Wagner Patrick, Boone Brian, Ramalingam Lekshmi, Jones Heather, Zureikat Amer, Holtzman Matthew, Ahrendt Steven, Pingpank James, Zeh Herbert, Choudry Haroon, Bartlett David
Division of Surgical Oncology, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Winchester Medical Center, Winchester, VA, USA.
Ann Surg Oncol. 2015 Dec;22 Suppl 3:S588-95. doi: 10.1245/s10434-015-4580-6. Epub 2015 May 7.
Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are used to treat peritoneal carcinomatosis from a variety of primary tumor sites. Little is known about the in vivo effects of CRS and HIPEC.
We examined tumor and non-neoplastic peritoneal tissue samples from 38 patients undergoing CRS and HIPEC for appendiceal or colorectal carcinomatosis, using conventional histologic analysis and immunohistochemical analysis for markers of early DNA damage (phosphorylated H2AX, γH2AX) and early necrosis (extracellular HMGB1). Findings were correlated with clinicopathologic features and oncologic outcome.
Histologic findings corresponding with CRS and HIPEC included extensive submesothelial inflammatory infiltrate, endothelial activation, mesothelial karyolysis and surface fibrin deposition. Endothelial activation in submesothelial vessels exhibited high specificity for samples obtained following HIPEC relative to samples obtained following CRS but prior to HIPEC. Mesothelial nuclear γH2AX staining and submesothelial extracellular HMGB1 staining increased progressively following CRS and HIPEC, consistent with DNA damage and necrosis. No significant increase in tumor staining for markers was seen with CRS or HIPEC. Submesothelial HMGB1 staining was associated with increased progression-free survival on univariate analysis.
The immediate histologic effects of CRS and HIPEC are defined and provide evidence that DNA damage and early steps of necrosis are underway in mesothelial tissues at the conclusion of the procedure. Further research will be necessary to investigate the impact of these findings on long-term oncologic outcome, and may provide insight into the downstream effects of CRS and HIPEC that could facilitate refinement of regional therapeutic regimens for carcinomatosis.
细胞减灭术（CRS）和腹腔内热灌注化疗（HIPEC）用于治疗源自多种原发肿瘤部位的腹膜癌病。关于CRS和HIPEC的体内效应知之甚少。
我们使用常规组织学分析以及针对早期DNA损伤（磷酸化H2AX，γH2AX）和早期坏死（细胞外高迁移率族蛋白B1，HMGB1）标志物的免疫组化分析，检查了38例因阑尾或结直肠癌病接受CRS和HIPEC治疗的患者的肿瘤和非肿瘤性腹膜组织样本。研究结果与临床病理特征和肿瘤学结局相关。
与CRS和HIPEC相应的组织学发现包括广泛的间皮下炎性浸润、内皮细胞活化、间皮核溶解和表面纤维蛋白沉积。相对于CRS后但HIPEC前获取的样本，HIPEC后获取的样本中间皮下血管的内皮细胞活化表现出高特异性。CRS和HIPEC后，间皮细胞核γH2AX染色和间皮下细胞外HMGB1染色逐渐增加，这与DNA损伤和坏死一致。CRS或HIPEC后未观察到标志物的肿瘤染色有显著增加。单因素分析显示，间皮下HMGB1染色与无进展生存期延长相关。
定义了CRS和HIPEC的即时组织学效应，并提供了证据表明在手术结束时间皮组织中正在发生DNA损伤和坏死的早期步骤。有必要进行进一步研究以调查这些发现对长期肿瘤学结局的影响，并可能有助于深入了解CRS和HIPEC的下游效应，从而有助于完善腹膜癌病的区域治疗方案。
