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Abstract：
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a \'difficult-to-treat\' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are areas at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression.
METHODS: We reviewed the SARIFA status of 166 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.
RESULTS: In total, 53 cases (32%) were classified as SARIFA positive and 113 (68%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 11.0 months vs. 22.0 months, HR: 1.570 (1.082-2.278), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p < 0.0001) and higher concentrations of CD68+ macrophages (p = 0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm2 and 1812 ± 1008 µm2 for the SARIFA-negative and -positive cases, respectively (p < 0.001).
CONCLUSIONS: SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
METHODS: We reviewed the SARIFA status of 166 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.
RESULTS: In total, 53 cases (32%) were classified as SARIFA positive and 113 (68%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 11.0 months vs. 22.0 months, HR: 1.570 (1.082-2.278), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p < 0.0001) and higher concentrations of CD68+ macrophages (p = 0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm2 and 1812 ± 1008 µm2 for the SARIFA-negative and -positive cases, respectively (p < 0.001).
CONCLUSIONS: SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
摘要：
背景：胰腺导管腺癌（PDAC）是一种“难以治疗”的实体。为了预测其预后，我们引入了一种新的生物标志物，SARIFA(基质活动侵入前沿区域),这是肿瘤侵袭前沿的区域，在周围组织的恶性侵袭时缺乏增生性基质反应，导致肿瘤细胞和脂肪细胞之间的直接接触。SARIFA在胃癌和大肠癌中具有重要意义，揭示促进肿瘤进展的脂质代谢变化。
方法：我们回顾了来自存档Whipple切除标本的所有可用H＆E染色肿瘤载玻片上166例PDAC的SARIFA状态。SARIFA阳性定义为在至少66%的可用载玻片中检测到SARIFA。为了研究肿瘤代谢和微环境的变化，我们对FABP4,CD36和CD68进行了免疫组织化学染色.为了验证和量化假定的脂肪细胞脱脂，脂肪组织进行了数字化形态金属化.
结果：总计，53例(32%)为SARIFA阳性,113例(68%)为SARIFA阴性。与SARIFA阴性病例相比，SARIFA阳性PDAC患者的总生存期明显更差（中位总生存期：11.0个月22.0个月，HR：1.570（1.082-2.278），95%CI，p=0.018)，独立于其他预后标志物（p=0.014）。在SARIFA阳性PDAC的入侵前沿,我们观察到FABP4表达显著升高(p<0.0001),CD68+巨噬细胞浓度升高(p=0.031)与肿瘤进展风险较高有关.CD36染色显示无显著表达差别。侵袭前沿的脂肪细胞面积明显较小，SARIFA阴性和阳性病例的平均值为4021±1058µm2和1812±1008µm2，分别(p<0.001)。
结论：SARIFA是PDAC的一个有前景的预后生物标志物。其评估的特点是简单和低努力。SARIFA背后的机制表明肿瘤促进脂质代谢增加和免疫背景改变，两者都显示出新的治疗途径。
方法：我们回顾了来自存档Whipple切除标本的所有可用H＆E染色肿瘤载玻片上166例PDAC的SARIFA状态。SARIFA阳性定义为在至少66%的可用载玻片中检测到SARIFA。为了研究肿瘤代谢和微环境的变化，我们对FABP4,CD36和CD68进行了免疫组织化学染色.为了验证和量化假定的脂肪细胞脱脂，脂肪组织进行了数字化形态金属化.
结果：总计，53例(32%)为SARIFA阳性,113例(68%)为SARIFA阴性。与SARIFA阴性病例相比，SARIFA阳性PDAC患者的总生存期明显更差（中位总生存期：11.0个月22.0个月，HR：1.570（1.082-2.278），95%CI，p=0.018)，独立于其他预后标志物（p=0.014）。在SARIFA阳性PDAC的入侵前沿,我们观察到FABP4表达显著升高(p<0.0001),CD68+巨噬细胞浓度升高(p=0.031)与肿瘤进展风险较高有关.CD36染色显示无显著表达差别。侵袭前沿的脂肪细胞面积明显较小，SARIFA阴性和阳性病例的平均值为4021±1058µm2和1812±1008µm2，分别(p<0.001)。
结论：SARIFA是PDAC的一个有前景的预后生物标志物。其评估的特点是简单和低努力。SARIFA背后的机制表明肿瘤促进脂质代谢增加和免疫背景改变，两者都显示出新的治疗途径。
