Impact of Driver Mutations on the Evolution of Isolated Metachronous Lung Metastasis of Pancreatic Ductal adenocarcinoma.
- 作者列表："Vitellius C","Griveaux O","Morvant B","Pedrono E","Venara A","Ingster O","Baize N","Dincuff E","Rousselet MC","Guardiola P","Caroli-Bosc FX
BACKGROUND:The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing sharply. The survival of patients with metastases is usually about a year. However, the occurrence of isolated lung metastases after resection of the primary tumor, although rare, seems to indicate a better prognosis, with an average survival ranging from 40 to 80 months. KRAS, TP53, CDK2NA, and SMAD4 are the most common driver genes in pancreatic adenocarcinoma. OBJECTIVE:Our objectives were to determine whether a link exists between survival and mutations of driver genes in patients with isolated pulmonary metastases. METHODS:All patients who underwent curative surgery in our institution between 2010 and 2018 were included in the study. From these, we identified patients for whom recurrence was only pulmonary and those with metastases at other sites. KRAS, TP53, CDK2NA, and SMAD4 were analyzed on the primary tumor of patients with pulmonary metastases. RESULTS:Among 233 patients diagnosed with PDAC in our institution over 8 years, 41 (17.5%) underwent curative surgery. Of these, seven (3%) developed isolated pulmonary metastases, 32 developed other metastases, and two did not recur. Median survival was 59 months for patients with isolated lung metastases and 25.3 months for patients with metastases at other sites. An absence of mutations of two driver genes in primary tumors (CDK2NA and SMAD4) was observed in patients with isolated pulmonary metastases. CONCLUSIONS:The absence of mutations in the CDK2NA and SMAD4 tumor-suppressor genes in patients with isolated pulmonary metastases contrasts with the commonly observed high rates of driver gene mutations and suggests a link with overall survival.
背景: 胰腺导管腺癌 (PDAC) 的发病率正在急剧增加。转移患者的生存期通常约为一年。然而，原发肿瘤切除后孤立性肺转移的发生虽然罕见，但似乎预示着较好的预后，平均生存期为 40 ~ 80 个月。KRAS 、 TP53 、 CDK2NA 和 SMAD4 是胰腺癌中最常见的驱动基因。 目的: 我们的目的是确定孤立性肺转移患者的生存和驱动基因突变之间是否存在联系。 方法: 本研究纳入了 2010 年至 2018 年间在我机构接受根治性手术的所有患者。从这些患者中，我们确定了复发仅为肺部的患者和其他部位有转移的患者。分析 KRAS 、 TP53 、 CDK2NA 和 SMAD4 对肺转移瘤患者原发肿瘤的影响。 结果: 在我们机构 8 年诊断为 PDAC 的 233 例患者中，41 例 (17.5%) 接受了根治性手术。其中，7 例 (3%) 发生孤立性肺转移，32 例发生其他转移，2 例未复发。孤立性肺转移患者的中位生存期为 59 个月，其他部位转移患者的中位生存期为 25.3 个月。在孤立性肺转移瘤患者中观察到原发性肿瘤 (CDK2NA 和 SMAD4) 中两个驱动基因的突变缺失。 结论: 孤立性肺转移患者中 CDK2NA 和 SMAD4 抑癌基因不存在突变，与通常观察到的高驱动基因突变率形成对比，并提示与总生存期相关。
METHODS::Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.
METHODS::Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly-expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.
METHODS:PURPOSE:Pre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC. METHODS:We prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability. RESULTS:Pre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P 50% was determined at 1.40 × 10-3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy. CONCLUSIONS:Post-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.