Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell death.Apatinib is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis pathway.However,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported yet.Tumor.secreted exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered.Here,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of Apatinib.In conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

Erratum to Treatment strategies for patients with HER2-positive gastric cancer

For the affiliation information,the affiliation for author Feixue Wang should be Department of GI Medical Oncology,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Tianjin's Clinical Research Center for Cancer,Tianjin Key Laboratory of Digestive Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin Medical University,Tianjin 300060,China.

Treatment strategies for patients with HER2-positive gastric cancer

Gastric cancer (GC) is a major health concern globally,ranking fifth in frequency and fourth in cancer-associated mortality1.In China,an estimated 396,500 new cases are diagnosed each year,and late-stage disease comprises more than 80%of cases2.Because of late diagnosis and heterogeneous characteristics,the prognosis of GC remains poor.For patients with advanced disease,traditional chemotherapy has been the mainstay of treatment,but its clinical outcomes are far from satisfactory,with a 5-year survival rate below 10%.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023

The 2023 update of the Chinese Society of Clinical Oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-based medicine,healthcare resource availability,and precision medicine.These updates address the differences in epidemiological characteristics,clinicopatho-logical features,tumor biology,treatment patterns,and drug selections between Eastern and Western gastric cancer patients.Key revisions include a structured template for imaging diagnosis reports,updated standards for molecular marker testing in pathological diagnosis,and an elevated recommendation for neoadju-vant chemotherapy in stage III gastric cancer.For advanced metastatic gastric cancer,the guidelines introduce new recommendations for immunotherapy,anti-angiogenic therapy and targeted drugs,along with updated management strategies for human epidermal growth factor receptor 2(HER2)-positive and deficient DNA mismatch repair(dMMR)/microsatellite instability-high(MSI-H)patients.Additionally,the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer.The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice,particularly in the heterogeneous healthcare landscape of China,while maintaining a commitment to scientific rigor,impartiality,and timely revisions.

Comparative analysis of dideoxy sequencing,the KRAS StripAssay and pyrosequencing for detection of KRAS mutation

AIM:To compare the differences between dideoxy sequencing/KRAS StripAssay/pyrosequencing for detection of KRAS mutation in Chinese colorectal cancer (CRC) patients.METHODS:Formalin-f ixed, paraff in-embedded (FFPE) samples with tumor cells ≥ 50% were collected from 100 Chinese CRC patients at Beijing Cancer Hospital. After the extraction of genome DNA from FFPE samples, fragments contained codons 12 and 13 of KRAS exon 2 were amplified by polymerase chain reaction and analyzed by dideoxy sequencing, the KRAS Strip Assay and pyrosequencing. In addition, the sensitivities of the 3 methods were compared on serial dilutions (contents of mutant DNA: 100%,50%,20%, 5%,10%, 5%,1%,0%) of A549 cell line DNA (carrying the codon 12 Gly>Ser mutation) into wild-type DNA (human normal intestinal mucosa). The results of dideoxy sequencing,the KRAS StripAssay and pyrosequencing were analyzed by Chromas Software, Collector forKRAS Strip Assay and the pyrosequencing PyroMarkTM Q24 system, respectively.RESULTS: Among 100 patients, KRAS mutations were identif ied in 34%, 37% and 37% of patients by dideoxy sequencing, the KRAS StripAssay and pyrosequencing, respectively. The sensitivity was highest with the KRAS Strip Assay (1%), followed by pyrosequencing (5%), and dideoxy sequencing was lowest (15%). Six different mutation types were found in this study with 3 main mutations Gly12 Asp (GGT>GAT), Gly12 Val (GGT>GTT) and Gly13 Asp (GGC>GAC). Thirty-three patients were identifi ed to have KRAS mutations by the 3 methods, and a total of 8 patients had conflicting results between 3 methods: 4 mutations not detected by dideoxy sequencing and the KRAS StripAssay were identified by pyrosequencing; 3 mutations not detected by dideoxy sequencing and pyrosequencing were identif ied by the KRAS StripAssay; and 1 mutation not detected by pyrosequencing was conf irmed by dideoxy sequencing and the KRAS StripAssay. Among these discordant results, the results identif ied by dideoxy sequencing were consistent either with the KRAS StripAssay or with pyrosequencing, which indicated that the accuracy of dideoxy sequencing was high. CONCLUSION: Taking a worldwide view of reports and our results,dideoxy sequencing remains the most popular method because of its low cost and high accuracy.

Retrospective study of cetuximab in combination with chemotherapy for patients with colorectal cancer

Objective: To evaluate the efficacy and safety of cetuximab combined with chemotherapy in colorectal cancer (CRC). Methods: 35 cases of CRC were retrospectively analyzed. Efficacy and adverse events were observed. Results: 29 cases of CRC were evaluated by RECIST criteria, showing 7 PR (partial response, 24.1%) and 15 SD (stable disease, 51.8%), disease control rate (DC) was 75.9%. Subgroup analysis showed response rate (RR) of 36.4% and DC of 91% in the 1st line therapy, RR of 20% and DC of 70% in the 2nd line therapy, RR of 12.5% and DC of 62.5% in heavily pretreated cases. Rash appeared in 74.3% of patients (grade 3 was 8.6%), and the severity was relevant with disease control rate (DC). Neutropenia of grade 3/4 was 14.3%, and infusion related reaction (IRR) of grade 3 happened in 1 case (2.9%). Conclusion: Cetuximab combined with chemotherapy is safe and effective for patients with metastatic colorectal cancer. The combination therapy shows high DC, especially in 1st line therapy. Severity of rash may predict efficacy.

Recent advances in the diagnostic evaluation of pancreatic cystic lesions

Pancreatic cystic lesions(PCLs)are becoming more prevalent due to more frequent abdominal imaging and the increasing age of the general population.It has become crucial to identify these PCLs and subsequently risk stratify them to guide management.Given the high morbidity associated with pancreatic surgery,only those PCLs at high risk for malignancy should undergo such treatment.However,current diagnostic testing is suboptimal at accurately diagnosing and risk stratifying PCLs.Therefore,research has focused on developing new techniques for differentiating mucinous from non-mucinous PCLs and identifying high risk lesions for malignancy.Cross sectional imaging radiomics can potentially improve the predictive accuracy of primary risk stratification of PCLs at the time of detection to guide invasive testing.While cyst fluid glucose has reemerged as a potential biomarker,cyst fluid molecular markers have improved accuracy for identifying specific types of PCLs.Endoscopic ultrasound guided approaches such as confocal laser endomicroscopy and through the needle microforceps biopsy have shown a good correlation with histopathological findings and are evolving techniques for identifying and risk stratifying PCLs.While most of these recent diagnostics are only practiced at selective tertiary care centers,they hold a promise that management of PCLs will only get better in the future.

Leptomeningeal carcinomatosis as the initial manifestation of gastric adenocarcinoma:A case report

Leptomeningeal involvement is usually reported as a secondary event in advanced gastric carcinoma.Leptomeningeal carcinomatosis(LMC),as the initial manifestation of asymptomatic gastric cancer,is exceedingly rare with only a few cases reported in recent years.The presenting neurologic symptoms include headache,vomiting and seizures and are usually clinically atypical.The diagnosis of LMC is made via identification of malignant cells that originate from epithelial cells in the cerebrospinal fluid by cytological examination and provides cues to track the primary tumor.Endoscopic examinations are crucial to confirm the presence of gastric cancer,and imaging studies,especially gadolinium-enhanced magnetic resonance imaging of the brain,are sometimes helpful in diagnosis.Thus far,there is no standard therapy for LMC,and despite all measures,the prognosis of the condition is extremely poor.Here,we report on the clinical features and diagnostic procedures for a patient with occult gastric cancer with Bormann typeⅠmacroscopic appearance and poor differentiation in pathology,who presented with LMC-induced neurological symptoms as the initial clinical manifestation.Additionally,we review the similar cases reported over the past years,making comparison among cases in order to provide more information for the future diagnosis.

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM:To evaluate effects of UDP-glucuronosyltransferase1A1(UGT1A1) and thymidylate synthetase(TS) gene polymorphisms on irinotecan in metastatic colorectal cancer(mCRC).METHODS:Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1*28,UGT1A1*6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS:One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1*28(TA6/6) compared with a Caucasian population(69.9% vs 45.2%).No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants(17.9% vs 24.2% for UGT1A1*28,15.7% vs 26.8% for UGT1A1*6).When TS was considered,the subgroup with homozygous UGT1A1*28(TA7/7) and non-3RG genotypes showed the highest response rate(33.3%),while wild-type UGT1A1*28(TA6/6) with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea(27.8% vs 100%),and significantly reduced the risk of grade 4 neutropenia compared with TA7/7(7.8% vs 37.5%).Wild-type UGT1A1*6(G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant(A/A) genotype(13.0% vs 40.0%).Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes,when TA6/6 was compared with TA7/7(35.3% vs 100.0%).No significant association with time to progression(TTP) and overall survival(OS) was observed with either UGT1A1 or TS gene polymorphisms,although slightly longer TTP and OS were found with UGT1A1*28(TA6/6).Irinotecan PK was investigated in 34 patients,which showed high area under concentration curve(AUC) of irinotecan and SN-38,but low AUC ratio(SN-38G /SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION:A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Electro-acupuncture to prevent prolonged postoperative ileus:A randomized clinical trial

AIM:To examine whether acupuncture can prevent prolonged postoperative ileus(PPOI)after intraperitoneal surgery for colon cancer. METHODS:Ninety patients were recruited from the Fudan University Cancer Hospital,Shanghai,China. After surgery,patients were randomized to receive acupuncture(once daily,starting on postoperative day 1, for up to six consecutive days)or usual care.PPOI was defined as an inability to pass flatus or have a bowel movement by 96 h after surgery.The main outcomes were time to first flatus,time to first bowel movement, and electrogastroenterography.Secondary outcomes were quality of life(QOL)measures,including pain, nausea,insomnia,abdominal distension/fullness,and sense of well-being. RESULTS:No significant differences in PPOI on day 4 (P=0.71)or QOL measures were found between the groups.There were also no group differences when the data were analyzed by examining those whose PPOI had resolved by day 5(P=0.69)or day 6(P= 0.88).No adverse events related to acupuncture were reported. CONCLUSION:Acupuncture did not prevent PPOI andwas not useful for treating PPOI once it had developed in this population.

Capecitabine Maintenance Therapy after First-Line Chemotherapy in Patients with Metastatic Colorectal Cancer

Objective:To evaluate the efficacy and toxicity of capecitabine maintenance therapy in metastatic colorectal cancer(mCRC) patients.Methods:From June 2001 to November 2006,after they had achieved clinical response from first-line chemotherapy,patients with mCRC in our hospital received two different treatment strategies.Thirty-three patients in maintenance group were treated with capecitabine 1000 mg/m2 po bid d1-14,q21d.Fifty-two patients in non-maintenance group did not receive any further chemotherapy.Results:Patients in maintenance group and non-maintenance group both received FOLFOX,FOLFIRI and XELOX as first-line therapy.The median chemotherapy cycles the two groups received were the same(6 vs 6).The response rates of first-line chemotherapy were 33.3% in maintenance group and 32.7% in non-maintenance group.Patients in maintenance group received 3-9 cycles of capecitabine therapy(median cycle 4).29/33(87.9%) patients in maintenance group and 47/52(90.4%) in non-maintenance group received following second-line chemotherapy,and no patients underwent targeted therapy.The median survival time and TTP were 40.4 months(95%CI:24.2-56.6) and 9.0 months(95%CI:6.7-11.3) in maintenance group,as compared with 21.5 months(95%CI:14.9-28.0,P=0.015) and 6.5 months(95%CI:4.4-8.5,P=0.007) in non-maintenance group.No severe adverse event was observed in the capecitabine maintenance group.Conclusion:mCRC patients could benefit from capecitabine maintenance therapy by prolonging survival time and TTP.

Novel biomarkers and the future of targeted therapies in cholangiocarcinoma:a narrative review

Background and Objectives:Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree,comprising 15%of all primary liver cancers.The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients.Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma(CCA)since 2010,with a median overall survival of 11.7 months.The five-year survival for CCA remains 5-10%,revealing a clear need for improved treatment options.Methods:This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development.Key Content and Findings:These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis,provide prognostic information,and guide treatment decisions for patients with CCA.Specifically,the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies.Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice.Other biomarkers including KRAS and B-raf protooncogenes,Her2/neu genes,and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies,with early data showing promise for new drug development.Conclusions:The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a“one-size fits all”for treatment of CCA,and generated optimism that these novel treatments will soon be available for patients with CCA.

Gastric molecular classification and practice in immunotherapy

Gastric cancer(GC) is a highly heterogeneous malignancy with a high incidence worldwide; the prevalence of GC is relatively higher in China than in other countries. Treatment of advanced GC has been slow to develop due to lack of a proper classification system to guide clinical practice. With the development of molecular biology techniques, the molecular classification of GC has been established and may have applications in guiding precise and personalized therapy. To date, three or four molecular classifications for GC have been recognized; these include Singapore, the Cancer Genome Atlas(TCGA) Research Network, and Asian Cancer Research Group(ACRG) classifications. Here, we review the development of molecular classifications and characteristics of different subtypes, and discuss the applications of molecular classifications in clinical practice, with a focus on immunotherapy.

Circulating biomarkers for nonfunctional gastroenteropancreatic neuroendocrine neoplasm:Where do we stand?

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs) encompass a heterogeneous group of tumors associated with variable presentations, growth rates, and prognoses. The majority of GEP-NENs are nonfunctional, and their diagnosis remains challenging given the often subtle and variable clinical manifestations of these tumors. As a consequence, GEP-NENs are often recognized at an advanced stage; indeed, most patients with nonfunctional GEP-NENs exhibit metastatic disease at diagnosis. Lack of treatment options as well as limitations in currently available imaging modalities and biomarkers make it challenging to manage NENs. Thus, novel biomarkers are needed to provide high sensitivity and specificity for minimum disease detection and to predict treatment efficacy and prognosis. Although tissue-based biomarker data can provide such information, circulating biomarkers such as NETests, circulating tumor cells, and micro RNAs, are superior owing to their easy accessibility and the ability for repeated real-time sampling.

Progress in TNM staging of pancreatic neuroendocrine tumors

In recent years,staging classifications for well-differentiated pancreatic neuroendocrine tumors(NETs)have evolved significantly(1-3).Historical classifications,which attempted to combine clinical,pathological,and radiographic findings,were found to be overly complex.It was not until 2006 that Rindi et al.proposed a standard four-stage TNM classification,which was subsequently endorsed by the European Neuroendocrine Tumor Society(ENETS)(4).The T stage distinguished between tumors smaller than 2 cm(T1),2-4 cm(T2),>4 cm or invading duodenum/bile ducts(T3),and invading adjacent structures(T4).N and M stages were defined simply by the presence or absence of regional lymph nodes and distant metastases(Figure 1A).The American Joint Committee on Cancer(AJCC)seventh edition adopted a different TNM classification in 2010,derived from the staging for pancreatic adenocarcinoma.In this classification,T1 referred to a tumor<2 cm,T2 referred to a tumor>2 cm,T3 referred to disease extending beyond the pancreas,and T4 referred to the invasion of the celiac axis or SMA(unresectable).As in the ENETS classification,N and M stage were defined simply by the presence or absence of metastases(Figure 1B).

Advances in the treatment of gastroenteropancreatic neuroendocrine neoplasms with somatostatin analogs

Neuroendocrine neoplasms (NENs) include well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Somatostatin receptors (SSTRs) are highly expressed on NETs cells, and somatostatin analogs (SSAs) could bind to SSTRs with high affinities, regulating cell proliferation and hormone secretion. As many clinical trials have demonstrated the antiproliferative efficacy and safety of SSAs in metastatic gastroenteropancreatic NETs (GEP-NETs), SSAs have been recommended by multiple NEN guidelines as the first-line therapy of GEP-NETs. In recent years, more and more researches have been exploring new therapeutic possibilities of SSA in GEP-NETs, such as high-dose SSA as second-line therapy, SSA in metastatic GEP-NETs with Ki-67 > 10%, SSA as adjuvant therapy for postoperative pancreatic NETs patients, and combinations of SSA with chemotherapy or targeted therapy. In this review, we summarized the latest published or released researches and discussed new application attempts of SSA in GEP-NETs.

Advances in the treatment of gastroenteropancreatic neuroendocrine neoplasms with somatostatin analogues

Neuroendocrine neoplasms(NENs)include well-differentiated neuroendocrine tumors(NETs)and poorly-differentiated neuroendocrine carcinomas(NECs).Somatostatin receptors(SSTRs)are highly expressed on NETs cells,and somatostatin analogs(SSAs)could bind to SSTRs with high affinities,regulating cell proliferation and hormone secretion.As many clinical trials have demonstrated the antiproliferative efficacy and safety of SSAs in metastatic gastroenteropancreatic NETs(GEP-NETs),SSAs have been recommended by multiple NEN guidelines as the first-line therapy of GEP-NETs.In recent years,more and more researches have been exploring new therapeutic possibilities of SSA in GEP-NETs,such as high-dose SSA as second-line therapy,SSA in metastatic GEP-NETs with Ki67>10%,SSA as adjuvant therapy for postoperative pancreatic NETs patients,and combinations of SSA with chemotherapy or targeted therapy.In this review,we summarized the latest published or released researches and discussed new application attempts of SSA in GEP-NETs.

Two distinct stem cell-like subtypes of hepatocellular carcinoma with clinical significance and their therapeutic potentials

Dear Editor Hepatocellular carcinoma(HCC)is among the most com-mon cancers worldwide,causing about 600,000 deaths annully[1].In HCC,stem cell-like characteristics,which drive early recurrence and therapy resistance,are major contributors to poor prognosis[2].In this current study,we integrated and analyzed gene expression data from human fetal liver cells and primary HCC tumors(n=1231)and.uncovered two clinically and biologically distinct hepatic stem cell(HS)subtypes,potential biomarkers associated with these subtypes,and a potential new therapeutic inter-vention for these subtypes.

Gastroenteropancreatic neuroendocrine tumor registry study in China

Objectives:The aim of this multicenter,prospective,registry study was to summarize the epidemiology of Chinese patients with locally advanced and end-stage gastroenteropancreatic neuroendocrine tumors(GEP-NETs)as well as the diagnostic methods and treatment strategies used for these patients.Methods:GEP-NET patients from 11 departments of 8 hospitals in China were prospectively enrolled for a pre-defined period(June 30,2011 to May 29,2012).The patients’demographic,pathological,and treatment data were recorded,analyzed,and released on June 29,2015.Results:Seventy-nine eligible patients were enrolled,and most of these patients were classified according to the World Health Organization 2010 classifications.The most common primary tumor site was the pancreas.The liver was the most common site of metastases,followed by the lymph nodes.The majority of the patients underwent surgical interventions.Patients also received local treatment,medication,or chemotherapy.Conclusion:The pancreas was the most common primary tumor site of locally advanced and end-stage GEP-NETs.Surgical interventions are currently the most common treatment strategy.

经自然腔道取标本手术(NOSES)治疗结直肠癌的国际共识

近年来,经自然腔道取标本手术(NOSES)治疗结直肠癌已引起了广泛关注。NOSES应用于结直肠手术的潜在优势包括减轻术后疼痛,减少伤口并发症,减少对术后镇痛的需求,加快肠道功能的恢复,缩短住院时间,更好的美容效果,以及给患者带来了更佳的心理状态。尽管NOSES的手术创伤显著减轻,然而该技术也存在一些潜在问题。尤其随着这项新技术的兴起,人们对其无菌的把控、肿瘤学结果和病例选择等问题表示出关切。因此,迫切需要一部操作指南来规范NOSES手术在结直肠癌中的开展。经过国际NOSES联盟全体成员的三轮讨论,最终形成了该部共识。这一共识有助于NOSES在全球范围内的长远发展。