Supplementary Material for: Prognostic Factors and Long-Term Outcome of Pancreatic Neuroendocrine Neoplasms: Ki-67 Index Shows a Greater Impact on Survival than Disease Stage. The Large Experience of the Spanish National Tumor Registry (RGETNE)

<b><i>Introduction:</i></b> Pancreatic neuroendocrine neoplasms (PNENs) are uncommon neoplasms with a wide spectrum of clinical behavior. The objective of this study was to assess in a large cohort of patients the relative impact of prognostic factors on survival. <b><i>Methods:</i></b> From June 2001 through October 2010, 1,271 patients were prospectively registered online (www.getne.org) at the Spanish National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE) by participating centers. Clinical and histopathological features were assessed as potential prognostic factors by uni- and multivariate analyses. <b><i>Results:</i></b> Of 483 PNENs, 171 (35%) were functional (F) and 312 (65%) non-functional (NF). NF-PNENs were associated with a higher incidence of histological features denoting more aggressive disease, such as poor tumor differentiation, Ki-67 &gt;20%, or vascular invasion (NF- vs. F-PNENs, respectively, p &lt; 0.05). Nevertheless, functionality was not a significant predictor of survival (p = 0.19). Stage at diagnosis, Ki-67 index, tumor differentiation and surgical resection of the primary tumor were all significant prognostic factors in univariate analysis. However, Ki-67 (&gt;20 vs. ≤2%) (hazard ratio (HR) 2.21, p = 0.01) and surgical resection (yes vs. no) (HR 0.92, p = 0.001) were the only independent predictors of survival in multivariate analysis. Among patients who underwent surgery, high Ki-67 index (HR 10.37, p = 0.02) and poor differentiation (HR 8.16, p = 0.03) were the only independent predictors of clinical outcome. <b><i>Conclusion:</i></b> Ki-67 index and tumor differentiation are key prognostic factors influencing survival of patients with PNENs and, in contrast to what it is observed for other solid malignancies, they seem to have a greater impact on survival than the extent of disease. This should be borne in mind by physicians in order to appropriately tailor therapeutic strategies and surveillance of these patients.

**<i>引言：</i>** 胰腺神经内分泌肿瘤（Pancreatic neuroendocrine neoplasms, PNENs）是一类较为罕见的肿瘤，其临床行为谱跨度较大。本研究旨在通过大型患者队列，分析各类预后因素对患者生存的相对影响。
**<i>方法：</i>** 2001年6月至2010年10月期间，1271例患者由参与中心通过西班牙国家胃肠胰神经内分泌肿瘤注册数据库（RGETNE）的在线平台（www.getne.org）完成前瞻性登记。本研究采用单因素与多因素分析，评估临床及组织病理学特征作为潜在预后因素的价值。
**<i>结果：</i>** 纳入分析的483例胰腺神经内分泌肿瘤患者中，171例（35%）为功能性（F型）肿瘤，312例（65%）为无功能性（NF型）肿瘤。无功能性肿瘤更易出现提示疾病侵袭性更高的组织病理学特征，例如肿瘤低分化、Ki-67指数＞20%或血管侵犯（无功能性vs.功能性肿瘤，各组p值均＜0.05）。然而，肿瘤功能性并非患者生存的显著预测因子（p=0.19）。单因素分析显示，确诊时的临床分期、Ki-67指数、肿瘤分化程度以及原发肿瘤手术切除情况均为显著的预后因素。但在多因素分析中，仅Ki-67指数（＞20% vs. ≤2%，风险比HR=2.21，p=0.01）与原发肿瘤手术切除情况（是vs.否，HR=0.92，p=0.001）为患者生存的独立预测因子。在接受手术治疗的患者亚组中，高Ki-67指数（HR=10.37，p=0.02）与肿瘤低分化（HR=8.16，p=0.03）是临床结局的唯一独立预测因子。
**<i>结论：</i>** Ki-67指数与肿瘤分化程度是影响胰腺神经内分泌肿瘤患者生存的关键预后因素；与其他实体恶性肿瘤不同的是，这两项指标对患者生存的影响似乎大于疾病分期。临床医师应牢记这一结论，以便为该类患者制定个体化治疗策略并优化随访管理方案。