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Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status

Chenfei Zhou, Jun Zhang

《医学前沿（英文）》 2019年 第13卷 第1期   页码 12-23 doi: 10.1007/s11684-019-0685-9

摘要：

Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients’ outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.

关键词： gastrointestinal cancer     immune checkpoint inhibitor     combination therapy    

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Detection of digestive malignancies and post-gastrectomy complications via gastrointestinal fluid examination

null

《医学前沿（英文）》 2017年 第11卷 第1期   页码 20-31 doi: 10.1007/s11684-016-0493-4

摘要：

To date, gastric carcinoma (GC) is one of the common and fatal digestive malignancies worldwide. The prognosis of GC is not always satisfactory because of late diagnosis. Scholars are keen on discovering novel accurate and economical biomarkers in body liquids for GC screening to detect and evaluate the lesion before the results of imaging techniques are obtained. While traditional serum assays have limited sensitivity and specificity, gastrointestinal juice may provide relevant specific biomarkers because of its close contact with the tumor. Herein, the current progress in the relationship between gastrointestinal fluid analyses and GC is systematically and comprehensively reviewed. The detection of gastric juice pH, fluorescence spectrum, cytology, Helicobacter pylori-associated markers, nitrosamines, conventional tumor markers, amino acids, proteomics, microRNAs, long noncoding RNAs, protein-coding genes, vitamin C, etc., and combination tests of different category markers could provide important diagnostic and prognostic clues for gastrointestinal diseases. Particularly, early GC may be efficiently screened using gastric juice. Gastrointestinal fluid examination could also predict the adverse effects of postgastrectomy, such as pancreatic leakage, fistula, and abscess. Gastric fluid markers should be further studied to reveal the early predicators of malignancy and complications. The methods for obtaining the samples of gastrointestinal juice with minimum incision should also be comprehensively investigated.

关键词： gastrointestinal fluid     gastric carcinoma     biomarker     diagnosis     prognosis     gastrectomy     adverse events    

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A ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 108-111 doi: 10.1007/s11684-014-0344-0

摘要：

Hemoperitoneum is a rare and potentially life-threatening complication of GIST. We reported a 54-year-old man who developed disseminated intra-abdominal recurrence from a previously resected gastrointestinal stromal tumour (GIST) of the small bowel, and the patient presented with hemoperitoneum. Emergent debulking surgery was performed. A high dose imatinib was prescribed. Despite the presence of residual disease, the patient was well clinically 8 months after the operation. Even though, there is no evidence to support the routine use of debulking surgery in the management of GIST. In our patient, disease progression after second line targeted therapy and the absence of alternative treatment options for spontaneous rupture and hemoperitoneum prompted us to treat the patient aggressively. Resection of the ruptured GIST was carried out for control of bleeding and to prevent recurrent bleeding in this patient with good surgical risks. During the treatment decision-making, the patient’s general condition, the risk of surgery and the extent of dissemination were taken into consideration. In this patient who presented with spontaneous rupture of a small intestinal GIST, the novel use of targeted therapy and aggressive surgical treatment produced reasonably good survival outcome.

关键词： gastrointestinal stromal tumour     hemoperitoneum     small bowel GIST     small bowel neoplasm     imatinib    

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Potential indicators predict progress after surgical resection of gastrointestinal stromal tumors

null

《医学前沿（英文）》 2012年 第6卷 第3期   页码 317-321 doi: 10.1007/s11684-012-0203-9

摘要：

In order to find out the potential indicators predicting prognosis of malignant gastrointestinal stromal tumors (GISTs) after surgical resection, we collected clinical records of 80 patients with malignant GISTs. Tumor location, size, mitotic index, necrosis were compared with the prognosis of malignant GISTs by Kaplan-Meier method and log-rank test. After a median follow-up of 844 days (52–2 145), we found that as National Institutes of Health suggested, tumors with intermediate risk had more favorable prognosis than that with high risk. Their 3-year survival rate were 65.3% and 41.3%, respectively (P<0.001). Moreover, tumor size and mitotic index were associated with free survival. The 3-year survival rate for patients with tumor size≤10 cm and>10 cm were 62.3% and 41.8%, respectively (P = 0.002), Tumors with mitotic index≤5/50 HPF had a higher 3-year survival rate than tumors with mitotic index>5/50 HPF (67.1% versus 40.7%, P = 0.005). The presence of necrosis was directly related to the malignant behavior. The 3-year survival rate for presence and absence necrosis were 50.8% and 64.8% (P = 0.008). From the present study, we can conclude that besides tumors size and mitotic index, tumor location and necrosis also influence on the long-term survival of patient with malignant GISTs after surgical resection.

关键词： gastrointestinal stromal tumors     surgery     survival    

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Gastrointestinal damage caused by swallowing multiple magnets

null

《医学前沿（英文）》 2012年 第6卷 第3期   页码 280-287 doi: 10.1007/s11684-012-0207-5

摘要：

Swallowing multiple magnets is not uncommon worldwide and it frequently leads to serious consequences. However, most patients fail to receive timely and correct diagnosis and treatment. A literature search was performed to establish an algorithm for these accidents by the authors to identify relevant articles published from June 1987 to October 2010 in Google, Medline, ISI Web of Knowledge Ovid, CNKI, Korea Med and library document delivery, using search terms “magnet ingestion, ” “fistula, ” and “perforation. ” A total of 149 patients with ingestion of magnetic foreign bodies from 20 countries and areas were identified. 22 of them were companioned with neurological and psychiatric disorders. Swallowing magnets occurred throughout childhood and adolescent, mostly ranging 2 to 4 years in age. Various gastrointestinal damages such as necrosis and intestinal perforation or fistula were encountered. Damage from swallowing multiple magnets carries a significant risk of morbidity and even mortality throughout childhood to adolescent worldwide. Older children and adults with neurological and psychiatric problems may be at high risk for such accidents. Early intervention is crucial.

关键词： magnet     ingestion     fistula     perforation    

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血清免疫球蛋白G N-糖基的高通量分析——一种消化道癌症的非侵入性生物标志物 Article

刘鹏程, 王小兵, 顿爱社, 李昱潼, 李厚强, 王璐, 张怡春, 李灿灿, 张金霞, 张晓雨, 马立兴, 侯海峰

《工程（英文）》 2023年 第26卷 第7期   页码 44-53 doi: 10.1016/j.eng.2023.02.008

摘要： 从中国医学科学院肿瘤医院招募749名消化道癌症患者，包括食管癌 (esophageal cancer, EC)、胃癌 (gastric cancer, GC)、结直肠癌 (colorectal cancer, CRC) 和胰腺癌 (pancreatic cancer, PC) 患者。

关键词： 消化道癌症     糖基化     免疫球蛋白 G     诊断生物标志物    

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Prognostic significance of clinicopathologic parameters in gastrointestinal stromal tumors: a study of

LIANG Yumei, LI Xianghong, LU Youyong, LV Yali, ZHONG Mei, PU Xiaolu, LI Wenmei

《医学前沿（英文）》 2008年 第2卷 第1期   页码 87-94 doi: 10.1007/s11684-008-0016-z

摘要： The biological behavior of gastrointestinal stromal tumors (GISTs) are highly variable. To investigate the biological behavior of GIST, we collected 83 cases of gastric and 62 cases of small intestinal GIST from the Department of Pathology of the Chinese PLA General Hospital. The parameters include age, primary tumor location, tumor diameter, mitotic index, tumor necrosis, risk assessment, clinical stage and the exon 11 mutation. All these were analyzed in 105 cases along with the follow-up data and tested by log rank and COX hazard proportional model. We find that the average age of gastric GIST was 55.4 years. Of the 62 cases that were followed up, 17 cases had metastasis or recurrence and the 5-year survival rate was (66.51 ± 17.06)%. For the small intestinal GIST, the average age was 50.6 years and 43 cases were followed up. Of these, 22 cases had metastasis or recurrence and the 5-year survival rate was (61.76 ± 18.30)%. Small intestinal GIST was more frequently associated with metastasis and tumor relapse than gastric GIST ( = 6.131, = 0.013). For gastric GIST, patients younger than 50 years ( = 0.046), the advanced clinical stage ( = 0.0001), the large tumor diameter ( = 0.0001), a high mitotic index ( = 0.0001), necrosis ( = 0.0001) and a high risk grade ( = 0.004) were all correlated with a lower survival rate. The COX hazard proportional model revealed that advanced clinical stage ( = 0.001), large tumor size ( = 0.001), a high mitotic index ( = 0.002) and the high risk grade ( = 0.018) indicated a poorer prognosis in gastric GIST. For small intestinal GIST, necrosis ( = 0.036) and advanced clinical stage ( = 0.010) were associated with lower survival rates and the clinical stage was shown to be an independent prognostic indicator. A total of 25 cases harbored mutations in exon 11. The frequency of mutation was 32% and 22.5% for gastric and small intestinal GIST, respectively. In gastric GIST, the mutated was predominant in patients older than 50 years of age. But in the small intestinal GIST, the mutated was predominant in the age group of 40–49 years. In conclusion, for gastric GIST, clinical stage, tumor size, mitotic index, and risk grade are the prognostic indicators. For small intestinal GIST, necrosis and clinical stage are the prognostic indicators. Small intestinal GIST are more aggressive than gastric GIST. The occurrence of mutation may correlate with the age of patients.
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Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li

《医学前沿（英文）》 2020年 第14卷 第1期   页码 101-111 doi: 10.1007/s11684-019-0698-4

摘要： Growing evidence suggests that somatic hypermutational status and programmed cell death-1 overexpression are potential predictive biomarkers indicating treatment benefits from immunotherapy using immune checkpoint inhibitors. However, biomarker-matched trials are still limited, and many of the genomic alterations remain difficult to target. To isolate the potential somatic hypermutational tumor from microsatellite instability low/microsatellite stability (MSI-L/MSS) cases, we employed two commercial kits to determine MSI and forensic short tandem repeat (STR) alternations in 250 gastrointestinal (GI) tumors. Three types of forensic STR alternations, namely, allelic loss, Aadd, and Anew, were identified. 62.4% (156/250) of the patients with GI exhibited STR alternation, including 100% (15/15) and 60% (141/235) of the microsatellite high instability and MSI-L/MSS cases, respectively. 30% (75/250) of the patients exhibited STR instability with more than 26.32% (26.32%–84.21%) STR alternation. The cutoff with 26.32% of the STR alternations covered all 15 MSI cases and suggested that it might be a potential threshold. Given the similar mechanism of the mutations of MSI and forensic STR, the widely used forensic identifier STR kit might provide potential usage for identifying hypermutational status in GI cancers.

关键词： mismatch repair protein deficiency (MMR-D)     microsatellite instability (MSI)     short tandem repeats (STR)     gastrointestinal tumor     hypermutability    

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Ingestible wireless capsules for enhanced diagnostic inspection of gastrointestinal tract

Mahdi RASOULI, Andy Prima KENCANA, Van An HUYNH, Eng Kiat TING, Joshua Chong Yue LAI, Kai Juan WONG, Su Lim TAN, Soo Jay PHEE

《机械工程前沿（英文）》 2011年 第6卷 第1期   页码 40-44 doi: 10.1007/s11465-011-0204-4

摘要：

Wireless capsule endoscopy has become a common procedure for diagnostic inspection of gastrointestinal tract. This method offers a less-invasive alternative to traditional endoscopy by eliminating uncomfortable procedures of the traditional endoscopy. Moreover, it provides the opportunity for exploring inaccessible areas of the small intestine. Current capsule endoscopes, however, move by peristalsis and are not capable of detailed and on-demand inspection of desired locations. Here, we propose and develop two wireless endoscopes with maneuverable vision systems to enhance diagnosis of gastrointestinal disorders. The vision systems in these capsules are equipped with mechanical actuators to adjust the position of the camera. This may help to cover larger areas of the digestive tract and investigate desired locations. The preliminary experimental results showed that the developed platform could successfully communicate with the external control unit via human body and adjust the position of camera to limited degrees.

关键词： wireless capsule endoscopy     ingestible medical device     in-body medical device     miniature actuator     medical robot     medical imaging    

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Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer

《医学前沿（英文）》 2021年 第15卷 第6期   页码 942-942 doi: 10.1007/s11684-021-0876-z

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Progress and challenges in RET-targeted cancer therapy

《医学前沿（英文）》 2023年 第17卷 第2期   页码 207-219 doi: 10.1007/s11684-023-0985-y

摘要： The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

关键词： pralsetinib     selpercatinib     RET-alteration     lung cancer     thyroid cancer     tumor-agnostic therapy     drug resistance    

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Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

Yun Zhang, Robert A. Weinberg

《医学前沿（英文）》 2018年 第12卷 第4期   页码 361-373 doi: 10.1007/s11684-018-0656-6

摘要：

The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.

关键词： epithelial-to-mesenchymal transition     cancer     metastasis     cancer stem cell    

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Metformin for cancer prevention

Yonghua Yang

《医学前沿（英文）》 2011年 第5卷 第2期   页码 115-117 doi: 10.1007/s11684-011-0112-3

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Orlistat induces ferroptosis-like cell death of lung cancer cells

《医学前沿（英文）》 2021年 第15卷 第6期   页码 922-932 doi: 10.1007/s11684-020-0804-7

摘要： Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P<0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.

关键词： orlistat     ferroptosis     FAF2     lung cancer    

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Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

《医学前沿（英文）》 2012年 第6卷 第4期   页码 376-380 doi: 10.1007/s11684-012-0228-0

摘要：

The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.

关键词： FOXO3a     FOXM1     transcription factor     cancer     drug resistance     tumorigenesis    

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标题 作者 时间 类型 操作

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status

Chenfei Zhou, Jun Zhang

期刊论文

Detection of digestive malignancies and post-gastrectomy complications via gastrointestinal fluid examination

null

期刊论文

A ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum

null

期刊论文

Potential indicators predict progress after surgical resection of gastrointestinal stromal tumors

null

期刊论文

Gastrointestinal damage caused by swallowing multiple magnets

null

期刊论文

血清免疫球蛋白G N-糖基的高通量分析——一种消化道癌症的非侵入性生物标志物

刘鹏程, 王小兵, 顿爱社, 李昱潼, 李厚强, 王璐, 张怡春, 李灿灿, 张金霞, 张晓雨, 马立兴, 侯海峰

期刊论文

Prognostic significance of clinicopathologic parameters in gastrointestinal stromal tumors: a study of

LIANG Yumei, LI Xianghong, LU Youyong, LV Yali, ZHONG Mei, PU Xiaolu, LI Wenmei

期刊论文

Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li

期刊论文

Ingestible wireless capsules for enhanced diagnostic inspection of gastrointestinal tract

Mahdi RASOULI, Andy Prima KENCANA, Van An HUYNH, Eng Kiat TING, Joshua Chong Yue LAI, Kai Juan WONG, Su Lim TAN, Soo Jay PHEE

期刊论文

Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer

期刊论文

Progress and challenges in RET-targeted cancer therapy

期刊论文

Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

Yun Zhang, Robert A. Weinberg

期刊论文

Metformin for cancer prevention

Yonghua Yang

期刊论文

Orlistat induces ferroptosis-like cell death of lung cancer cells

期刊论文

Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

期刊论文