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《科学》刊发颠覆理念: “手术可能播散癌症或唤醒它”
有时人们的幻觉让自己误入歧途,但没有人指点迷津。关于癌症的治疗,什么是精准、最佳?至今无人知晓。

如果有人梳理关于癌症的常见“误区和观点”,可能会发现类似观点:“手术治疗可能导致癌症扩散到身体其他部位”。换句话讲,手术切除癌组织非但没有治疗效果,反而播散或唤醒了它。

无论你是否认同此观点或从来没听说过,在医学界和肿瘤医生群里这是默认的事实。医生们经常担心如此,也很难对患者解释其中道理,这是医生难言的事实。

你可以想象一下癌细胞被扩散到身体其他部位,那些癌细胞是否真的能附着在其他组织或器官里再次“生长”?甚至有人认为为确诊而做组织活检本身也有类似风险。

以乳腺癌为例,尽管医生和患者都知晓手术治疗效果还是相对不错。但常识也告知患者和医生,在术后12至18个月通常是转移性乳腺癌复发高峰。这是否是手术(或其他方式)导致癌细胞播散而复发?不好说绝对无关联,但复发风险的时间节点是不争的事实。

研究人员以此临床观察(乳腺癌术后复发时间点)做了一个合理性假设,探究其复发的缘由。

首先,在双侧全乳房切除术患者中也观察到同样结果(复发时间点)。由于全乳房切除术不会对肿瘤本身造成干扰或根本不会触动肿瘤部分。那么,可能的解释是一些癌细胞在术前就已经扩散了或因为太小而无法检测出来。无论是哪种解释,目前仍无法辨认谁是诱导癌症复发的“元凶”。

还有一种似是而非的机制:即那些癌细胞可能在手术前就已经扩散了。但不知怎的,那些癌细胞并没有增长或处于“休眠”,当机体发生了什么事情改变了“休眠”状态,比如说手术唤醒了癌细胞并开始增长了。这种假设有科学依据吗?

上周《科学:转化医学》刊发了一篇实验论文,其结论或许给出了比较合理的诠释和答案。

该研究是针对手术对转移癌小鼠模型的影响。结论是手术后“伤口愈合反应”可能是唤醒癌细胞生长复发的“罪魁祸首”。

具体机理如下:机体内免疫T细胞持续性反应压制着那些潜在的转移性癌细胞生长。但在手术后受到炎症反应而被破坏了,即实验小鼠(乳腺癌模型)在手术后,创伤引发异地癌细胞生长是通过炎性单核细胞(或分化为巨噬细胞)的作用。

阐明上述诱发癌细胞生长的证据更有意思:在小鼠动物模型手术后给以NSAIDs治疗以减轻炎症反应,即可轻而易举地消除诱发复发风险的影响因素!研究人员对比了癌细胞与抗炎药物之间的相互作用,在手术伤口部位注射美洛昔康,同时给以或不给以NSAID治疗做对照。效果截然不同。

另外一项对比乳腺癌患者的回顾性研究也表明,给以NSAIDs治疗可以降低肿瘤转移率。但是,研究人员无法确认是否手术治疗对事先转移存在的肿瘤细胞有直接作用。上述动物实验结果表明了手术后炎性反应可能是一种“激活机制”。为此,研究人员建议癌症手术后患者应当给以NSAID治疗,以防止已经扩散的癌细胞复发生长。

有意思的“纠结”是手术治疗肿瘤不仅是经典中的经典,而且大量临床数据证明手术对肿瘤的显著疗效。如果从动物实验结果推断不建议手术切除肿瘤,不仅彻底颠覆了临床肿瘤学的“金标准”,也会动摇患者积极配合手术治疗。

因此,该论文作者在归纳结论时强调:联合手术与短期抗炎治疗可能会降低乳腺癌手术后的预后康复(有可能避免或降低癌症复发率)。明确的结论是,手术切除癌症过程中或之后,抗炎药美洛昔康能有效地抑制手术创伤(炎性反应)对肿瘤生长的刺激影响。

在《科学:转化医学》刊发这篇论文后,业界专家的反馈不一,但是的确引起了关注。为什么不关注呢?

首先,该动物实验结果和推论值得关注,其次,没有理由不在肿瘤治疗中应用或尝试联合短期抗炎治疗。因为所用非甾体类抗炎药价格便宜,耐受性好,风险/收益比有益于患者的预后康复。

患者都渴望疗效尽善尽美, As Good as it gets

再来回顾一下有关机体免疫系统与癌症发生发展的相关性,各种假设和研究仍在继续研讨中。无论是应当将机体免疫反应激活(细胞治疗的核心思想)或抑制(在上述情形下),科学家们仍需要做更多的精准研究和临床验证。

凡事一概而论,不仅会误导癌症的精准治疗,更会让许多本来有希望带瘤生存的患者(手术切除后)错过了天赐良机。

再补充几句,医生通常建议多数乳腺癌患者手术后再给以化疗+放疗联合方案。由此理解手术仅仅移除了原位癌,化疗+放疗是预防性治疗可能转移或潜伏的癌细胞,效果怎样?患者的生存率又如何?业界权威人士的观点不一。

关于癌症手术后+抗炎治疗联合方案,以色列的临床医生已经应用了20多年。十年多前默沙东也曾主持过在结肠癌患者术后使用NSAIDs的临床试验,得到的效果是确实的,但是,由于增加了患者突发心脏病风险而不了了之。

文摘

The Systemic Response to Surgery Triggers the Outgrowth of Distantimmune-controlled Tumors in Mouse Models of Dormancy

Jordan A. Krall, etc, and RobertA. Weinberg,Science Translational Medicine 11Apr 2018: Vol. 10, Issue 436, eaan3464

Can Wound Healing Worsen Metastasis?

Relatively early metastatic recurrence after primary surgical resection is common in breast cancer patients.

Summary

This phenomenon could be due to tumor cells released into the circulation during surgery or could be the result of existing metastatic outgrowth.

To distinguish between these possibilities, Krall et al. used a common wound-healing model in mice harboring breast cancer cells. In this model, there is no surgery to disturb a primary tumor bed. They discovered that T cells are able to keep distant tumor cells in check, but that inflammation induced during wound healing may disrupt this delicate balance.

Anti-inflammatory treatment reduced metastasis in the mice, and existing clinical data also suggest that perioperative anti-inflammatories reduced early metastatic recurrence in breast cancer patients. By separating surgery from resection, these results may explain this curious clinical occurrence.

Abstract

Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery.

The cause of early metastatic relapse in breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Other shave proposed that some aspect of surgical tumor resection triggers the outgrowth of other wise-dormant metastases, leading to the synchronous pattern of relapse.

Clinical data cannot distinguish between these hypotheses, and previous experimental approaches have not provided clear answers.

Such uncertainty hinders the development and application of therapeutic approaches that could potentially reduce early metastatic relapse. We describe an experimental model system that definitively links surgery and the subsequent wound-healing response to the outgrowth of tumor cells at distant anatomicalsites. Specifically, we find that the systemic inflammatory response induced after surgery promotes the emergence of tumors whose growth was otherwise restricted by a tumor-specific T cell response.

Furthermore, we demonstrate that perioperative anti-inflammatory treatment markedly reduces tumor outgrowth in this model, suggesting that similar approaches might substantially reduce early metastatic recurrence in breast cancer patients.

https://mp.weixin.qq.com/s/KT8ZTKBJeMVXiH1M9ehDKQ