Multidisciplinary consensus statement on the clinical management of patients with pancreatic cancer

Pancreatic cancer (PC) remains one of the most aggressive tumors with an increasing incidence rate and reduced survival. Although surgical resection is the only potentially curative treatment for PC, only 15-20% of patients are resectable at diagnosis. To select the most appropriate treatment and thus improve outcomes, the diagnostic and therapeutic strategy for each patient with PC should be discussed within a multidisciplinary expert team. Clinical decision-making should be evidence-based, considering the staging of the tumor, the performance status and preferences of the patient. The aim of this guideline is to provide practical and evidence-based recommendations for the management of PC

Hepatic metastases from colorectal cancer: preoperative detectiona and assessment of resectability with helical CT

Purpose: to prospectively evaluate helical computed tomography (CT) in the preoperative detection of hepatic metastases and assessment of resectability with surgical, intraoperative ultrasonographic (US), and histopathologic correlation. Materials and methods: between October 1995 and December 1998, preoperative staging with helical CT (5-mm collimation; reconstruction interval, 5 mm) was performed in 157 patients with hepatic metastases. Iodinated contrast material was injected intravenously (160-170 mL; rate, 2.5-3.0 mL/sec); acquisition began at 60-70 seconds. Four radiologists prospectively assessed the metastatic involvement of the liver by indicating the number and location of the lesions; resection was indicated in 113 patients (119 instances). Helical CT findings were correlated with pathologic and surgical findings on a lesion-by-lesion basis. Results: intraoperative US, palpation, and histopathologic examination revealed 290 liver metastases; helical CT correctly depicted 247. Helical CT results were the following: overall detection rate, 85.1% (95% CI: 80.8%, 89.3%); positive predictive value, 96.1% (95% CI: 92.9%, 98.1%); and false-positive rate, 3.9% (10 of 257 findings; 95% CI: 1.9%, 7.1%). False-positive findings were related to hemangioendothelioma, hemangioma, hepatic peliosis, biliary adenoma, centrilobar hemorrhage, biliary hamartoma, periportal fibrosis, and normal liver parenchyma. Curative resection was performed in 112 instances with a resectability rate of 94.1%. Four-year patient survival rate was 58.6%. Conclusion: helical CT is a noninvasive, reliable, and accurate technique for imaging the liver and should be considered as the standard preoperative work-up of hepatic metastases from colorectal cancer

Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer

MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR- 200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overex- pressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family mem- bers and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respec- tively. Interestingly, we identified significant changes in expres- sion of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, func- tional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tu- mor suppressor gene in pancreatic cancer

Studies with the Golgi method in central gangliogliomas and dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease)

The rapid Golgi method, combined with current optical and electronmicroscopica1 techniques, was used in three central gangliogliomas and in one dysplastic gangliocytoma of the cerebellum to study the morphology of ganglionic cells. Gangliogliomas were composed of bipolar, fusiform and radiate cells with dense core and clear vesicles in the perikaryon and cellular processes, the number of each cellular type varying from one case to another. These features, together with the fact that isodendritic neurons are considered to be phylogenetically old neurons, suggest that these tumours are composed of 'primitive' neurons that are not homogeneous with regard to their morphology. In contrast, ganglionic cells in dysplastic gangliocytoma are huge cells with long, stereotyped neurites that establish unique asymmetric contacts with neighbouring perikarya and neurites by means of claw-shaped processes covered with synaptic buttons. These morphological characteristics are different from those of any other neuron of the CNS

Options in the surgical treatment of cavemous haemangioma of the rectum

El hemangioma cavernoso difuso del recto es una malformación congénita poco frecuente. de tipo hamartomatoso. Suele manifestarse en forma de rectorragias abundantes. en pacientes jóvenes y habitualmente requiere cirugía. Para evitar la resección abdóminoperineal en estos pacientes, se ha descrito una técnica de tipo «pull-through», que incluye una mucosectomía amplia del recto y una anastomosis colo-anal. Sin embargo. nosotros consideramos que si es posible descartar preoperatoriamente la afectación de otras vísceras pélvicas, es más adecuado realizar de una proctectomía conservadora seguida de anastomosis coloanal. Presentamos un caso en un paciente de 17 años

Prognostic value and risk stratification of residual disease in patients with incidental gallbladder cancer

Background and aim: given their poor prognosis, patients with residual disease (RD) in the re-resection specimen of an incidental gallbladder carcinoma (IGBC) could benefit from a better selection for surgical treatment. The Gallbladder Cancer Risk Score (GBRS) has been proposed to preoperatively identify RD risk more precisely than T-stage alone. The aim of this study was to assess the prognostic value of RD and to validate the GBRS in a retrospective series of patients. Material and methods: a prospectively collected database including 59 patients with IGBC diagnosed from December 1996 to November 2015 was retrospectively analyzed. Three locations of RD were established: local, regional, and distant. The effect of RD on overall survival (OS) was analyzed with the Kaplan-Meier method. To identify variables associated with the presence of RD, characteristics of patients with and without RD were compared using Fisher's exact test. The relative risk of RD associated with clinical and pathologic factors was studied with a univariate logistic regression analysis. Results: RD was found in 30 patients (50.8%). The presence of RD in any location was associated with worse OS (29% vs. 74.2%, p = 0.0001), even after an R0 resection (37.7% vs 74.2%, p = 0.003). There was no significant difference in survival between patients without RD and with local RD (74.2% vs 64.3%, p = 0.266), nor between patients with regional RD and distant RD (16.1% vs 20%, p = 0.411). After selecting patients in which R0 resection was achieved (n = 44), 5-year survival rate for patients without RD, local RD, and regional RD was, respectively, 74.2%, 75%, and 13.9% (p = 0.0001). The GBRS could be calculated in 25 cases (42.3%), and its usefulness to predict the presence of regional or distant RD (RDRD) was confirmed (80% in high-risk patients and 30% in intermediate risk p = 0.041). Conclusion: RDRD, but not local RD, represents a negative prognostic factor of OS. The GBRS was useful to preoperatively identify patients with high risk of RDRD. An R0 resection did not improve OS of patients with regional RD

Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition

The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-β is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-β is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-β-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-β upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic

2-[18F]FDG PET/CT as a Predictor of Microvascular Invasion and High Histological Grade in Patients with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) generally presents a low avidity for 2-deoxy-2-[18F]fluoro-d-glucose (FDG) in PET/CT although an increased FDG uptake seems to relate to more aggressive biological factors. To define the prognostic value of PET/CT with FDG in patients with an HCC scheduled for a tumor resection, forty-one patients were prospectively studied. The histological factors of a poor prognosis were determined and FDG uptake in the HCC lesions was analyzed semi-quantitatively (lean body mass-corrected standardized uptake value (SUL) and tumor-to-liver ratio (TLR) at different time points). The PET metabolic parameters were related to the histological characteristics of the resected tumors and to the evolution of patients. Microvascular invasion (MVI) and a poor grade of differentiation were significantly related to a worse prognosis. The SULpeak of the lesion 60 min post-FDG injection was the best parameter to predict MVI while the SULpeak of the TLR at 60 min was better for a poor differentiation. Moreover, the latter parameter was also the best preoperative variable available to predict any of these two histological factors. Patients with an increased TLRpeak60 presented a significantly higher incidence of poor prognostic factors than the rest (75% vs. 28.6%, p = 0.005) and a significantly higher incidence of recurrence at 12 months (38% vs. 0%, p = 0.014). Therefore, a semi-quantitative analysis of certain metabolic parameters on PET/CT can help identify, preoperatively, patients with histological factors of a poor prognosis, allowing an adjustment of the therapeutic strategy for those patients with a higher risk of an early recurrence

The level of caveolin-1 expression determines response to TGF-ß as a tumor suppressor in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is a heterogeneous tumour associated with poor prognostic outcome. Caveolin-1 (CAV1), a membrane protein involved in the formation of caveolae, is frequently overexpressed in HCC. Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine having a dual role in hepatocarcinogenesis: inducer of apoptosis at early phases, but pro-tumourigenic once cells acquire mechanisms to overcome its suppressor effects. Apoptosis induced by TGF-β is mediated by upregulation of the NADPH oxidase NOX4, but counteracted by transactivation of the epidermal growth factor receptor (EGFR) pathway. Previous data suggested that CAV1 is required for the anti-apoptotic signals triggered by TGF-β in hepatocytes. Whether this mechanism is relevant in hepatocarcinogenesis has not been explored yet. Here we analysed the TGF-β response in HCC cell lines that express different levels of CAV1. Accordingly, stable CAV1 knockdown or overexpressing cell lines were generated. We demonstrate that CAV1 is protecting HCC cells from TGF-β-induced apoptosis, which attenuates its suppressive effect on clonogenic growth and increases its effects on cell migration. Downregulation of CAV1 in HLE cells promotes TGF-β-mediated induction of the pro-apoptotic BMF, which correlates with upregulation of NOX4, whereas CAV1 overexpression in Huh7 cells shows the opposite effect. CAV1 silenced HLE cells show attenuation in TGF-β-induced EGFR transactivation and activation of the PI3K/AKT pathway. On the contrary, Huh7 cells, which do not respond to TGF-β activating the EGFR pathway, acquire the capacity to do so when CAV1 is overexpressed. Analyses in samples from HCC patients revealed that tumour tissues presented higher expression levels of CAV1 compared with surrounding non-tumoural areas. Furthermore, a significant positive correlation among the expression of CAV1 and TGFB1 was observed. We conclude that CAV1 has an essential role in switching the response to TGF-β from cytostatic to tumourigenic, which could have clinical meaning in patient stratification

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer

Background & Aims: Upon ligand binding, tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), are recruited into clathrin-coated pits for internalization by endocytosis, which is relevant for signalling and/or receptor degradation. In liver cells, transforming growth factor-beta (TGF-beta) induces both pro- and anti-apoptotic signals; the latter are mediated by the EGFR pathway. Since EGFR mainly traffics via clathrin-coated vesicles, we aimed to analyse the potential role of clathrin in TGF-beta-induced signalling in liver cells and its relevance in liver cancer. Methods: Real-Time PCR and immunohistochemistry were used to analyse clathrin heavy-chain expression in human (CLTC) and mice (Cltc) liver tumours. Transient knockdown (siRNA) or overexpression of CLTC were used to analyse its role on TGF-beta and EGFR signalling in vitro. Bioinformatic analysis was used to determine the effect of CLTC and TGEB1 expression on prognosis and overall survival in patients with hepatocellular carcinoma (HCC). Results: Clathrin expression increased during liver tumorigenesis in humans and mice. CLTC knockdown cells responded to TGF-beta phosphorylating SMADs (canonical signalling) but showed impairment in the anti-apoptotic signals (EGFR transactivation). Experiments of loss or gain of function in HCC cells reveal an essential role for clathrin in inhibiting TGF-beta-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-beta signalling in invasive HCC cells upregulates CLTC expression, switching its role to pro-tumorigenic. A positive correlation between TGEB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGEB1 and CLTC had a worse prognosis and lower overall survival. Conclusions: This work describes a novel role for clathrin in liver tumorigenesis, favouring non-canonical pro-tumorigenic TGF-beta pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-beta-targeted therapy. Lay summary: Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Mc), altering the cellular response to TGF-beta in favour of anti-apoptotic/pro-tumorigenic signals. A positive correlation between TGEB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGEB1 and CLTC had a worse prognosis and lower overall survival. CLTC expression in HCC human samples could help select patients that would benefit from therapies targeting TGF-beta. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B