Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland.
PLoS One. 2014 Jan 3;9(1):e83618. doi: 10.1371/journal.pone.0083618. eCollection 2014.
Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system.
41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and/or low muscularity (LM). Four diagnostic criteria were used >5%WL, >10%WL, LM, and LM+>2%WL. All patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, Western blots for markers of autophagy, SMAD signalling, and inflammation.
Compared with non-cachectic cancer patients, patients with LM or LM+>2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either >5%WL or LM+>2%WL. Compared with non-cachectic patients, SMAD3 protein levels were increased in patients with >5%WL (p = 0.022) and with >10%WL, beclin (p = 0.05) and ATG5 (p = 0.01) protein levels were increased. There were no differences in phospho-NFkB or phospho-STAT3 levels across any of the groups.
Muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the diagnostic criteria for cachexia are based on weight loss alone, a measure of low muscularity alone or a combination of the two. For intervention trials where the primary end-point is a change in muscle mass or function, use of combined diagnostic criteria may allow identification of a more homogeneous patient cohort, reduce the sample size required and enhance the time scale within which trials can be conducted.
恶病质影响大多数晚期癌症患者，与治疗耐受性降低、治疗反应以及生存时间缩短有关。有效治疗恶病质的一个障碍是缺乏经过验证的分类系统。
41 例可切除上消化道（GI）或胰腺癌症患者根据体重减轻（WL）和/或低肌肉量（LM）进行恶病质特征分析。使用了 4 种诊断标准，包括>5%WL、>10%WL、LM 和 LM+>2%WL。所有患者均接受了腹直肌活检。分析包括纤维大小和类型的免疫组织化学、蛋白质和核酸浓度、自噬、SMAD 信号和炎症标志物的 Western blot。
与非恶病质癌症患者相比，有 LM 或 LM+>2%WL 的患者，平均肌纤维直径减小约 25%（p=0.02 和 p=0.001 分别）。如果患者仅存在 WL，则纤维直径无显著差异。无论分类如何，所有肌球蛋白重链同工型的纤维数量或纤维类型比例均无差异。有>5%WL 或 LM+>2%WL 的患者肌肉蛋白含量降低，RNA/DNA 比值降低。与非恶病质患者相比，>5%WL 的患者 SMAD3 蛋白水平升高（p=0.022），>10%WL 的患者 beclin（p=0.05）和 ATG5（p=0.01）蛋白水平升高。任何一组患者的磷酸化 NFkB 或磷酸化 STAT3 水平均无差异。
根据诊断恶病质的标准是仅基于体重减轻、仅基于低肌肉量还是两者的组合，肌纤维大小、生化组成和途径表型可能会有所不同。对于主要终点为肌肉质量或功能变化的干预试验，使用联合诊断标准可能可以确定更同质的患者队列，减少所需的样本量，并缩短试验进行的时间范围。
