2015 Vol.27(2)

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Erratum
Erratum
2015, 27(2): E1-E1. doi: 10.3978/j.issn.1000-9604.2015.03.02
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Review Article
Transcatheter embolization therapy in liver cancer: an update of clinical evidences
Yì-Xiáng J. Wáng, Thierry De Baere, Jean-Marc Idée, Sébastien Ballet
2015, 27(2): 96-121. doi: 10.3978/j.issn.1000-9604.2015.03.03
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Transarterial chemoembolization (TACE) is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization. Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma (HCC) patients who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. TACE for liver cancer has been proven to be useful in local tumor control, to prevent tumor progression, prolong patients’ life and control patient symptoms. Recent evidence showed in patients with single-nodule HCC of 3 cm or smaller without vascular invasion, the 5-year overall survival (OS) with TACE was similar to that with hepatic resection and radiofrequency ablation. Although being used for decades, Lipiodol® (Lipiodol® Ultra Fluid®, Guerbet, France) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology. There have been efforts to improve the delivery of chemotherapeutic agents to tumors. Drug-eluting bead (DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner. Three DEBs are available, i.e., Tandem® (CeloNova Biosciences Inc., USA), DC-Beads® (BTG, UK) and HepaSphere® (BioSphere Medical, Inc., USA). Transarterial radioembolization (TARE) technique has been developed, and proven to be efficient and safe in advanced liver cancers and those with vascular complications. Two types of radioembolization microspheres are available i.e., SIR-Spheres® (Sirtex Medical Limited, Australia) and TheraSphere® (BTG, UK). This review describes the basic procedure of TACE, properties and efficacy of some chemoembolization systems and radioembolization agents which are commercially available and/or currently under clinical evaluation. The key clinical trials of transcatheter arterial therapy for liver cancer are summarized.
Progression of targeted therapy in advanced cholangiocarcinoma
Yingying Huang, Xiaomei Li, Yunbo Zhao
2015, 27(2): 122-127. doi: 10.3978/j.issn.1000-9604.2015.04.01
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It is necessary to establish an effective therapy to improve the survival of patients with advanced cholangiocarcinoma (CCA). Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.
The status, limitation and improvement of adoptive cellular immunotherapy in advanced urologic malignancies
Haoqing Shi, Xiangjie Qi, Bin Ma, Yanwei Cao, Lina Wang, Lijiang Sun, Haitao Niu
2015, 27(2): 128-137. doi: 10.3978/j.issn.1000-9604.2014.12.15
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In recent years, immunotherapy has been gradually established as the fourth frequently adopted antitumor therapy, following surgery, chemotherapy and radiotherapy, for advanced urologic malignancies with an improved understanding of theoretical basis, such as molecular biology and immunology. Thereinto, adoptive cellular immunotherapy (ACI) has become one of the hotspots, which comprises a variety of treatment approaches, such as TIL, CIK cell, γδ T cell, CAR-engineered T cell and Allogeneic stem cell transplantation (alloSCT). Although preclinical efficacy has been demonstrated remarkably, clinical trials could not consistently show the benefit due to multi-factors in complex immunosuppressive microenvironment in vivo compared to that of in vitro. Here we review some timely aspects of ACI for advanced urologic malignancies, and describe the current status and limitation of immunotherapy from the cellular level. It’s our expectation to provide prompting consideration of novel combinatorial ACI strategies and a resurgence of interest in ACI for advanced urologic malignancies.
Original Article
China’s landscape in oncology drug research: perspectives from research collaboration networks
Han You, Jingyun Ni, Michael Barber, Thomas Scherngell, Yuanjia Hu
2015, 27(2): 138-147. doi: 10.3978/j.issn.1000-9604.2015.04.05
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ObjectiveBetter understanding of China’s landscape in oncology drug research is of great significance for discovering anti-cancer drugs in future. This article differs from previous studies by focusing on Chinese oncology drug research communities in co-publication networks at the institutional level. Moreover, this research aims to explore structures and behaviors of relevant research units by thematic community analysis and to address policy recommendations.MethodsThis research used social network analysis to define an institutions network and to identify a community network which is characterized by thematic content.ResultsA total of 675 sample articles from 2008 through 2012 were retrieved from the Science Citation Index Expanded (SCIE) database of Web of Science, and top institutions and institutional pairs are highlighted for further discussion. Meanwhile, this study revealed that institutions based in the Chinese mainland are located in a relatively central position, Taiwan’s institutions are closely assembled on the side, and Hong Kong’s units located in the middle of the Chinese mainland’s and Taiwan’s. Spatial division and institutional hierarchy are still critical barriers to research collaboration in the field of anti-cancer drugs in China. In addition, the communities focusing on hot research areas show the higher nodal degree, whereas communities giving more attention to rare research subjects are relatively marginalized to the periphery of network.ConclusionsThis paper offers policy recommendations to accelerate cross-regional cooperation, such as through developing information technology and increasing investment. The brokers should focus more on outreach to other institutions. Finally, participation in topics of common interest is conducive to improved efficiency in research and development (R&D) resource allocation.
Kaiso mainly locates in the nucleus in vivo and binds to methylated, but not hydroxymethylated DNA
Sisi Qin, Baozhen Zhang, Wei Tian, Liankun Gu, Zheming Lu, Dajun Deng
2015, 27(2): 148-155. doi: 10.3978/j.issn.1000-9604.2015.04.03
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ObjectiveKaiso is upregulated in many cancers and proposed to bind with both methylated- and unmethylated-DNA in the nucleus as a transcriptional repressor. The objective is to define its subcellular localization in vivo and exact binding DNA sequences in cells.MethodsCompartmentalization of exogenous Kaiso in cells was tracked with enhanced green fluorescence protein (EGFP) tag. The endogenous Kaiso expression in gastric carcinoma tissue was examined with immunohistochemical staining. Kaiso-DNA binding was tested using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP).ResultsKaiso mainly localized in the nucleus of cancer and stromal cells in vivo, but remained in the cytoplasm of cultured cells. Most importantly, nuclear Kaiso can bind with the methylated-CGCG-containing sequence in the CDKN2A promoter, but not with the hydroxymethylated-CGCG sequence in HCT116 cells.ConclusionsKaiso locates mainly in the nucleus in vivo where it binds with the methylated-CGCG sequences, but does not bind with the hydroxymethylated-CGCG sequences.
Variant TP53BP1 rs560191 G>C is associated with risk of gastric cardia adenocarcinoma in a Chinese Han population
Sheng Zhang, Weifeng Tang, Guowen Ding, Chao Liu, Ruiping Liu, Suocheng Chen, Haiyong Gu, Chunzhao Yu
2015, 27(2): 156-162. doi: 10.3978/j.issn.1000-9604.2015.03.05
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ObjectiveTo investigate the association between gastric cardia adenocarcinoma (GCA) and ten functional single nucleotide polymorphisms (SNPs), including TP53BP1 rs560191 G>C, CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A, and six C1orf10/CRNN variants. We performed a hospital-based case-control study to evaluate the genetic effects of these SNPs.MethodsTwo hundred and forty-three GCA cases and 476 controls were enrolled in this study. A custom-by-design 48-Plex SNPscanTM Kit was used to determine their genotypes.ResultsWhen the TP53BP1 rs560191 GG homozygote genotype was used as the reference group, the GC genotype was associated with a significantly increased risk of GCA. The CC genotype was not associated with the risk of GCA compared with the GG genotype. None of the CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A or the six C1orf10/CRNN polymorphisms showed a significant difference in genotype distributions between the cases and the controls.ConclusionsThe results demonstrated that the functional polymorphism TP53BP1 rs560191 G>C might contribute to GCA susceptibility. However, the statistical power of our study was limited. Large, well-designed studies and further functional investigations are needed to confirm our findings.
HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis
Zhi Peng, Jianling Zou, Xiaotian Zhang, Yehong Yang, Jing Gao, Yilin Li, Yanyan Li, Lin Shen
2015, 27(2): 163-171. doi: 10.3978/j.issn.1000-9604.2014.12.09
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BackgroundA number of studies have examined human epidermal growth factor receptor 2 (HER2) status in primary gastric cancer (GC) and associated metastasis, some showed their great concordance in HER2 expression, but others demonstrated notable discordance. There is still little consensus on HER2 discordance, therefore, a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis.MethodsPubMed, EMBASE, ASCO and The Cochrane Library were searched for studies that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March, 2014. Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions.ResultsEighteen articles including 1,867 patients were included for the meta-analysis in accordance with the selection criteria. Pooled discordance proportions were 7% [95% confidence interval (CI): 5-10%] for HER2 status. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17% (95% CI: 7-29%) and 4% (95% CI: 2-6%) respectively. No publication bias was found in the meta-analysis.ConclusionsThe discordance of HER2 status is not rare in primary and metastatic GC through our meta-analysis. Prospective studies are needed to testify the clinical significance of the discordance of HER2 status.
Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage III non-small cell lung cancer: a preliminary report
Di Liu, Yu-Xin Shen, Wei-Xin Zhao, Guo-Liang Jiang, Jia-Yan Chen, Min Fan
2015, 27(2): 172-180. doi: 10.3978/j.issn.1000-9604.2014.11.05
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ObjectiveIn recent years, the combination of cetuximab and chemoradiotherapy (CRT) has been used to treat stage III non-small cell lung cancer (NSCLC); however, limited data are available for Chinese patients. Herein, we report preliminary data from a phase I/II study testing the combination of cetuximab with inductive chemotherapy, followed by concurrent CRT (CCRT) in Chinese patients with stage III NSCLC.MethodsEligibility criteria were Zubrod performance status (PS) 0-1, forced expiratory volume in 1 second (FEV1) ≥1.2 L and adequate organ function. Enrolled patients received weekly cetuximab (initial dose of 400 mg/m2 on day 1 of week 1 and a maintenance dose of 250 mg/m2 on week 2 to the end of CCRT) with cisplatin/vinorelbine (NP) chemotherapy (every 3 weeks for 2 cycles from week 2, followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy (TRT) (60-66 Gy/2 Gy). The primary endpoints were toxicity and feasibility. All patients received positron emission tomography-computerized tomography (PET-CT) scans within the 2 weeks prior to enrollment. Univariate analyses were used to assess the correlation between SUV-T, SUV-N, SUV-TOTAL, gender, age, histology, tumor-node-metastasis (TNM) stage, PS and smoking status and survival. Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test.ResultsSeventeen patients were enrolled and 16 completed the full regime. The overall response rate (ORR) was 58.8% and 82.3% after the induction and CCRT phases, respectively. With a median follow-up duration of 27.6 months, the median survival was 27.6 months [95% confidence interval (CI): 11.3-43.9 months] with 1- and 2-year survival rates of 88.2% (95% CI, 60.6-96.9%) and 58.8% (95% CI, 60.6-77.8%), respectively. Three patients remain progression-free to date, and the median progression-free survival (PFS) was 13.5 months (95% CI, 6.8-20.2 months). No treatment-related death occurred; however, 76% of the patients experienced grade 3+ adverse events (AEs), including nausea/vomiting, intestinal obstruction, and esophagitis (<6%), while other AEs were mostly of hematological nature (71%). The cut-off values for SUV-T and SUV-TOTAL were 11 and 20, respectively. Univariate analyses revealed SUV-TOTAL (P=0.027), SUV-T (P=0.025), and PS (P=0.006) as potential survival predictors, with a hazard ratio (HR) of 3.4, 3.7, and 9.9, respectively.ConclusionsThe combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising. Local and locoregional maximal SUVs, defined by 18F-FDG PET-CT scanning, may represent a prognostic indicator for long-term survival for these patients, which warrants further study.
Activation of Toll-like receptors signaling in non-small cell lung cancer cell line induced by tumor-associated macrophages
Xing Ke, Meng Wu, Jianfang Lou, Shuping Zhang, Peijun Huang, Ruihong Sun, Lei Huang, Erfu Xie, Fang Wang, Bing Gu
2015, 27(2): 181-189. doi: 10.3978/j.issn.1000-9604.2015.03.07
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BackgroundInflammation is often linked with the progress and poor outcome of lung cancer. The understanding of the relationship between tumor-associated macrophages (TAMs) and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production. Toll-like receptors (TLRs) are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology.MethodsTo investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytokines in lung cancer cells, we established an in vitro coculture system using TAMs and human non-small cell lung cancer (NSCLC) cell line SPC-A1. Levels of interleukin (IL)-1β, IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs. Expression changes of TLRs and TLRs signaling pathway proteins in SPC-A1 were further confirmed by RT-PCR and western blot. The level changes of IL-1β, IL-6 and IL-8 in SPC-A1 were also detected after the stimulation of TLRs agonists.ResultsWe found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-13-acetate (PMA). Higher mRNA and supernate secretion levels of IL-1β, IL-6 and IL-8 were detected in SPC-A1 after being cocultured with TAMs. We also found that TLR1, TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs. Meanwhile, TLRs signaling pathway proteins were also significantly activated. Moreover, pre-treatment with agonist ligands for TLR1, TLR6 and TLR7 could dramatically promote inductions of IL-1β, IL-6 and IL-8.ConclusionsThese findings demonstrated that TAMs may enhance IL-1β, IL-6 and IL-8 expressions via TLRs signaling pathway. We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.
Nab-paclitaxel (abraxane)-based chemotherapy to treat elderly patients with advanced non-small-cell lung cancer: a single center, randomized and open-label clinical trial
Hanrui Chen, Xuewu Huang, Shutang Wang, Xinting Zheng, Jietao Lin, Peng Li, Lizhu Lin
2015, 27(2): 190-196. doi: 10.3978/j.issn.1000-9604.2014.12.17
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BackgroundThe purpose of this study is to evaluate the clinical efficacy and safety of abraxane-based chemotherapy with/without nedaplatin in elderly patients with non-small-cell lung cancer (NSCLC).Materials and methodsFrom October 2009 to January 2013, 48 elderly patients (≥65 years) with NSCLC were investigated in this clinical trial. The patients were randomized and equally allocated into arms A and AP: (A) abraxane (130 mg/m2, days 1, 8); (B) abraxane + nedaplatin (20 mg/m2 days 1-3, q3w). The parameters of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and side effects were evaluated between two arms.ResultsOver 80% of the patients completed four cycles of chemotherapy. The total ORR was 21.3%, DCR was 55.3%, PFS 4.5 months and OS 12.6 months. No significant difference was found between arms A and AP in terms of ORR (16.7% vs. 26.1%, P=0.665) or DCR (55.3% vs. 56.5%, P=0.871). The median PFS in arm A was 3.3 months [25-75% confidence interval (CI): 3.1-7.2] and 5.5 months (25-75% CI: 3.2-7.0) in arm AP with no statistical significance (P=0.640). The median OS in arm A was 12.6 months (25-75% CI: 5.7-26.2) and 15.1 months (25-75% CI: 6.4-35.3) in arm AP with no statistical significance (P=0.770). The side effects were mainly grade 1-2. The incidence of grade 3-4 toxicities was 29.1% in arm A and 62.5% in arm AP with a statistical significance (P=0.020).ConclusionsCompared with combined therapy, abraxane alone chemotherapy was beneficial for elderly NSCLC patients with better tolerability and less adverse events, whereas did not significantly differ in terms of ORR, DCR, PFS or OS.
Nonintubated uniportal video-assisted thoracoscopic surgery for primary spontaneous pneumothorax
Shuben Li, Fei Cui, Jun Liu, Xin Xu, Wenlong Shao, Weiqiang Yin, Hanzhang Chen, Jianxing He
2015, 27(2): 197-202. doi: 10.3978/j.issn.1000-9604.2015.03.01
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ObjectiveThe objective of the current study was to evaluate the feasibility and safety of nonintubated uniportal video-assisted thoracoscopic surgery (VATS) for the management of primary spontaneous pneumothorax (PSP).MethodsFrom November 2011 to June 2013, 32 consecutive patients with PSP were treated by nonintubated uniportal thoracoscopic bullectomy using epidural anaesthesia and sedation without endotracheal intubation. An incision 2 cm in length was made at the 6th intercostal space in the median axillary line. The pleural space was entered by blunt dissection for placement of a soft incision protector. Instruments were then inserted through the incision protector to perform thoracoscopic bullectomy. Data were collected within a minimum follow-up period of 10 months.ResultsThe average time of surgery was 49.0 min (range, 33-65 min). No complications were recorded. The postoperative feeding time was 6 h. The mean postoperative chest tube drainage and hospital stay were 19.3 h and 41.6 h, respectively. The postoperative pain was mild for 30 patients (93.75%) and moderate for two patients (6.25%). No recurrences of pneumothorax were observed at follow-up.ConclusionsThe initial results indicated that nonintubated uniportal video-assisted thoracoscopic operations are not only technically feasible, but may also be a safe and less invasive alternative for select patients in the management of PSP. This is the first report to include the use of a nonintubated uniportal technique in VATS for such a large number of PSP cases. Further work and development of instruments are needed to define the applications and advantages of this technique.
Activity estimation in radioimmunotherapy using magnetic nanoparticles
Samira Rasaneh, Hossein Rajabi, Fariba Johari Daha
2015, 27(2): 203-208. doi: 10.3978/j.issn.1000-9604.2015.03.06
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ObjectiveEstimation of activity accumulated in tumor and organs is very important in predicting the response of radiopharmaceuticals treatment. In this study, we synthesized 177Lutetium (177Lu)-trastuzumab-iron oxide nanoparticles as a double radiopharmaceutical agent for treatment and better estimation of organ activity in a new way by magnetic resonance imaging (MRI).Methods177Lu-trastuzumab-iron oxide nanoparticles were synthesized and all the quality control tests such as labeling yield, nanoparticle size determination, stability in buffer and blood serum up to 4 d, immunoreactivity and biodistribution in normal mice were determined. In mice bearing breast tumor, liver and tumor activities were calculated with three methods: single photon emission computed tomography (SPECT), MRI and organ extraction, which were compared with each other.ResultsThe good results of quality control tests (labeling yield: 61%±2%, mean nanoparticle hydrodynamic size: 41±15 nm, stability in buffer: 86%±5%, stability in blood serum: 80%±3%, immunoreactivity: 80%±2%) indicated that 177Lu-trastuzumab-iron oxide nanoparticles could be used as a double radiopharmaceutical agent in mice bearing tumor. Results showed that 177Lu-trastuzumab-iron oxide nanoparticles with MRI had the ability to measure organ activities more accurate than SPECT.ConclusionsCo-conjugating radiopharmaceutical to MRI contrast agents such as iron oxide nanoparticles may be a good way for better dosimetry in nuclear medicine treatment.
Diffusion-tensor imaging as an adjunct to dynamic contrast-enhanced MRI for improved accuracy of differential diagnosis between breast ductal carcinoma in situ and invasive breast carcinoma
Yuan Wang, Xiaopeng Zhang, Kun Cao, Yanling Li, Xiaoting Li, Liping Qi, Lei Tang, Zhilong Wang, Shunyu Gao
2015, 27(2): 209-217. doi: 10.3978/j.issn.1000-9604.2015.03.04
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ObjectiveTo determine the value of diffusion-tensor imaging (DTI) as an adjunct to dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for improved accuracy of differential diagnosis between breast ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC).MethodsThe MRI data of 63 patients pathologically confirmed as breast cancer were analyzed. The conventional MRI analysis metrics included enhancement style, initial enhancement characteristic, maximum slope of increase, time to peak, time signal intensity curve (TIC) pattern, and signal intensity on FS-T2WI. The values of apparent diffusion coefficient (ADC), directionally-averaged mean diffusivity (Davg), exponential attenuation (EA), fractional anisotropy (FA), volume ratio (VR) and relative anisotropy (RA) were calculated and compared between DCIS and IBC. Multivariate logistic regression was used to identify independent factors for distinguishing IBC and DCIS. The diagnostic performance of the diagnosis equation was evaluated using the receiver operating characteristic (ROC) curve. The diagnostic efficacies of DCE-MRI, DWI and DTI were compared independently or combined.ResultsEA value, lesion enhancement style and TIC pattern were identified as independent factor for differential diagnosis of IBC and DCIS. The combination diagnosis showed higher diagnostic efficacy than a single use of DCE-MRI (P=0.02), and the area of the curve was improved from 0.84 (95% CI, 0.67-0.99) to 0.94 (95% CI, 0.85-1.00).ConclusionsQuantitative DTI measurement as an adjunct to DCE-MRI could improve the diagnostic performance of differential diagnosis between DCIS and IBC compared to a single use of DCE-MRI.
Case Report
A case of small intestinal hemorrhage secondary to metastatic lung cancer in the elderly
Bangchao Lu, Congzhu Ding, Chun Wang, Juan Cao
2015, 27(2): 218-220. doi: 10.3978/j.issn.1000-9604.2014.11.01
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Gastrointestinal metastasis from primary lung cancer is rare. In the present study, we report the case of a 78-year-old male who was admitted to the emergency department with acute bleeding of the digestive tract. During evaluation, he was found to have lung adenocarcinoma metastasis in the small bowel leading to hemorrhage. A jejunum wedge resection was carried out and bleeding was controlled. However, 2 months after the operation, the patient died from severe pulmonary infection. We also review the published literature of primary lung cancer with gastrointestinal metastasis.