SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS: In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS: In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Role of Arctiin in Fibrosis and Apoptosis in Experimentally Induced Hepatocellular Carcinoma in Rats.

Background and objectives Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. It is currently the second most common cause of cancer-related mortality. Arctiin, a compound found in plants commonly used as a vegetable in Asian countries and as an ingredient in traditional European dishes, possesses various properties, including anti-proliferative, anti-senescence, anti-oxidative, anti-tumor, toxic, anti-adipogenic, and anti-bacterial effects. Our study aims to investigate the potential antitumor activity of arctiin against HCC in rats by inhibiting cell fibrosis and apoptosis. Methods Rats were induced with HCC by administering thioacetamide. Arctiin was orally administered to some rats twice a week for 16 weeks at a dose of 30 mg/kg. The liver impairment was evaluated by measuring serum α-fetoprotein (AFP) and examining liver sections stained with Masson trichrome or anti-hypoxia-induced factor-1α (HIF-1α) antibodies. The hepatic expression of messenger RNA and protein levels of HIF-1α, protein kinase C (PKC), extracellular signal-regulated kinase (ERK), ß-catenin, and mothers against decapentaplegic homolog 4 (SMAD4) were analyzed. Results Our study demonstrated that arctiin can potentially increase the survival rate of rats. This is achieved through a reduction in serum AFP levels and hepatic nodules. We also observed that arctiin has the ability to inhibit the formation of fibrotic tissues and necrotic nodules in HCC rats. Additionally, arctiin can significantly decrease the expression of HIF-1α, PKC, ERK, ß-catenin, and SMAD4. Conclusion Arctiin has demonstrated potential anti-tumor properties that could ameliorate HCC. Studies have shown that it may increase survival rates and reduce the number of tumors and AFP levels. Arctiin works by inhibiting HCC-induced hypoxia, thus blocking the expression of HIF-1α. It also helps to slow down tumor fibrosis by decreasing the expression of ß-catenin and SMAD4. Furthermore, arctiin has been found to downregulate PKC and ERK, reducing hepatic tissue apoptosis.

Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy.

BACKGROUND: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. METHODS: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. RESULTS: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8-18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7-24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1-0.8) were associated with higher and lower locoregional recurrence, respectively. CONCLUSIONS: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.