在乳腺癌局部精准治疗中的新进展：联合免疫治疗未来可期

乳腺癌是女性最常见的恶性肿瘤,早期乳腺癌治疗以手术为主。目前,早期乳腺癌的诊治已取得了显著进展,但仍需要创新的方法来减少创伤和改善预后。随着乳腺癌治疗手段创新性研究的深入,乳房和腋窝的非手术治疗成为早期乳腺癌治疗的研究热点。微波消融作为一种微创的精准局部治疗方式,具有消融迅速、操作方式简易、术后并发症较少等特点,目前已尝试用于治疗早期乳腺癌,获得了较好的临床效果。此外,有研究报道,早期乳腺癌经微波消融可调节肿瘤免疫微环境,激发体内抗原特异性的抗肿瘤免疫反应。该免疫效应可能与微波消融后肿瘤抗原的大量释放有关。乳腺癌单用免疫治疗效果差,有研究者提出通过联合免疫治疗增强消融免疫效应的方案,但其具体疗效仍需要更多的临床数据支持。随着对于微波消融引起体内免疫效应的研究深入,微波治疗联合免疫检查点抑制剂疗法有望成为全新的精准治疗策略和理念。本文对微波消融在乳腺癌局部精准治疗中的应用研究新进展及未来发展方向进行总结。     

微波消融治疗骨肉瘤诱导免疫原性细胞死亡的机制研究

目的 探讨是否经微波消融导致肿瘤细胞死亡引起免疫原性肿瘤抗原释放,从而诱导肿瘤特异性免疫反应。方法 3种分别来源于小鼠、大鼠和人类骨肉瘤细胞系作为微波消融模型。在体外消融和原位消融过程中,通过对不同灭活时间及不同实验组设计,检测具有免疫原性分子的表达水平变化。结果 将经体外消融的肿瘤细胞或上清液作为肿瘤疫苗,再植入荷瘤动物模型后,肿瘤细胞生长得到了显著抑制。该效应的产生与疫苗诱导的特异性CD₈(+) T细胞密切相关。效应细胞作用的发挥是通过释放IFN-γ和TNF-α细胞因子来实现,该过程又启动了Fas/FasL介导的细胞凋亡机制。结论 本研究表明经微波消融处理的骨肉瘤细胞可用于诱导特定的抗肿瘤免疫效应。微波原位消融技术联合免疫治疗可望为那些因对化疗不敏感患者提供更多治疗选择。     

肺部肿瘤热消融联合免疫治疗现状与进展

近来的研究表明,肿瘤免疫微环境与肿瘤的进展、转移、复发以及对治疗的反应密切相关;一些免疫治疗也给肿瘤患者带来了希望.然而,肿瘤免疫治疗存在疗效的不确定性和一定的副作用,为了增强其疗效,肿瘤免疫治疗联合肿瘤热消融的研究开始出现.肿瘤热消融具有微创、恢复快、安全、并发症少、适形、效果可靠、可重复、费用低等优点,现已成为继手...     

立体定向放射治疗的免疫效应研究进展北大核心CSCD

放疗通过免疫和非免疫途径杀灭肿瘤细胞。根据吸收剂量的高低,放疗的免疫激活作用包括肿瘤微环境激活效应、免疫激活效应和免疫(次)消融效应等。放疗可以提高免疫治疗的疗效,免疫治疗也可以放大放疗对宿主免疫的激活作用。放疗剂量分割模式对免疫诱导效应的发生具有重要影响。立体定向放疗在激活干扰素效应、诱导远隔效应方面具有明显的优势。8 Gy×3次的分割方案是目前使用最广泛的立体定向放疗方案。针对转移性肿瘤,一些新的放疗模式得以探索,如混合照射、单一病灶照射和多位点照射等,以充分发挥免疫诱导效应,改善放疗与免疫治疗的协同效应。本综述围绕放疗免疫效应最新进展,介绍立体定向放疗新模式,以期为临床工作中改善免疫联合放疗的疗效提供参考。     

动脉介入治疗及经皮穿刺消融综合治疗肝脏肿瘤的临床研究

目的研究动脉介入治疗及经皮穿刺消融综合治疗肝脏肿瘤的临床疗效。方法 90例肝脏肿瘤患者随机分为单纯介入治疗组和介入治疗联合消融治疗两组各45例。单纯介入治疗组选择5-FU 1.0g;ADM 60 mg;DDP 80 mg;HCPT 20 mg动脉化疗并碘油栓塞,每月1次共3次。联合消融治疗组在介入治疗之后1周行微波凝固治疗（MTC）,微波治疗后同时行无水酒精注射。结果联合治疗组在AFP下降、B超周边血流减少、肿瘤生长速度减慢方面明显好于单纯介入组（P〈0.05）。结论介入治疗联合微波凝固治疗和无水酒精注射综合治疗肝脏肿瘤明显提高疗效,未增加不良反应。     

实体瘤免疫治疗疗效评价标准

免疫治疗已经成为实体瘤除手术、放疗、化疗、靶向治疗之外的重要治疗手段。然而免疫治疗的作用机制不同于既往的治疗手段,它是通过激活机体的免疫效应而杀伤肿瘤细胞,达到肿瘤负荷的下降及生存期延长的目的。所以传统的世界卫生组织（WHO）疗效评价标准和实体瘤疗效评价标准（RECIST）也就很难对肿瘤免疫治疗的临床疗效进行准确解读,新的免疫疗效评价标准则涵盖了免疫疗效的各种表现形式,正逐渐应用于临床。     

中晚期肝癌免疫治疗现状与前景

近年来,随着肿瘤免疫治疗的飞速发展及对肝癌免疫微环境认识的不断深入,以免疫检查点抑制剂为导向的新型系统治疗越来越受到关注。除此之外还有免疫治疗方法如肿瘤疫苗、溶瘤病毒、细胞因子等传统免疫方法也在肿瘤治疗中发挥着一定作用。而基于当前的多学科协作诊疗模式,肝癌的免疫治疗更多强调联合治疗,目前免疫联合治疗的方向主要有:双免疫检查点抑制剂联合、免疫检查点联合放化疗、免疫检查点联合抗血管生成药物等。对于肝癌的免疫治疗呈现了多方案的局面。因此,本文就肝癌免疫治疗的现状与前景进行综述,以期助于临床更好的应用。     

氩氦刀冷冻消融治疗脑胶质瘤的现状与展望

胶质瘤是中枢神经系统难治性肿瘤，冷冻消融治疗作为一种新兴的肿瘤治疗技术在胶质瘤治疗中的价值正逐渐被重视。本文回顾了大量文献，从病理及分子生物学角度总结了冷冻消融治疗胶质瘤的机制；通过众多临床病例分析了冷冻疗法的适用范围、临床疗效和存在的问题；基于国内外前瞻性研究展望了冷冻治疗胶质瘤的发展方向及前景。冷冻消融可以通过直接导致坏死和凋亡、改变局部微循环和调节抗肿瘤免疫等机制摧毁肿瘤细胞；在影像学技术实时监控下冷冻可以成为很好的手术辅助手段，现已取得了满意的临床效果；另外冷冻技术与化疗、放疗、免疫治疗等方法联合应用可更有利于发挥其治疗作用。随着冷冻设备的改进和冷冻技术的完善，冷冻消融将在胶质瘤治疗中占有重要的地位。      

肿瘤微环境与免疫治疗耐药的关系及应对

免疫治疗的革命性进展开创了肿瘤精准化治疗的新时代,为肿瘤患者带来了长期生存获益。然而,在临床实践中仍存在免疫治疗耐药等诸多挑战。肿瘤微环境（tumor microenvironment,TME）的动态抑制性变化、异质性等特点在肿瘤发生发展、恶性进展、免疫逃逸和治疗耐药中发挥重要作用。因此,了解免疫治疗与TME之间的相互作用不仅对剖析其作用机制至关重要,而且有助于为提高免疫治疗疗效提供新的途径。本综述就TME的起源、动态抑制性变化、异质性特点进行总结,介绍关于TME如何影响免疫疗效的研究进展,以期通过靶向TME角度或联合治疗方式寻求优化免疫治疗疗效的应对策略。     

非小细胞肺癌放疗联合免疫治疗的研究进展与挑战

由于部分晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者在免疫治疗后没有产生免疫应答或发生继发性耐药,NSCLC免疫治疗的疗效仍不能令人满意。因此,研究者们开展了多项包括放疗（radiation therapy,RT）联合免疫治疗在内的、致力于增强免疫治疗疗效方法的研究。本研究回顾分析了放疗联合免疫治疗提高NSCLC疗效相关研究的进展,并探索进一步增强这一联合治疗疗效的新途径。首先,我们讨论了目前仅有的两项随机试验（和一项汇总分析）。这些试验表明,免疫治疗联合放疗可提高转移性NSCLC患者的远隔客观缓解率、无进展生存期和总生存期。然后,讨论了与放疗免疫疗效相关的因素和生物标志物,例如低水平的程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)、肿瘤突变负荷（tumor mutational burden,TMB）和患者免疫功能。接下来,我们讨论了放疗逆转免疫治疗耐药的机制和应对措施。最后,讨论了低剂量放疗有助于调控肿瘤间质中抑制T细胞浸润的抑制信号的新作用。综上所述,通过对上述研究的深入分析使更多NSC...     

Immunological effect of local ablationcombined with immunotherapy on solidmalignancies

Recent comprehensive investigations clarified that immune microenvironment surrounding tumor cells are deeplyinvolved in tumor progression, metastasis, and response to treatment. Furthermore, several immunotherapeutic trialshave achieved successful results, and the immunotherapeutic agents are available in clinical practice. To enhancetheir demonstrated efficacy, combination of immunotherapy and ablation has begun to emerge. Local ablationshave considerable advantages as an alternative therapeutic option, especially its minimal invasiveness. In addition,local ablations have shown immune-regulatory effect in preclinical and clinical studies. Although the correspondingmechanisms are still unclear, the local ablations combined with immunotherapy have been suggested in the treatmentof several solid malignancies. This article aims to review the published data on the immune-regulatory effectsof local ablations including stereotactic body radiotherapy, cryoablation, radiofrequency ablation, and high-intensityfocusedultrasound. We also discuss the value of local ablations combined with immunotherapy. Local ablations havethe potential to improve future patient outcomes; however, the effectiveness and safety of local ablations combinedwith immunotherapy should be further investigated.     

内皮抑素联合微波消融治疗裸鼠肾癌移植瘤研究

目的研究内皮抑素联合微波消融对裸鼠肾癌移植瘤的抑制作用。方法将人源性肾癌细胞接种到48只小鼠的背部皮下,肿瘤直径约1.5 cm时随机分成4组,对照组：隔日尾静脉生理盐水;联合治疗组：隔日尾静脉推注内皮抑素＋皮下肿瘤微波消融;微波消融组：皮下肿瘤微波消融;内皮抑素组：隔日尾静脉推注内皮抑素。首先对联合治疗组及微波消融组局部皮下肾移植瘤进行微波消融治疗,其后经尾静脉注射药物。14天后每组处死6只小鼠,比较各组瘤重,计算抑瘤率,检测血浆VEGF浓度,剩余6只小鼠观察其存活期。结果联合治疗组小鼠肿瘤体积显著小于其他各组（P〈0.0 5）,其血浆VEGF水平较其他各组显著减低（P〈0.0 5）,存活时间较其他各组显著延长（P〈0.05）。结论内皮抑素联合微波消融抗肿瘤作用优于单用内皮抑素或微波消融治疗,并使小鼠存活期延长。     

微波消融治疗对肝癌小鼠调节性 T 细胞的影响

目的：研究微波消融治疗荷肿瘤后小鼠的Treg和淋巴细胞亚群的变化,探讨微波消融治疗荷瘤小鼠后的机体免疫功能的变化.方法：建立H22荷瘤小鼠模型,分为荷瘤对照组和微波消融组.微波消融荷瘤小鼠肿瘤.流式细胞术检测脾脏中的CD4＋CD25＋T细胞、CD25＋FOXP3＋T细胞、CD4＋T细胞、CD8＋T细胞.结果：与荷瘤对照组相比,微波消融治疗后21天、28天组小鼠CD25＋FOXP3＋T细胞明显下降,差异有统计学意义（P＜0.05）,以术后28天下降更为明显（P＜0.01）.微波消融术后各组小鼠CD4＋/CD8＋比值明显增高（P＜0.05）.结论：微波消融治疗减低Tregs比例可能是热消融治疗提高机体抗肿瘤免疫作用的主要机制.微波消融治疗肿瘤后,Treg数量下降及功能降低,且CD4＋/CD8＋比值升高,提示了微波消融治疗肝癌可以改善机体的免疫状态.     

循环肿瘤细胞监测在结直肠癌肝转移微波消融治疗中临床价值的评估

目的 探讨利用循环肿瘤细胞（CTCs）评估结直肠癌肝转移微波消融治疗的疗效及其与预后的关系。方法 收集2014年1月至2018年5月在南京市第二医院因结直肠癌肝转移行肝脏病灶微波消融治疗的29例患者的临床资料,并纳入术前与术后CTCs检测结果。计数资料分析采用χ2检验或Fisher确切概率法;生存分析采用Kaplan-Meier法和Log-rank检验。结果 经影像学评估,29例患者局部病灶微波消融的近期疗效为完全消融者8例、部分消融16例和进展5例。29例患者微波消融术后CTCs测量值较术前升高,差异有统计学意义（Z=-2.489,P=0.013）;患者的年龄、性别、术后CTCs升高与否、结直肠癌原发部位、同时性或异时性肝转移与微波消融近期疗效均无关（P＞0.05）。微波消融术后CTCs数目＜7个／ml患者局部肝转移病灶的近期疗效优于术后CTCs数目≥7个／ml者（P=0.031）。29例患者的中位生存时间（OS）为30.0个月（95％CI：10.7～49.3个月）。入组患者的年龄、结直肠癌原发部位及肝转移后的治疗方式与中位OS相关（P＜0.05）,而性别、同时性或异时性肝转移、术后CTCs升高与否及术后CTCs值／ml与中位OS均无关（P＞0.05）。结论 微波消融是结直肠癌肝转移局部治疗的有效手段,治疗前后CTCs数量的监测可能有助于评估其近期疗效。     

Microwave ablation treatment of liver cancer with a 2,450-MHz cooled-shaft antenna: pilot study on safety and efficacy

To evaluate efficacy of microwave ablation in a primary clinical study, sixty patients (44 men, 16 women; mean age 53 years) with 96, 1-8 cm (mean 3.20 ± 0.17 cm) liver cancers were treated with 2,450-MHz internally cooled-shaft antenna. Complete ablation (CA) and local tumor progression (LTP) rates as well as complications were determined. CA rates in small (< 3.0 cm), intermediate (3.1–5.0 cm) and large (5.1–8.0 cm) liver cancers were 96.4% (54/56), 92.3% (24/26) and 78.6% (11/14), respectively. During a mean follow-up period of 17.17 ± 6.52 months, LTP occurred in five (5.21%) treated cases. There was no significant difference in the CA and LTP rates between the HCC and liver metastasis patient subgroups (P<0.05). Microwave ablation provides a reliable, efficient, and safe technique to perform hepatic tumor ablation.     

肝癌微波治疗术对患者肾功能影响因素的分析

目的 探讨肝癌微波治疗术期出现肾功能不全的影响因素。方法 回顾性分析在2012年6月-2014年12月期间,哈尔滨医科大学附属肿瘤医院肝胆外科治疗的80例行肝癌微波治疗术患者的临床资料;根据围术期有无出现肾功能不全,将患者分为肾功能不全组(n=44)与肾功能正常组(n=36);对比分析两组患者术前ALT、TBIL、BUN、术中低血压、术中尿量、年龄、微波消融时间、肿瘤与肝大血管距离、微波消融范围、性别等危险因素的差异。结果 肾功能不全组与肾功能正常组患者之间的术中尿量无统计学差异(P＞0.05);而肾功能不全组与肾功能正常组患者之间的术前ALT、TBIL、BUN、术中低血压、年龄、微波消融时间、肿瘤与肝大血管距离、微波消融范围和性别具有统计学差异(P＜0.05)。BUN与术前ALT、术前TBIL、术前BUN、术中低血压、年龄、肿瘤与肝大血管距离、微波消融时间、微波消融范围、性别影响因素均呈正相关(r=0.63、0.60、0.58、0.49、0.45、0.40、0.35、0.46、0.52,P＜0.05)。BUN的影响因素强弱依次为肿瘤与肝大血管距离、微波消融范围、术中低血压、术前ALT、性别、术前TBIL、微波消融时间、年龄和术前BUN(标准化回归系数分别为-0.52、0.42、0.37、0.31、0.29、0.25、0.20、0.18和0.16,P＜0.05)。结论 肝癌微波治疗术患者出现肾功能不全的危险因素呈多方面,与术前ALT、术前TBIL、术前BUN、术中低血压、年龄、肿瘤与肝大血管距离、微波消融时间、微波消融范围、性别密切相关。     

Tumor ablation with MRI navigation--a novel method of microwave coagulation therapy for hepatic tumor]

Fifty-eight patients with hepatic tumor which consisted of 22 hepatocellular carcinomas and 36 metastatic liver tumors were treated by microwave coagulation therapy with MRI navigation. The tumors were located in all segments of liver except S1. In 24 cases among them, the abdominal approach was difficult, because the tumors were located just below the diaphragm. These cases were selected for thoracoscope-assisted microwave ablation under MR-guidance across the diaphragm. All MR data were collected on a vertically oriented open MRI system (0.5 T SIGNA SP/i system: GE Medical Systems). The microwave electrode was introduced into the liver through a 14G needle via a percutaneous puncture with real-time MR image navigation. Microwave ablations at 60 W for 60 seconds were repeated several times depending on the tumor size. MR imaging may be employed as a reliable guide for percutaneous puncture. Moreover, sufficient safety margin could be obtained for hepatic tumor ablation. MR-guided microwave thermoablation therapy is a feasible method of treatment for hepatic tumors.     

The efficacy and safety of percutaneous microwave coagulation by a new microwave delivery system in large hepatocellular carcinomas: Four case studies

Purpose: To demonstrate the efficacy and safety of percutaneous microwave coagulation treatment (PMCT) by a new microwave delivery system (Forsea Microwave?) in large hepatocellular carcinomas (HCC) (≥5 cm).

Materials and methods: Four patients with 4 HCC lesions measuring ≥6 cm in the greatest dimension underwent PMCT by means of the Forsea Microwave? microwave delivery system. Final therapeutic efficacy was evaluated with dynamic computer tomography (CT) scans performed within one month after PMCT. During and after PMCT, patients’ complaints and any abnormal physical signs were recorded for safety assay. CT or ultrasound scan (US) performed immediately after the treatment was used to detect acute complications related to the treatment. Repeated dynamic CT scans were performed every three to four months thereafter to detect local disease recurrence and/or other recurrences.

Results: Three of these patients achieved a complete ablation of the cancer nodules (two patients with two treatment sessions and one patient with three treatment sessions). One of these patients obtained a complete ablation of the cancer nodule with two treatment sessions except the lesion of portal vein tumour thrombus (PVTT). No obvious symptomatic complication was observed except abdominal pain during and after the treatment in two of these patients. All the patients remained asymptomatic and no recurrent tumour was observed during their follow-up (1-19 months).

Conclusions: PMCT by the Forsea Microwave? microwave delivery system could offer a satisfactory therapeutic effect and is applicable to the treatment of large HCC.     

Microwave ablation for multiple bilobar liver tumors from colorectal cancer

AIM: The aim of study was to evaluate the effectiveness of microwave ablation for multiple bilobar liver tumors from colorectal cancer. METHODS: Data from the patients undergoing a hepatic resection with or without microwave ablation at our department were analyzed retrospectively. Survival was estimated using the Kaplan-Meier method and compared using the logrank test. RESULTS: Seventeen percent of patients with combined resection/ablation at sites of initial recurrence at the liver and an extra hepatic metastasis in 11%. The difference between patients with combined resection/ablation and with resection was not significant (p = 0.84). Recurrence occurred near the resection or ablation line in 12.5% within combined resection/ablation. No significant differences were found for overall survivals: disease-free survival between resection/ablation group and with resection alone. CONCLUSION: Microwave ablation plus hepatic resection is suggested to be equally effective as hepatic resection, and it expanded indications for surgery to treat multiple bilobar liver tumors from colorectal cancer.