the growth of LUAD but also supported an important theoretical basis for the development of ivermectin during the therapy for LUAD.

Nomogram Predicting the Prognosis of Patients with Surgically Resected Stage IA Non-small Cell Lung Cancer.

The American Joint Committee on Cancer (AJCC) 8th stage system was limited in accuracy for predicting prognosis of stage IA non-small cell lung cancer (NSCLC) patients. This study aimed to establish and validate two nomograms that predict overall survival (OS) and lung cancer-specific survival (LCSS) in surgically resected stage IA NSCLC patients. Postoperative patients with stage IA NSCLC in SEER database between 2004 and 2015 were examined. Survival and clinical information according to the inclusion and exclusion criteria were collected. All patients were randomly divided into the training cohort and validation cohort with a ratio of 7:3. Independent prognosis factors were evaluated using univariate and multivariate Cox regression analyses, and predictive nomogram was established based on these factors. Nomogram performance was measured using the C-index, calibration plots, and DCA. Patients were grouped by quartiles of nomogram scores and survival curves were plotted by Kaplan-Meier analysis. In total, 33,533 patients were included in the study. The nomogram contained 12 prognostic factors in OS and 10 prognostic factors in LCSS. In the validation set, the C-index was 0.652 for predicting OS and 0.651 for predicting LCSS. The calibration curves for the nomogram-predicted probability of OS and LCSS showed good agreement between the actual observation and nomogram prediction. DCA indicated that the clinical value of the nomograms were higher than AJCC 8th stage for predicting OS and LCSS. Nomogram scores related risk stratification revealed statistically significant difference which have better discrimination than AJCC 8th stage. The nomogram can accurately predict OS and LCSS in surgically resected patients with stage IA NSCLC. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-022-01700-w.

A novel enemy of cancer: recent investigations into protozoan anti-tumor properties.

Cancer remains a significant global health issue, despite advances in screening and treatment. While existing tumor treatment protocols such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy have proven effective in enhancing the prognosis for some patients, these treatments do not benefit all patients. Consequently, certain types of cancer continue to exhibit a relatively low 5-year survival rate. Therefore, the pursuit of novel tumor intervention strategies may help improve the current effectiveness of tumor treatment. Over the past few decades, numerous species of protozoa and their components have exhibited anti-tumor potential via immune and non-immune mechanisms. This discovery introduces a new research direction for the development of new and effective cancer treatments. Through in vitro experiments and studies involving tumor-bearing mice, the anti-tumor ability of Toxoplasma gondii, Plasmodium, Trypanosoma cruzi, and other protozoa have unveiled diverse mechanisms by which protozoa combat cancer, demonstrating encouraging prospects for their application. In this review, we summarize the anti-tumor ability and anti-tumor mechanisms of various protozoa and explore the potential for their clinical development and application.

Plasmodium Circumsporozoite Protein Enhances the Efficacy of Gefitinib in Lung Adenocarcinoma Cells by Inhibiting Autophagy via Proteasomal Degradation of LC3B.

Background: Almost all lung adenocarcinoma (LUAD) patients with EGFR mutant will develop resistance to EGFR-TKIs, which limit the long-term clinical application of these agents. Accumulating evidence shows one of the main reasons for resistance to EGFR-TKIs is induction of autophagy in tumor cells. Our previous study found that circumsporozoite protein (CSP) in Plasmodium can suppress autophagy in host hepatocytes. However, it is unknown whether CSP-mediated inhibition of autophagy could improve the anti-tumor effect of EGFR-TKIs. Methods: We constructed A549 and H1975 cell lines with stable overexpression of CSP (OE-CSP cells). CCK-8, Lactate Dehydrogenase (LDH), flow cytometry, and colony analysis were performed to observe the effect of CSP overexpression on cell viability, apoptosis rate, and colony formation ratio. The sensitizing effect of CSP on gefitinib was evaluated in vivo using a subcutaneous tumor model in nude mice and immunohistochemical assay. The role of CSP in regulation of autophagy was investigated by laser confocal microscopy assay and western blotting. A transcriptome sequencing assay and real-time polymerase chain reaction were used to determine the levels of mRNA for autophagy-related proteins. Cycloheximide (CHX), MG132, TAK-243, and immunoprecipitation assays were used to detect and confirm proteasomal degradation of LC3B. Results: OE-CSP A549 and H1975 cells were more sensitive to gefitinib, demonstrating significant amounts of apoptosis and decreased viability. In the OE-CSP group, autophagy was significantly inhibited, and there was a decrease in LC3B protein after exposure to gefitinib. Cell viability and colony formed ability were recovered when OE-CSP cells were exposed to rapamycin. In nude mice with xenografts of LUAD cells, inhibition of autophagy by CSP resulted in suppression of cell growth, and more marked apoptosis during exposure to gefitinib. CSP promoted ubiquitin-proteasome degradation of LC3B, leading to inhibition of autophagy in LUAD cells after treatment with gefitinib. When LUAD cells were treated with ubiquitin activating enzyme inhibitor TAK-243, cell viability, apoptosis, and growth were comparable between the OE-CSP group and a control group both in vivo and in vitro. Conclusion: CSP can inhibit gefitinib-induced autophagy via proteasomal degradation of LC3B, which suggests that CSP could be used as an autophagy inhibitor to sensitize EGFR-TKIs.

Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer.

BACKGROUND: Chemotherapy is still the primary adjuvant strategy of cancer therapy; however, the emergence of multi-drug resistance has been a cause for concern. Autophagy has been demonstrated to have a protective role against chemotherapeutic drugs in cancer cells, and autophagy inhibition is generally considered to be a promising therapeutic strategy. However, the paucity of effective and specific autophagy inhibitors limits its application. PURPOSE: The objective of this study was to explore the effect of DCA, small molecular anti-tumor agent, on the autophagy regulation and chemosensitization in NSCLC cells. METHODS: We investigated the autophagy regulation of dichloroacetate (DCA) by laser confocal microscopy and western blotting in A549 and H1975 cell lines. The MTT assay and flow cytometry was performed for explore the chemosensitization effectiveness of DCA. The results were verified with subcutaneous tumor model in nude mice and the immunohistochemistry was applied for assessing the level of cell apoptosis and autophagy in vivo post treatment. RESULTS: We found that DCA, which exhibited antitumor properties in various carcinoma models, induced apoptosis of non-small cell lung cancer cells (NSCLC) by inhibiting cancer cell autophagy. Furthermore, Perifosine, an AKT inhibitor, can greatly weaken the capacity of inducing apoptosis by DCA. The results indicate that the AKT-mTOR pathway, a main negative regulator of autophagy, is involved in the DCA-induced inhibition of autophagy. Then, we detected the effectiveness of autophagy inhibition by DCA. When used in co-treatment with the chemotherapeutic drug paclitaxel (PTX), DCA markedly decreased cell autophagy, enhanced apoptosis and inhibited proliferation in A549 and H1975 cells. The results of the xenograft experiment demonstrate that co-treatment of PTX and DCA can significantly decrease cell proliferation in vivo and prolong the survival of mice. CONCLUSION: Our results suggest that DCA can inhibit cell autophagy induced by chemotherapeutics, providing a new avenue for cancer chemotherapy sensitization.

Plasmodium circumsporozoite protein suppresses the growth of A549 cells via inhibiting nuclear transcription factor κB.

Blocking the activation of nuclear factor κB (NF-κB) is a promising strategy for the treatment of non-small cell lung cancer. The circumsporozoite protein (CSP), a key component of the sporozoite stage of the malaria parasite, was previously reported to block NF-κB activation in hepatocytes. Therefore, in the present study, the effect of CSP on the growth of the human lung cancer cell line, A549, was investigated. It was demonstrated that transfection with a recombinant plasmid expressing CSP was able to inhibit the proliferation of A549 cells in a dose-dependent manner and induce the apoptosis of A549 cells. A NF-κB gene reporter assay indicated that CSP and its nuclear localization signal (NLS) motif were able to equally suppress the activation of NF-κB following stimulation with human recombinant tumor necrosis factor (TNF)-α in A549 cells. Furthermore, western blot analysis indicated that NLS did not affect the phosphorylation and degradation of IκB, but was able to markedly inhibit the nuclear translocation of NF-κB in TNF-α stimulated A549 cells. Therefore, the data suggest that CSP may be investigated as a potential novel NF-κB inhibitor for the treatment of lung cancer.

High expression of DJ-1 promotes growth and invasion via the PTEN-AKT pathway and predicts a poor prognosis in colorectal cancer.

Cancer cell invasion and unlimited proliferation are key factors in patients with colorectal cancer (CRC). Increased protein deglycase DJ-1 in cancer cells is known to promote tumor growth; however, its role in CRC progression is not well defined. In this study, we investigated 100 CRC patients with disease stages I-IV to determine whether DJ-1 could serve as a prognostic biomarker in CRC. These results showed that DJ-1 expression in CRC tissues was higher than that in normal colon tissues and was associated with the (Tumor Node Metastasis) TNM stage. CRC patients with low DJ-1 expression had a longer overall survival than those with high expression, and multivariate and univariate analyses indicated that DJ-1 expression was an independent prognostic factor for overall survival in CRC. Furthermore, DJ-1 overexpression in two colon cancer cell lines, HCT116 and SW480, activated protein kinase AKT and downregulated tumor suppressor PTEN, whereas DJ-1 knockdown upregulated PTEN expression and effectively suppressed CRC cell invasion and proliferation both in vitro and in vivo, revealing a mechanism underlying DJ-1 pro-oncogenic activity in CRC. Treatment of MK2206, the specific AKT inhibitor, significantly decreased DJ-1-mediated cell proliferation and mobility in vitro. Taken together, these results suggest that DJ-1 may be a novel prognostic biomarker and potential therapeutic target in human CRC.

Anastomotic reinforcement with omentoplasty reduces anastomotic leakage for minimally invasive esophagectomy with cervical anastomosis.

PURPOSE: Anastomotic leakage is the most feared postoperative complication after esophagectomy. Omentoplasty, wrapping the omentum around the alimentary tract anastomosis, is thought to decrease the anastomotic leakage rate. The purpose of this clinical study is to investigate the use of omentoplasty to reinforce cervical esophagogastrostomy after minimally invasive esophagectomy (MIE). PATIENTS AND METHODS: In this retrospective study, the data of 160 consecutive patients who underwent cervical esophagogastrostomy after MIE between September 2012 and May 2015 were analyzed, 87 who underwent omentoplasty (group A) and 73 who did not undergo omentoplasty (group B). The primary outcome was the incidence of anastomotic leakage and anastomotic strictures after the operation. Secondary outcomes were other complications and mortality rate. Univariate and multivariate analysis of variables associated with an increased risk for anastomotic leak was performed. RESULTS: The median age was 61 years (range, 37-82 years). The anastomotic leakage rates were 4.6% (4/87) in group A and 15.1% (11/73) in group B (P = 0.023). There was no statistical significance in anastomotic stricture rates between group A (6.9%) and group B (9.6%; P = 0.535). No difference was noted in other complications between the groups. There was a trend toward lower leak-associated mortality rates for group A (0%) compared with that for group B (4.1%). CONCLUSION: Cervical esophagogastrostomy with omentoplasty is more effective than esophagogastrostomy without omentoplasty for the prevention of anastomotic leakage in MIE with cervical anastomosis. Omentoplasty could be used as an adjunct technique to reduce the incidence of anastomotic leakage in cervical esophagogastrostomy following MIE.

Segmentectomy versus wedge resection for the treatment of high-risk operable patients with stage I non-small cell lung cancer: a meta-analysis.

BACKGROUND: Although lobectomy is still the preferred treatment for patients with stage I non-small cell lung cancer (NSCLC), segmentectomy or wedge resection is frequently performed on patients who cannot withstand the physiological rigors of lobectomy. The objective of this study was to compare the overall survival (OS), cancer-specific survival (CSS), and disease-free survival outcomes among patients with stage I NSCLC who have undergone these procedures. METHODS: A systematic electronic search in three online databases was conducted from their earliest publication dates to June 2015. The studies were evaluated according to rigorous, predefined inclusion criteria. The hazard ratio (HR) was used as the outcome measure for data combining. RESULTS: There were nine eligible studies. These studies included 1181 patients who underwent segmentectomy and 2003 patients who underwent wedge resection. Stage I NSCLC patients who underwent segmentectomy had significantly better OS (HR 0.80; 95% confidence interval [CI], 0.68-0.93; p = 0.004) and CSS (HR 0.42; 95% CI, 0.20-0.88; p = 0.02) rates than those who underwent wedge resection. However, there were no significant differences in OS (HR 0.39; 95% CI, 0.15-1.02; p = 0.06) and CSS (HR 1.87; 95% CI, 0.29-12.06; p = 0.51) rates between segmentectomy and wedge resection in patients with stage Ia NSCLC with tumor size ⩽ 2 cm. CONCLUSIONS: For patients with stage I NSCLC, segmentectomy results in higher survival rates than wedge resection, whereas the outcomes of wedge resection are comparable to those of segmentectomy for patients with stage Ia NSCLC with tumor size ⩽ 2 cm. Considering the limitations and heterogeneity of the included studies, this conclusion should be further confirmed by rigorous randomized clinical trials.

Single chest tube drainage is superior to double chest tube drainage after lobectomy: a meta-analysis.

BACKGROUND: In this meta-analysis, we conducted a pooled analysis of clinical studies comparing the efficacy of single chest tube versus double chest tube after a lobectomy. METHODS: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. We performed a systematic electronic search of the PubMed, Embase, Cochrane Library and Web of Science databases to identify articles to include in our meta-analysis. A literature search was performed using relevant keywords. A meta-analysis was performed using RevMan© software. RESULTS: Five studies, published between 2003 and 2014, including 630 patients (314 patients with a single chest tube and 316 patients with a double chest tube), met the selection criteria. From the available data, the patients using a single tube demonstrated significantly decreased postoperative pain [weighted mean difference [WMD] -0.60; 95 % confidence intervals [CIs] -0.68-- 0.52; P < 0.00001], duration of drainage [WMD -0.70; 95 % CIs -0.90-- 0.49; P < 0.00001] and hospital stay [WMD -0.51; 95 % CIs -0.91-- 0.12; P = 0.01] compared to patients using a double tube after a pulmonary lobectomy. However, there were no significant differences in postoperative complications [OR 0.91; 95 % CIs 0.57-1.44; P = 0.67] and re-drainage rates [OR 0.81; 95 % CIs 0.42-1.58; P = 0.54]. CONCLUSION: Our results showed that a single-drain method is effective, reducing postoperative pain, hospitalization times and duration of drainage in patients who undergo a lobectomy. Moreover, the single-drain method does not increase the occurrence of postoperative complications and re-drainage rates.

Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis.

BACKGROUND: We performed a meta-analysis to clarify whether the molecular detection of tumor cells or micrometastases in the lymph node (LN) indicates a high risk of disease recurrence and poor survival in negative pathologic lymph node status non-small cell lung cancer (NSCLC). METHODS: A literature search was performed using relevant keywords. We searched relevant studies from PubMed, Embase, and the Cochrane Library. Direct and indirect meta-estimates were generated using Review Manager software with fixed effects for the study. Study-to-study heterogeneity was summarized using I (2) statistics and predictive intervals (PIs). RESULTS: Our analysis of eight eligible studies revealed that patients with lymph node micrometastases (LNMM) were associated with poor overall survival (OS) (HR, 1.98; 95 % CI, 1.50 to 2.62; p < 0.00001) and disease-free survival (DFS) (HR, 2.34; 95 % CI, 1.67-3.27; p < 0.00001). CONCLUSION: LNMM is associated with an increased risk of disease recurrence and poor survival in patients with negative pathologic node negative NSCLC. Thus, these patients need to be carefully followed up after the initial pulmonary resection.

The Effectiveness of Postoperative Radiotherapy in Patients With Completely Resected Thymoma: A Meta-Analysis.

BACKGROUND: This meta-analysis aimed to provide a pooled analysis of clinical studies correlating postoperative radiotherapy (PORT) with survival in patients with completely resected thymoma. METHODS: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. An electronic search was conducted using online databases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used in this meta-analysis and were calculated from published survival data. A meta-analysis was conducted to assess the impact of PORT in completely resected thymoma on overall survival (OS), disease-free survival (DFS). and disease-specific survival (DSS). We also performed a subgroup analysis for OS of patients with stage II and stage III thymoma. RESULTS: Fourteen studies, which included 3,823 patients (2,096 patients who received PORT and 1,727 patients who did not receive PORT), met the selection criteria. From the available data, the thymoma patients with PORT who did not undergo resection did not have significantly improved OS (HR 0.99; 95% CI 0.87 to 1.13; p = 0.87), DFS (HR 1.21; 95% CI 0.97 to 1.51; p = 0.09), or DSS (HR 0.66; 95% CI 0.39 to 1.13; p = 0.13) compared with the patients who did not undergo PORT. However, our subgroup analysis showed a significant difference in OS in patients with stage II thymoma (HR 0.57; 95% CI 0.41 to 0.80; p = 0.001) and patients with stage III thymoma (HR 0.73; 95% CI 0.59 to 0.90; p = 0.004). CONCLUSION: Our results showed that for completely resected thymoma, PORT had no advantage in the overall group of patients but increased OS in the patients with stage II and III thymoma after a complete resection. On the basis of this study, PORT is beneficial in patients with stage II and III patients after a complete resection.

Status of the Parkinson's disease gene family expression in non-small-cell lung cancer.

BACKGROUND: The purpose of this study is to detect the Parkinson's disease gene family mRNA relative expression in the non-small-cell lung cancer (NSCLC) tumor tissue and analyze the association between tumor characteristics and the Parkinson's disease gene family. METHODS: Tumor tissue and tumor-adjacent tissue of 114 NSCLC patients were collected and SYBR quantitative analysis was used to detect the relative expression level of nine Parkinson's disease gene mRNAs. Then, paired sample test, two-sided Student's t-test, or two-sided Wilcoxon rank sum test was performed to analyze the mRNA relative expression level of nine Parkinson's disease gene mRNAs in different gender, tumor histology, and tumor stage. RESULTS: Overexpression in the tumors was detected in 46/114 (40.35%) PARK1/4, 74/114 (64.91%) PARK2, 104/114 (91.23%) PARK5, 95/114 (83.33%) PARK6, 80/114 (70.18%) PARK7, 55/114 (48.25%) PARK8, 100/114 (87.72%) PARK9, 55/114 (48.25%) PARK15, and 99/114 (86.84%) glucocerebrosidase (GBA). Five genes PARK5 (91.23%), PARK6 (83.33%), PARK7 (70.18%), PARK9 (87.72%), and GBA (86.84%) were supposed to be overexpressed in the lung tumor tissues compared with tumor-adjacent tissues. There was no significant difference in PARK1/4, PARK2, PARK5, PARK9, and GBA mRNA expression by different tumor stage, whereas, PARK6, PARK7, PARK8, and PARK15 mRNA expression were found to have significant difference in the comparison of different tumor stages. The expression of PARK6 (P=0.01, P=0.03) and PARK15 (P<0.001, P<0.001) were significantly higher in stages I and II when compared with stage III, respectively. NSCLC patients in stage I showed the higher expression PARK7 compared to the patients in stage II (P=0.003). CONCLUSIONS: The high expression of PARK6, PARK7, and PARK15 might lead to the occurrence of a primary NSCLC tumor, and the tumor with a decreasing expression of these three genes tends to be stages II and III. The results of our study indicate that the Parkinson's disease gene family may be a potential marker for the prediction of NSCLC.

Comparison of two different mechanical esophagogastric anastomosis in esophageal cancer patients: a meta-analysis.

OBJECTIVE: In this meta-analysis, we conducted a pooled analysis of clinical studies comparing Linear Stapled (LS) versus Circular Stapled (CS) esophagogastric anastomosis for esophageal cancer. METHODS: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. We performed a systematic electronic search of the PubMed, Embase, Cochrane Library, Web of Science, and Chinese Biomedical databases as well as Chinese scientific journals to identify articles to include in our meta-analysis. The primary outcomes compared were anastomotic leak, anastomotic stricture and 3-month mortality. RESULTS: Five controlled trials comprising 840 patients (523 LS vs. 317 CS) were included. Primary outcomes revealed a statistically significant decrease in anastomotic strictures [risk ratio (RR): 0.26, 95 % confidence interval (CI): 0.11-0.60, P = 0.002] compared with linear stapled anastomosis. However, there were no significant differences between the two groups with respect to anastomotic leakage [risk ratio (RR): 0.80, 95 % confidence interval (CI): 0.40-1.58, P = 0.52] and 3-month mortality [risk ratio (RR): 0.94, 95 % confidence interval (CI): 0.47-1.87, P = 0.85]. CONCLUSION: There were no statistical differences in the rate of 3-month mortality or anastomotic leakage between the two groups. However, the LS method contributed to a reduced rate of anastomotic strictures. This meta-analysis may offer some specific suggestions for esophagogastric anastomosis.

Hand-sewn vs linearly stapled esophagogastric anastomosis for esophageal cancer: a meta-analysis.

AIM: To compare the outcomes of hand-sewn (HS) and linearly stapled (LS) esophagogastric anastomosis for esophageal cancer. METHODS: Before beginning this study, a rigorous protocol was established according to the recommendations of the Cochrane Collaboration. Databases and references were searched for all randomized controlled trials and comparative clinical studies that compared LS with HS esophagogastric anastomosis for esophageal cancer. The primary outcomes compared were anastomotic leak and stricture. Subgroup analyses were performed according to site of anastomosis. RESULTS: Fifteen studies were used, comprising 3203 patients (n = 2027 LS and 1176 HS). Primary outcome analysis revealed a significant decrease in anastomotic leakage (RR = 0.51, 95%CI: 0.41-0.65; P < 0.00001) associated with LS anastomosis. A significantly reduced rate of anastomotic stricture associated with LS was also found (RR = 0.56, 95%CI: 0.49-0.64; P < 0.00001). A subgroup analysis according to the site of anastomosis revealed a significantly reduced rate of anastomotic stricture (P < 0.00001). Although there was no significant difference in the decrease in thoracic anastomotic leakage, there was a significant decrease in cervical anastomotic leakage associated with LS (P < 0.00001). CONCLUSION: This meta-analysis indicates that the LS technique contributes to a reduced rate of leakage and stricture compared with the HS method.

Bone marrow micrometastasis is associated with both disease recurrence and poor survival in surgical patients with node-negative non-small-cell lung cancer: a meta-analysis.

OBJECTIVES: We performed a meta-analysis in order to determine whether the molecular tumour cell detection of either micrometastasis or isolated tumour cells in the bone marrow micrometastasis is indicative of a high risk of both disease recurrence and poor survival in the setting of node-negative non-small-cell lung cancer (NSCLC). METHODS: Before beginning this study, a rigorous protocol was established in accordance with the recommendations of the Cochrane Collaboration. A systematic literature search of Medline, EMbase, the Cochrane Library and the Web of Science was conducted in order to identify studies regarding the prognostic value of molecular tumour cell detection in the bone marrow of node-negative NSCLC. Any study describing the use of both immunochemistry and flow cytometry to detect bone marrow metastasis was selected. We extracted the associated 95% confidence intervals (CIs) and hazard ratios (HRs) from the included studies and performed meta-analyses on overall survival and either disease-free survival (DFS) or disease-free recurrence. Meanwhile, we compared the occurrence of bone marrow micrometastasis among different pathological types and different stages of disease. RESULTS: Eleven studies with a cumulative sample size of 2159 patients were included in our analysis. Our meta-analyses revealed that the occurrence of bone marrow micrometastasis was not related to patient pathological types and stages in cancers ranging from adenocarcinoma and squamous cell carcinoma [relative risk (RR): 0.92; 95% CI: 0.78-1.08; P = 0.29], stages I and II (RR: 0.88; 95% CI: 0.67-1.17; P = 0. 39), stages II and III (RR: 0.98; 95% CI: 0.73-1.31; P = 0.89) and stages I and III (RR: 0.84; 95% CI: 0.68-1.05; P = 0.13). However, molecular tumour cell detection within the bone marrow was associated with both poor OS (HR: 1.84; 95% CI: 1.41-2.40; P < 0.00001) and poor DFS (HR: 1.75; 95% CI: 1.18-2.60; P = 0.005). Our subgroup analyses indicated that the presence of bone marrow micrometastasis was not a significant prognostic factor with respect to DFS at stage I (HR: 2.35; 95% CI: 0.67-8.25; P = 0.18). CONCLUSIONS: The molecular detection of isolated tumour cell in the bone marrow is associated with both poor survival and an increased rate of recurrence in patients with node-negative NSCLC; this approach may result in the development of a new metastatic cascade concept and the development of novel approaches to cancer therapy.

Esophageal Cancer with a Synchronous Multiple Carcinoid of the Duodenal Bulb.

Carcinoid tumors of the duodenum are relatively rare. Although they were considered benign lesions, they are now classified malignant, occasionally with poor prognosis. We report a case of esophageal cancer with a synchronous multiple carcinoid of the duodenal bulb. An upper endoscopy visualized with esophageal scan disclosed a stenotic lesion in the lower esophagus and revealed multiple 4--5-mm-diameter masses which were on the fore wall of the duodenal bulb. The postoperative pathology report confirmed the diagnosis of esophageal squamous cancer and duodenal bulb carcinoid.

Comparison of outcomes following end-to-end hand-sewn and mechanical oesophagogastric anastomosis after oesophagectomy for carcinoma: a prospective randomized controlled trial.

OBJECTIVES: The effects of the use of the stapler or hand-sewn method in oesophagogastric anastomosis on postoperative morbidity, mortality and quality of life after oesophagectomy remain controversial. The purpose of his study was to compare clinical outcomes of hand-sewn and stapler techniques in oesophagogastric anastomosis after oesophagectomy for oesophageal carcinoma. METHODS: We performed a prospective randomized controlled trial on 478 patients treated for oesophageal tumour between February 2009 and December 2011. Patients were randomly assigned to two treatment groups with 237 patients in the hand-sewn group and 241 patients in the circular stapler group (http://www.chictr.org: ChiCTR-TRC-13004428). RESULTS: The mean follow-up time was 18 months. The mean operating time of the stapled group and the hand-sewn group were 193 and 226 min, respectively (P < 0.001). Seventeen clinical and radiological leakages occurred in the hand-sewn group compared with 7 in the stapler group (P = 0.033). In the stapler group hospital mortality occurred in 10 patients (4.3%) and in the hand-sewn group in 9 patients (3.9%) (P = 0.837). Anastomotic strictures were noted in 31 patients from the stapler group (14.2%) and in 16 patients from the hand-sewn group (7.5%) (P = 0.027). CONCLUSIONS: Using the circular stapler method in oesophagogastric anastomoses had a lower anastomotic leakage rate and shorter operating time compared with the hand-sewn method. However, the circular stapler method was associated with a significantly increased risk of anastomotic strictures.

Preventing and localizing esophagogastric anastomosis leakage by sleeve-wrapping of the pedicled omentum.

AIM: To develop a technique of sleeve-wrapping the pedicled omentum around the esophagogastric anastomosis for preventing and localizing leakage. METHODS: This study includes data from 86 patients who were diagnosed with esophageal cancer and underwent the technique of sleeve-wrapping the pedicled omentum around esophagogastric anastomosis after esophagectomy between November 2011 and July 2013. The early complications that occurred during follow-up were analyzed. RESULTS: Postoperative complications included pulmonary complications (13/86; 15.1%) and abdominal or thoracic wound infection (3/86; 3.5%). Complications that occurred during follow-up included one case of anastomosis leakage (limited by omentum; 1.2%) and five case of anastomosis stricture (5.8%). No deaths occurred. All complications were resolved through traditional treatment. No additional surgery was needed. CONCLUSION: Sleeve-wrapping of the pedicled omentum around esophagogastric anastomosis after esophagectomy is safe and effective for preventing and localizing anastomosis leakage without increasing anastomosis stricture.