Can we prevent childhood Leukaemia?
Can we prevent childhood Leukaemia?
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DOI：
10.1038/s41375-021-01211-7
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Ford A
中科院分区：
文献类型：
--
作者：
Greaves M;Cazzaniga V;Ford A
尽管治疗效果取得了进步，但儿童癌症的发病率和死亡率仍然很高。由于这些癌症的相对罕见性、亚组的多样性以及一些人不愿投资罕见癌症的药物开发，探索新的治疗方案受到了限制。在成人癌症中，晚期或转移性疾病在很大程度上仍然不妥协，新兴的耐药性是恶性逃逸的门户。虽然涉及免疫疗法、进化或适应性控制的新型组合策略可能会很好地阻止耐药性[1-3]，但人们非常重视早期诊断和干预，因为根除或治愈的前景更加明确。但也有人认为，由于癌症的好战性是动态高度可变的渐进进化过程的结果，因此癌症控制的 A 计划应该是预防 [4]。或者，在它开始之前停止它。从理论上讲，这是有道理的，但要使其合理，更不用说实用，就需要我们能够识别因果路径中易于拦截的关键组成部分。对于许多常见的成人癌症，包括乳腺癌、前列腺癌和结直肠癌，这仍然具有挑战性。然而，吸烟与肺癌、皮肤癌与 UVB、宫颈癌与 HPV 之间一致的因果关系 [5] 为通过教育、谨慎避免以及预防性疫苗接种（就 HPV 而言）减轻疾病负担提供了非常令人鼓舞的例子。毫无疑问，癌症预防是可能的，并且可以对公共健康产生重大的全球影响。对于包括实体瘤和白血病在内的儿科癌症，情况有所不同。对于发病率罕见且具有生物学多样性的癌症来说，确定因果途径极其困难。此外，人们普遍认为，许多（如果不是大多数）儿童癌症是由随机的、发育错误加上遗传易感性引起的[6]，这进一步削弱了考虑预防的热情。然而，这种普遍悲观的观点有一个例外，那就是儿童急性淋巴细胞白血病（ALL）。这是最常见的儿科癌症类型（约占所有病例的三分之一），但其本身具有异质性，起源于多谱系或淋巴祖细胞。区分这些亚型一直是揭示可能的因果路径的关键组成部分。对于最常见的亚型 B 细胞前体 ALL（约占总数的 75%），基础生物学研究和大型协作病例/对照流行病学研究相结合，提供了一个合理的因果机制，阐明了预防的前景 [7]。但首先，需要注意的是。 ALL 提供了肿瘤学领域真正的成功案例之一。在缺乏有效治疗的情况下，这种癌症普遍致命[8]，但通过联合化疗的系统临床试验，这种癌症已通过逐步、渐进的进展得到转变，目前治愈率约为 90%[9]。那么，我们为什么要对预防感兴趣呢？听起来很油嘴滑舌，但有效的答案是“问问病人的任何一位家长”。现实情况是，这种治疗对于年幼的患者及其家人来说是一种创伤，而且是有毒的，在发病率和长期健康影响方面会产生一定的成本或有害的权衡[10, 11]。治疗的良好前景对受影响的家庭来说非常重要，但如果可能的话，预防肯定会更好吗？
Despite advances in treatment efficacy, childhood cancers continue to exert a heavy toll in morbidity and mortality. Exploring new therapeutic options has been restrained by the relative rarity of these cancers coupled with their subgroup diversity and some reluctance to invest in drug development for rare cancers. In adult cancers, later stage or metastatic disease remains largely intransigent with emergent drug resistance as the portal for malignant escape. Whilst novel combinatorial strategies involving immunotherapy, evolutionary or adaptive control might well thwart resistance [1–3], much emphasis is placed on early diagnosis and intervention where prospects for eradication or cure are more tangible. But it has also been argued that since the belligerence of cancer is the result of a progressive evolutionary process with highly variable dynamics Plan A for cancer control should be prevention [4]. Or, to stop it before it gets started. In theory, this makes sense but for this to be plausible, let alone practicable, requires that we can identify critical components of the causal pathway that are amenable to interception. For many common adult cancers, including breast, prostate and colorectal this remains challenging. However, the consistent, causal links between smoking and lung cancer, skin cancer and UVB and cervical cancer and HPV [5] provide hugely encouraging examples of reduction in disease burden via education, prudent avoidance and, in the case of HPV, prophylactic vaccination. There is little doubt that cancer prevention is possible and can have a substantial, global impact on public health. For paediatric cancers including both solid tumours and leukaemia, the picture has been different. Identifying causal pathways is extremely difficult for cancers that are both rare in prevalence and biologically diverse. Moreover, the common view that many if not most childhood cancers arise via stochastic, developmental errors compounded by inherited susceptibility [6] further dampens any enthusiasm to consider prevention as a possibility. There is however one exception to this generally pessimistic perspective and that is with childhood acute lymphoblastic leukaemia (ALL). This is the most common type of paediatric cancer (around one-third of all cases) but is itself heterogeneous, originating from multi-lineage or lymphoid progenitors. Discriminating between these subtypes has been a key component of unravelling likely causal pathways. And for the most frequent subtype, B cell precursor ALL (~ 75% of total), a combination of basic biological investigations and large collaborative case/control epidemiological studies has delivered a plausible causal mechanism which illuminates prospects for prevention [7]. But first, a caveat. ALL has provided one of the real success stories in oncology. Universally lethal in the absence of effective treatment [8], this cancer has been transformed by stepwise, incremental gains via systematic clinical trials of combination chemotherapy with a current cure rate of around 90%[9]. So, why should we be interested in prevention? One glib sounding but the valid answer would be to say,‘ask any parent of a patient’. The reality is that the treatment is traumatic for very young patients and their families, and toxic with some cost or deleterious trade off in terms of morbidity and long-term health impacts [10, 11]. The excellent prospects for curative treatment are massively important to the affected families but prevention, if possible, would surely be even better?
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影响因子：
16.6
作者：
Durack J;Kimes NE;Lin DL;Rauch M;McKean M;McCauley K;Panzer AR;Mar JS;Cabana MD;Lynch SV
通讯作者：
Lynch SV
DOI：
10.1084/jem.20180448
发表时间：
2019-01-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Durack J;Lynch SV
通讯作者：
Lynch SV
影响因子：
11.8
作者：
Böiers C;Richardson SE;Laycock E;Zriwil A;Turati VA;Brown J;Wray JP;Wang D;James C;Herrero J;Sitnicka E;Karlsson S;Smith AJH;Jacobsen SEW;Enver T
通讯作者：
Enver T
影响因子：
3.7
作者：
Aumeunier A;Grela F;Ramadan A;Pham Van L;Bardel E;Gomez Alcala A;Jeannin P;Akira S;Bach JF;Thieblemont N
通讯作者：
Thieblemont N
DOI：
10.1016/s1470-2045(14)70265-7
发表时间：
2014-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Essig S;Li Q;Chen Y;Hitzler J;Leisenring W;Greenberg M;Sklar C;Hudson MM;Armstrong GT;Krull KR;Neglia JP;Oeffinger KC;Robison LL;Kuehni CE;Yasui Y;Nathan PC
通讯作者：
Nathan PC