Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

A new breakthrough:ESD using a newly developed grasping type scissor forceps for early gastrointestinal tract neoplasms

Endoscopic submucosal dissection(ESD) has allowed the achievement of histologically curative en bloc resection of gastrointestinal neoplasms regardless of size,permitting the resection of previously non-resectable tumors.The ESD technique for treatment of early gastric cancer has spread rapidly in Japan and a few other Asian countries due to its excellent eradication rate compared to endoscopic mucosal resection.Although numerous electrosurgical knives have been developed for ESD,technical difficulties and high complication rates(bleeding and perforation) have limited their use worldwide.We developed the grasping type scissor forceps(GSF) to resolve such ESD-related problems.Our animal and preliminary clinical studies showed that ESD using GSF is a safe(no intraoperative complication) and technically efficient(curative en bloc resection rate 92%) method for dissection of early gastrointestinal tumors.The use of GSF is a promising option for performing ESD on early stage GI tract tumors both safely and effectively.

Photodynamic therapy for middle-advanced stage upper gastrointestinal carcinomas: A systematic review and meta-analysis

AIM To determine the therapeutic effect of photodynamic therapy(PDT) for middle-advanced stage upper gastrointestinal carcinomas. METHODS We searched PubM ed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang Database from inception to April 2018 for randomized controlled studies. These studies compared PDT with other palliative therapies(radiotherapy, chemotherapy, or Nd:YAG laser) and compared PDT, radiotherapy, or chemotherapy alone with PDT combined with chemotherapy/radiotherapy. In our meta-analysis, both fixed and random effects models were used to estimate the risk ratio(RR) for dichotomous outcomes(the response rate and one-year survival rate).RESULTS Ten random controlled clinical studies with 953 patients were included in the analysis. The effective rate for PDT was better than that of radiotherapy or Nd:YAG laser for the treatment of middle-advanced upper gastrointestinal carcinomas [RR = 1.36; 95% confidence interval(CI): 1.13-1.65; P = 0.001]. In addition, PDT combined with chemotherapy had significantly better efficacy and a higher one-year survival rate than PDT or chemotherapy alone(significant remission rate, RR = 1.62; 95%CI: 1.34-1.97; P < 0.00001; one-year survival rate, RR = 1.81; 95%CI: 1.13-2.89; P = 0.01).CONCLUSION PDT is a useful method for the treatment of middleadvanced stage upper gastrointestinal carcinomas. PDT combined with chemotherapy or radiotherapy can enhance its efficacy and prolong survival time.

Role of circular RNAs in gastrointestinal tumors and drug resistance

The incidence of gastrointestinal cancers has increased significantly over the past decade and gastrointestinal malignancies now rank among the leading causes of mortality globally.Although newer therapeutic strategies such as targeted therapies have greatly improved patient outcomes,their clinical success is limited by drug resistance,treatment failure and recurrence of metastatic disease.Therefore,there is an urgent need for further research identifying accurate and reliable biomarkers for precise treatment strategies.Circular RNAs(circRNAs)exhibit a covalently closed structure,high stability and biological conservation,and their expression is associated with the occurrence and development of gastrointestinal tumors.Moreover,circRNAs may significantly influence drug resistance of gastrointestinal cancers.In this article,we review the role of circRNAs in the occurrence and development of gastrointestinal cancer,their association with drug resistance,and potential application for early diagnosis,treatment and prognosis in gastrointestinal malignancies.Furthermore,we summarize characteristics of circRNA,including mechanism of formation and biological effects via mRNA sponging,chromatin replication,gene regulation,translational modification,signal transduction,and damage repair.Finally,we discuss whether circRNA-related noninvasive testing may be clinically provided in the future.This review provides new insights for the future development of diagnostics and therapeutics based on circRNAs in gastrointestinal tumors.

Experimental study on effect of recombinant human growth hormone combined with chemotherapy on stomach neoplasms implanted in nude mice

Objective: To investigate the effect of different doses of recombined growth hormone (rhGH) on stomach neo- plasms implanted in nude mice, and its efficacy in combining with chemotherapy (flurouracil, 5-FU). Methods: Human stom- ach neoplasms model was established in nude mice. The nude mice were divided into control group, moderate-dose of rhGH group, low-dose rhGH group, 5-FU group, moderate-dose rhGH/5-FU group, and low-dose rhGH/5-FU group. The results of each group were observed after ten days. Results: After therapy, the body mass of rhGH groups was significantly increased compared with control group (P<0.05), the body mass of rhGH/5-FU groups was significantly increased compared with 5-FU group (P<0.05), but it was no significant difference between rhGH/5-FU groups and control group (P>0.05). The average tumor mass and volume of rhGH groups were not significantly increased compared with control group (P>0.05), but they were significantly reduced in 5-FU group and rhGH/5-FU groups (P<0.05). They were no significant difference between rhGH/5- FU groups and 5-FU group (P>0.05). After treatment, the percentages of S, G0/G1 and G2/M phases and proliferation index (PI) were not significantly changed in rhGH groups compared with control group (P>0.05), and the same with rhGH/5-FU groups compared with 5-FU group (P>0.05). The difference caused by dose of rhGH was not significant. Conclusion: rhGH enhances body mass, does not stimulate tumor growth, and has no adverse effects on tumor bearing nude mice. Combined with flurouracil, rhGH does not influence the efficacy of chemotherapy, and has no effect on tumor cell cycle kinetics.

Anemia and iron deficiency in gastrointestinal and liver conditions

Iron deficiency anemia(IDA) is associated with a number of pathological gastrointestinal conditions other than inflammatory bowel disease, and also with liver disorders. Different factors such as chronic bleeding, malabsorption and inflammation may contribute to IDA. Although patients with symptoms of anemia are frequently referred to gastroenterologists, the approach to diagnosis and selection of treatment as well as follow-up measures is not standardized and suboptimal. Iron deficiency, even without anemia, can substantially impact physical and cognitive function and reduce quality of life. Therefore, regular iron status assessment and awareness of the clinical consequences of impaired iron status are critical. While the range of options for treatment of IDA is increasing due to the availability of effective and well-tolerated parenteral iron preparations, a comprehensive overview of IDA and its therapy in patients with gastrointestinal conditions is currently lacking. Furthermore, definitions and assessment of iron status lack harmonization and there is a paucity of expert guidelines on this topic. This review summarizes current thinking concerning IDA as a common co-morbidity in specific gastrointestinal and liver disorders, and thus encourages a more unified treatment approach to anemia and iron deficiency, while offering gastroenterologists guidance on treatment options for IDA in everyday clinical practice.

Gastrointestinal Stromal Tumors in the 21^stCentury

Gastrointestinal stromal tumours (GISTs) are rare mesenchymal lesions accounting for only 0.2% of all gastrointestinal neoplasms. These tumors arise from the interstitial cells of Cajal, with mutations described in proto-oncogenes such as KIT, PDGFRA, DOG-1, and SDH. The majority of these lesions are asymptomatic, thus the true incidence remains unknown. While patients typically undergo initial endoscopy, CT scan and/or MRI, findings are often nonspecific and require a biopsy to identify the tumor. As such, immunohistochemical evaluation is the gold-standard for the accurate diagnosis of GIST. Though surgical excision remains the gold-standard for curative management, the discovery of imatinib, a tyrosine kinase inhibitor (TKI), has revolutionized the treatment of GIST in the 21st?century as a “prototype” of molecular targeted therapy for solid tumors. Risk assessment for recurrence divides these tumors into low and high-risk categories. In the latter, a role for adjuvant therapy with TKI confers a significantly better prognosis than previously observed. However, secondary mutations conferring drug resistance remain an ongoing challenge for management, as few alternative treatment options are available for patients intolerant/refractory to TKI therapy. In this review, we summarize the epidemiology, molecular pathogenesis, clinical presentation, diagnosis, pathology features, management options, and prognostic features of GISTs.

Immunotherapy for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is presented frequently in late stages that are not amenable for curative treatment.Even for patients who can undergo resection for curative treatment of HCC,up to 50%recur.For patients who were not exposed to systemic therapy prior to recurrence,recurrence frequently cannot be subjected to curative therapy or local treatments.Such patients have several options of immunotherapy(IO).This includes programmed cell death protein 1(PD-1)and cytotoxic T-lymphocyte associated protein 4 treatment,combination of PD-1 and vascular endothelial growth factor inhibitor or single agent PD-1 therapy when all other options are deemed inappropriate.There are also investigational therapies in this area that explore either PD-1 and tyrosine kinase inhibitors or a novel agent in addition to PD-1 with vascular endothelial growth factor inhibitors.This minireview explored IO options for patients with recurrent HCC who were not exposed to systemic therapy at the initial diagnosis.We also discussed potential IO options for patients with recurrent HCC who were exposed to first-line therapy with curative intent at diagnosis.

肝癌靶向联合免疫治疗耐药后的二线治疗方案研究进展

近年来,靶向和免疫单药及联合治疗晚期肝癌的临床研究为一线用药方案选择提供了丰富的疗效与安全性证据。然而,对于肝癌二线治疗方案的选择,目前各项临床指南尚无统一意见,原因在于现有循证医学证据局限于索拉非尼失败后的选择,而对于新的一线方案,如靶向免疫联合治疗肝癌耐药后的二线治疗方案,依然缺乏高证据等级的临床试验结论。本文回顾了目前临床试验研究结果,根据药物作用的不同机制,对靶向免疫一线治疗耐药后肝癌二线治疗方案的研究进行了归纳,并系统总结近年研究进展。对于一线靶免联合治疗耐药的肝癌患者,靶向联合治疗、免疫双抗治疗均有望提高疗效、改善生存,未来还需更多前瞻性临床研究数据,为靶免联合治疗耐药的肝癌患者提供有效、安全的治疗方案。

垂体催乳素瘤的临床特点及诊治要点更新--基于《2022版ICCE/AME垂体催乳素瘤临床实践共识》解读

垂体催乳素瘤是一种由垂体催乳素细胞瘤过量合成和分泌催乳素引起的神经内分泌疾病,垂体催乳素瘤的规范化诊疗对于恢复并维持患者的正常垂体功能并提高其生活质量具有重要意义。2022年1月,《欧洲内分泌杂志》发布了国际临床内分泌学分会(ICCE)与意大利临床内分泌学家协会(AME)关于垂体催乳素瘤的临床实践最新共识申明——《2022版ICCE/AME垂体催乳素瘤临床实践共识》(简称2022版ICCE/AME新共识)。2022版ICCE/AME新共识立足最新循证医学证据,对于垂体催乳素瘤的临床诊治问题进行系统性阐述、分析和建议。本文围绕2022版ICCE/AME新共识关于垂体催乳素瘤的诊断、治疗、特殊人群、多巴胺激动剂抵抗及侵袭性疾病等诊治要点更新进行解读,希望有助于全科医生及内分泌专科医生对于垂体催乳素瘤的认识,为其临床实践的规范化诊疗提供参考。

儿童胃肠道炎性肌纤维母细胞瘤的诊断与治疗

目的总结儿童胃肠道炎性肌纤维母细胞瘤(inflammatory myofibroblastic tumor,IMT)的临床特征及诊治经验。方法回顾性分析湖南省儿童医院普外科2010年1月至2021年12月收治的11例胃肠道IMT患儿临床资料,男7例,女4例;发病年龄8个月至15岁,收集患儿临床特点、影像学检查、病理学诊断、外科治疗及随访情况等。结果11例主要以腹痛、呕吐、发热、血便及腹部肿物就诊。10例行一期手术完整切除肿瘤,其中1例术后予化疗;1例经活检确诊后未予手术,仅行化疗。11例均病理诊断明确,均获随访(随访时间6~60个月),其中9例治愈,2例带瘤生存(1例于术后2年复发)。结论儿童胃肠道IMT临床少见,手术是首选治疗方法。复发、难治性IMT的治疗亟待进一步积累经验。

免疫细胞及炎症因子对晚期肺癌一线化疗效果的预测价值

【目的】探讨T淋巴细胞亚群、肿瘤浸润T淋巴细胞(Tils)及炎症因子对晚期肺癌一线化疗效果的预测价值。【方法】检测98例首诊TNM分期为Ⅲ/Ⅳ期的非小细胞肺腺癌患者的血清白细胞介素1α(IL-1α)、IL-6、IL-17、γ-干扰素(INF-γ)水平及T淋巴细胞亚群CD4^(+)T、CD8^(+)T、调节性T细胞、CD57^(+)细胞、Granzyme B^(+)细胞、CD45RO^(+)细胞比例;所有患者均接受紫杉醇注射液+顺铂化疗,治疗4个周期后评定疗效,并据此分为有效组和无效组,分析化疗无效的影响因素及预测疗效的有效标志物。【结果】化疗后,98例患者中69例化疗有效,29例无效。无效组患者淋巴结转移占比及调节性T细胞、IL-1α表达水平均高于有效组(P<0.05),CD57^(+)细胞、CD45RO^(+)细胞比例均低于有效组(P<0.05)。多因素逐步Logistic回归分析结果显示,调节性T细胞、IL-1α水平高是肺癌患者化疗无效的危险因素(P<0.05),CD57^(+)细胞、CD45RO^(+)细胞比例高是保护因素(P<0.05)。受试者工作特征(ROC)曲线分析显示,调节性T细胞、CD57^(+)细胞、CD45RO^(+)细胞、IL-1α水平预测化疗效果的灵敏度分别为82.76%、86.21%、89.66%、93.10%,四者联合的灵敏度、特异度和曲线下面积(AUC)分别为82.76%、97.10%、0.957。【结论】T淋巴细胞亚群、Tils及炎症因子水平与晚期肺癌治疗效果密切相关,其可作为预测疗效的敏感指标。

胃肠间质瘤靶向药物伊马替尼的个体化用药管理中国专家共识

目的 为指导胃肠间质瘤(GIST)靶向药物伊马替尼的个体化用药管理,提高患者生存率、改善患者生活质量提供参考。方法 采用名义群体法,由多学科(临床、药学、循证)专家组成编写组,经共同讨论确定《胃肠间质瘤靶向药物伊马替尼的个体化用药管理中国专家共识》编写大纲。编写组专家针对大纲涉及内容进行系统检索、分析、归纳,并根据我国现状、临床需求和研究证据制定相关共识。由临床实践经验丰富的多学科专家组成外审组。采用德尔菲法问卷方式,开放收集专家的外审意见,并对意见进行整理、归纳、分析、反馈、修订,最终形成共识。结果与结论 本共识内容包括伊马替尼针对GIST的新辅助治疗、手术切除后具有明显复发风险的成人患者的辅助治疗、复发转移性或不可切除患者的药物治疗的临床应用,药学监测及其长期用药管理。本共识的发布为我国医疗机构在GIST患者个体化用药管理方面提供了规范化的流程与方法,对提高伊马替尼的临床疗效、保障用药安全具有重要意义。

滋肾润肺方辅助化疗治疗中晚期肺癌气阴两虚证患者的临床疗效

【目的】探讨滋肾润肺方联合化疗治疗中晚期肺癌气阴两虚证患者的疗效。【方法】两院收治的80例中晚期肺癌气阴两虚证患者,随机分为化疗组与联合组,每组40例。化疗组采用常规肺癌化疗方案,联合组在此基础上同时给予滋肾润肺方口服。比较两组患者的疗效、疾病进展时间(TTP)、1年存活率、1年无进展生存(PFS)率,治疗前后中医症状积分、卡氏评分(KPS)改善情况,骨髓抑制发生情况。【结果】联合组治疗总有效率(RR)为37.5%(15/40)、疾病控制率(DCR)为82.5%(33/40),化疗组RR为27.5%(11/40)、DCR为70.0%(28/40),两组比较差异均无统计学意义(P>0.05)。化疗组TTP为6.5(4.2~8.4)个月,1年存活率为30.0%(12/40),1年PFS率为85.0%(34/40);联合组TTP为7.2(5.5~9.3)个月,1年存活率35.0%(14/40),1年PFS率为87.5%(35/40),两组比较差异均无统计学意义(P>0.05)。与治疗前比较,两组治疗后中医症状积分均明显降低,且观察组各项指标下降更显著(P<0.05)。治疗后,联合组KPS评分稳定率为90.00%(36/40),明显高于化疗组的70.00%(28/40)(P<0.05)。联合组骨髓抑制的总发生率为17.5%(7/40),低于化疗组的42.5%(17/40)(P<0.05)。【结论】滋肾润肺方联合化疗可有效改善患者的生活质量,且能降低骨髓抑制的发生率。

基于妇科肿瘤耐药治疗中工程化外泌体的应用研究进展

妇科恶性肿瘤严重威胁着女性健康,在女性各类疾病中其发病率和死亡率均位居前列,关键原因在于传统化疗对复发、耐药患者的疗效欠佳。近年来,探讨肿瘤细胞化疗的耐药机制,开发新型药物逆转耐药已成为妇科肿瘤研究者关注的热点。外泌体(exosome)是一种来源于细胞内溶酶体微粒内陷的多囊泡体,具有低免疫原性、先天靶向性及获得靶向性和高传递效率等生物学特性。因此,外泌体可作为一种理想的、天然的纳米递送药物载体,不仅可以降低肿瘤细胞对化疗药物的耐药性,提高药物治疗效果,还可以减少化疗药物对全身的毒副反应。本文就外泌体作为妇科肿瘤耐药治疗中药物载体的研究进展进行综述,以期对妇科肿瘤的临床治疗提供帮助。

PARP抑制剂在上皮性卵巢癌中的耐药机制及解决策略

上皮性卵巢癌(epithelial ovarian cancer,EOC)的致死率在女性生殖系统恶性肿瘤中居首位。EOC的传统治疗方案是肿瘤细胞减灭术联合铂类药物为基础的化疗,但2年内仍有约70%的患者复发或耐药。多腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂通过对乳腺癌相关基因(breast cancer-related gene,BRCA)突变的肿瘤细胞发挥合成致死效应,为EOC提供了全新的治疗模式。PARP抑制剂为EOC靶向维持治疗带来重大突破,然而仍有患者在治疗中逐步耐药,主要的耐药机制包括同源重组修复途径恢复、药物靶点变化和致死性DNA损伤减少,目前的解决策略包括PARP抑制剂联合DNA损伤修复抑制剂、联合抑制同源重组修复通路的药物、联合传统抗癌方案、联合P-糖蛋白(P-glucoprotein,P-gp)抑制剂以及更换其他类型的PARP抑制剂。

多发性骨髓瘤耐药机制和分子靶向治疗新进展——第20届国际骨髓瘤学会年会研究热点报道

多发性骨髓瘤(MM)是一种血液恶性肿瘤,其特征为恶性浆细胞的克隆性增殖。蛋白酶体抑制剂、免疫调节药物以及自体造血干细胞移植治疗明显改善了MM患者的生活质量和生存状况,然而几乎所有患者都将产生耐药导致疾病复发难治,预后较差。因此,探究MM患者耐药性产生的分子机制,寻找新的治疗靶点并开发新的靶向治疗策略尤为重要。现对MM耐药机制和分子靶向治疗研究的最新进展进行综述。

Hippo及Notch信号通路在眼睑基底细胞癌中的研究进展

眼睑基底细胞癌(BCC)是眼睑恶性肿瘤中最常见的类型。手术切除是治疗眼睑BCC的公认金标准,但对于局部晚期或转移性BCC,较大的手术风险和不良预后是困扰医患的最大问题,因此有必要探索新治疗方案。目前靶向治疗具有良好前景,但现有的靶向药物(Hedgehog信号通路抑制剂)面临难以完全清除肿瘤、毒性作用严重以及耐药的发生问题。鉴于以上情况,开发新的靶向药物对治疗该病具有重要意义。Hippo信号通路和Notch信号通路在眼睑BCC的发生和发展中起着重要作用,可能成为治疗的新靶点。因此,本文综述了Hippo信号通路和Notch信号通路在眼睑BCC中的研究进展,旨在为眼睑BCC的靶向治疗提供新的思路。

抗体药物偶联物在人表皮生长因子受体2低表达胃癌中的应用研究进展

胃癌(GC)是极具异质性和侵袭性的消化系统恶性肿瘤之一,传统化疗药物及曲妥珠单抗等人表皮生长因子受体2(HER2)靶向药物在GC的治疗过程中仍然存在耐药性发生率高、毒副作用大、患者耐受差等缺点。因此,研发更为有效的抗GC药物势在必行。目前针对HER2的新型靶向药层出不穷,但在某些情况下无效或产生耐药,这与HER2在某些GC细胞中低表达有关,HER2低表达(HER2 IHC1+或IHC2+/ISH-)约占全部类型的40%~60%,但在临床实践中,这类患者仍被报告为HER2阴性GC。因此准确检测HER2表达状态对于确定可能受益于曲妥珠单抗治疗的患者至关重要。抗体药物偶联物(ADC)的出现为HER2阳性GC提供了新的治疗选择,凭借其精准高效的抗肿瘤作用,有望在未来替代传统GC化学疗法。近期有研究发现ADC可能在HER2低表达GC中具有潜在抗肿瘤活性,相关临床研究正在评估其在HER2低表达GC治疗中的有效性和安全性。本文就靶向治疗时代ADC在HER2低表达GC患者中的应用和最新研究进展作一综述,并讨论HER2靶向ADC在应用和研发过程中面临的挑战。

The value of postoperative hepatic regional chemotherapy in prevention of recurrence after radical resection of primary liver cancer

INTRODUCTIONIn China,primary liver cancer (PLC) ranks secondin cancer mortality since the 1990s.In the field ofPLC treatment,surgical resection remains the best,which includes large PLC resection,small PLCresection,re-resection of subclinical recurrence,aswell as cytoreduction and sequential resection forunresectable PLC.However,recurrence