Aryl hydrocarbon receptor interacting protein (AIP) significantly influences prognosis of pancreatic carcinoma.

INTRODUCTION: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Aryl hydrocarbon receptor interacting protein (AIP) in one of AHR ligands. The aim of this study is to analyze the prognostic influence of AIP in pancreatic carcinoma. MATERIAL AND METHODS: Retrospective case series with immunohistochemical analysis of AIP. We have estimated a multivariate Cox's model for the outcome (progression free and overall survival). RESULTS: 204 patients were included in the study. As expected prognosis was poor and 67.8% died of disease. As for AIP 9.8% of the cases showed nuclear staining of the epithelial tumor cells and 59.4% a cytoplasmic one. Stroma was stained in 53.1% of the cases. Univariate survival analysis revealed a significantly worse prognosis of patients with cytoplasmic AIP expression (stroma and epithelium), but nuclear expression was associated to a better prognosis. In the multivariate analysis stromal AIP expression was an independent prognosticator of progression free survival, together with pT stage, histological grade and history of diabetes. DISCUSSION: AIP Is a conserved cochaperone protein binding to many proteins. AIP has been proposed as a potential tumor suppressor gene. To date, no study has analyzed the immunohistochemical expression of AIP in pancreatic carcinoma. Our results indicate that both epithelial and stromal cytoplasmic expression of AIP is associated to bad prognosis, while nuclear translocation seems to improve prognosis. CONCLUSION: Although we must deepen into the complex signaling pathways underlying this potential association, our results open a way to inhibiting AHR as a potential target against pancreatic carcinoma.

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.

Still a place for conventional histopathological analysis in the era of molecular medicine: predicting prognosis of resectable ductal pancreatic adenocarcinoma.

INTRODUCTION: Our aim is to find features that define prognosis in surgically resected ductal pancreatic adenocarcinoma readily accessible in everyday practice. MATERIALS AND METHODS: Longitudinal retrospective case series of pancreatic adenocarcinoma operated with a curative intent in a large tertiary hospital in Madrid between 2009 and 2015. RESULTS: 162 were enrolled. 40.8% survived less than 1 year. Multivariate Cox's regression model revealed that gender, presence of symptoms, T and N stage independently influenced progression-free survival, while overall survival was determined by gender, smoking, presence of symptoms and N stage. Logistic regression analysis revealed that only symptoms at diagnosis could predict death, while gender, symptoms, histopathological type, vessel invasion, T stage and necrosis could independently predict recurrence. DISCUSSION: Our series show that patients with symptomatic disease at the time of diagnosis and females showed a shorter progression-free and overall survival. We herein propose a regression model to predict outcome.

The potential predictive value of DEK expression for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer.

BACKGROUND: Limited data are available regarding the ability of biomarkers to predict complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Complete response translates to better patient survival. DEK is a transcription factor involved not only in development and progression of different types of cancer, but is also associated with treatment response. This study aims to analyze the role of DEK in complete pathological response following chemoradiotherapy for locally advanced rectal cancer. METHODS: Pre-treated tumour samples from 74 locally advanced rectal-cancer patients who received chemoradiation therapy prior to total mesorectal excision were recruited for construction of a tissue microarray. DEK immunoreactivity from all samples was quantified by immunohistochemistry. Then, association between positive stained tumour cells and pathologic response to neoadjuvant treatment was measured to determine optimal predictive power. RESULTS: DEK expression was limited to tumour cells located in the rectum. Interestingly, high percentage of tumour cells with DEK positiveness was statistically associated with complete pathological response to neoadjuvant treatment based on radiotherapy and fluoropyrimidine-based chemotherapy and a marked trend toward significance between DEK positiveness and absence of treatment toxicity. Further analysis revealed an association between DEK and the pro-apoptotic factor P38 in the pre-treated rectal cancer biopsies. CONCLUSIONS: These data suggest DEK as a potential biomarker of complete pathological response to treatment in locally advanced rectal cancer.

PLK-1 Expression is Associated with Histopathological Response to Neoadjuvant Therapy of Hepatic Metastasis of Colorectal Carcinoma.

Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and overexpressed in multiple human cancers, including leukemia and also many solid tumors. PLK1 knockdown has been shown to block proliferation of leukemic cell lines and the clonogenic potential of tumor cells grown from patients with cancer. PLK1 inhibition is a promising strategy for the treatment of some tumors. We aim to analyze expression of PLK1 in metastatic colorectal carcinoma. Retrospective analysis of colorectal carcinomas with hepatic metastasis during follow-up receiving neoadjuvant chemotherapy (NAC), based on oxaliplatin. Immunohistochemistry for PLK-1 in paraffin-embedded tissue from the primary and also from the metastasis. 50 patients. 32% showed good histopathological response. 43% of the primaries were positive for PLK1, as opposed to 23.5% of the metastasis. Expression of PLK1 was significantly reduced in metastasis compared with the primaries (p = 0.05), what could be due to therapy or to a phenotypic change of the metastatic nodule. Analysis of the prognostic influence of PLK1 expression showed significant association between PLK1 expression in metastasis and lower overall survival (p = 0.000). We have also found a significant association between PLK1 expression and histopathological response (p = 0.02). All the tumors with high expression of PLK1 showed minor response (11/11). This study shows the association between survival and poor histopathological response to therapy and high expression of PLK1 in metastasis. Our results could open a new therapeutic approach through the inhibition of PLK1.

Identification of Poor-outcome Biliopancreatic Carcinoma Patients With Two-marker Signature Based on ATF6α and p-p38 "STARD Compliant".

Biliopancreatic cancer is one of the most aggressive solid neoplasms, and incidence is rising worldwide. It is known that ATF6α is one of the transmembrane proteins that acts crucially in endoplasmic reticulum stress response, and knockdown induces apoptosis of pancreatic cells. Apart from this, p-p38 has been previously correlated with better outcome in pancreatic cancer. Interestingly, ATF6α knockdown pancreatic cells showed increased p-p38. The aim of this study was to evaluate the expression of these 2 proteins, p-p38 and ATF6α, and their correlation with the outcome of biliopancreatic adenocarcinoma patients. Samples from patients with biliopancreatic adenocarcinoma that underwent pancreaticoduodenectomy from 2007 to 2013 were used to construct a tissue microarray to evaluate p-p38 and ATF6α proteins by immunohistochemistry. We observed that both markers showed a tendency to impact in the time to recurrence; then a combination of these 2 proteins was analyzed. Combination of ATF6α(high) and p-p38(low) was strongly associated with a higher risk of recurrence (hazard ratio 2.918, P = 0.013). This 2-protein model remained significant after multivariate adjustment.We proposed a 2-protein signature based on ATF6α(high) and p-p38(low) as a potential biomarker of risk of recurrence in resected biliopancreatic adenocarcinoma patients.

Morphological aspects of the hepatic response to neoadjuvant therapy.

INTRODUCTION: Therapy of metastatic colorectal carcinoma has greatly evolved in recent years. Surgery is still the best curative option and can improve survival in stage IV disease. Neoadjuvant chemotherapy (NAC) has emerged as a widely used therapeutic option before surgery. Pathologists have developed several systems to grade response, mainly adapting the grading systems used for the response in primary esophageal or rectal tumors. There are many reports confirming the prognostic utility of these grading systems. However, there have been fewer references to the potential significance of the pattern of histological response. The objective of the present study is to describe the histopathological lesions found in the tumor bed after NAC and their potential significance in terms of prognosis. MATERIAL AND METHODS: We reviewed the files of patients with colorectal carcinoma that developed hepatic metastasis during follow-up and received NAC before surgical resection of metastasis. We gathered demographic, analytical and morphological data of the cases, and also reviewed the hepatic resection samples to measure the pathological response to chemotherapy according to Blazer's criteria, and to define the predominant patterns of response (mucin pools, fibrosis or necrosis). We also determined the presence of satellitosis, measured the thickness of the tumor-normal interface (TNI) as proposed by Maru et al., and searched for vascular and bile duct invasion. All these pieces of information were collected in an Excel database and analyzed with SPSS 20.0 for Windows statistical package. The outcome measures were disease-free survival and overall survival in months since the first surgery to resect metastatic disease. RESULTS: Fifty patients fulfilled the inclusion criteria for the present study. All of them had received a chemotherapeutic regimen mainly based on platinum, associated or not with targeted drugs (18% received anti-EGFR drugs and 24% anti-VEGFR drugs). Of the primaries, 66% were of sigmoid-rectal origin, and 32% of the cases showed a major histopathological response to therapy (including 3 cases with a complete response). In 76% of the tumors, the predominant histological pattern was necrosis, followed by fibrosis (57.4%). Mucin pools were the predominant feature in 23.4% of the tumors. We found satellitosis (microscopic tumor nodules separated by more than 1mm from the principal tumor) in 53.2% of the cases. A prominent inflammatory reaction was found in 19% of the cases, and it was mainly composed of lymphocytes and hystiocytes (70% of the cases). Vessel invasion was seen in 30% of the cases, and perineural invasion was only found in 4%. We found no case of bile duct invasion by the tumor. The thickness of the TNI measured less than 2.5mm in 60% of the present series. Statistical analysis of the series revealed that thickness of the tumor-liver interface was significantly associated with recurrence and overall survival. We found a significant association between response and thickness of the tumor-normal liver interface. In our series, the presence of satellitosis tended to predict a shorter DFS. The comparison of Kaplan-Meier curves with the log-rank test showed a significant association between overall survival and the presence of mucin pools and fibrosis in the tumor bed. The other histopathological factors did not predict differences in prognosis. These differences were independent of the use of targeted drugs. DISCUSSION: The pathological reports of hepatic metastasis from colorectal carcinoma resected after NAC usually indicate only the number, the size and the response of the tumor cells to therapy, apart from the distance to the resection margin of the specimen. Few reports have analyzed the possible prognostic significance of the different kinds of histopathological responses. The results of the present study indicate that those tumors with extensive pools of mucin show a significantly worse prognosis as compared to tumors with less mucin secretion. Fibrosis indicates a better prognosis, except when desmoplasia is present. Our study further supports the prognostic significance of the thickness of the tumor-hepatic interface. We conclude that pathology reports should specify the kind of histopathological response to therapy, besides grading it, because this might add significant prognostic information.

Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy.

BACKGROUND: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. METHODS: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. RESULTS: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05). CONCLUSIONS: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.