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27 pages, 7083 KiB

Open AccessArticle

Monocarboxylate Transporters Are Involved in Extracellular Matrix Remodelling in Pancreatic Ductal Adenocarcinoma

by Ayşe Ufuk, Terence Garner, Adam Stevens and Ayşe Latif

Cancers 2022, 14(5), 1298; https://doi.org/10.3390/cancers14051298 - 2 Mar 2022

Cited by 5 | Viewed by 3024

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of <8%. PDAC is characterised by desmoplasia with an abundant extracellular matrix (ECM) rendering current therapies ineffective. Monocarboxylate transporters (MCTs) are key regulators of cellular metabolism and are upregulated in [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of <8%. PDAC is characterised by desmoplasia with an abundant extracellular matrix (ECM) rendering current therapies ineffective. Monocarboxylate transporters (MCTs) are key regulators of cellular metabolism and are upregulated in different cancers; however, their role in PDAC desmoplasia is little understood. Here, we investigated MCT and ECM gene expression in primary PDAC patient biopsies using RNA-sequencing data obtained from Gene Expression Omnibus. We generated a hypernetwork model from these data to investigate whether a causal relationship exists between MCTs and ECMs. Our analysis of stromal and epithelial tissues (n = 189) revealed nine differentially expressed MCTs, including the upregulation of SLC16A2/6/10 and the non-coding SLC16A1-AS1, and 502 ECMs, including collagens, laminins, and ECM remodelling enzymes (false discovery rate < 0.05). A causal hypernetwork analysis demonstrated a bidirectional relationship between MCTs and ECMs; four MCT and 255 ECM-related transcripts correlated with 90% of the differentially expressed ECMs (n = 376) and MCTs (n = 7), respectively. The hypernetwork model was robust, established by iterated sampling, direct path analysis, validation by an independent dataset, and random forests. This transcriptomic analysis highlights the role of MCTs in PDAC desmoplasia via associations with ECMs, opening novel treatment pathways to improve patient survival. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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13 pages, 1332 KiB

Open AccessArticle

Serum Sorbitol Dehydrogenase as a Novel Prognostic Factor for Hepatocellular Carcinoma after Surgical Resection

by Dongsub Jeon, Won-Mook Choi, Jin-Sun Kim, Yusun Jung, Su-Yeon Lee, Haeng Ran Seo and Kang Mo Kim

Cancers 2021, 13(23), 6143; https://doi.org/10.3390/cancers13236143 - 6 Dec 2021

Cited by 9 | Viewed by 2602

Abstract

The majority of patients with hepatocellular carcinoma (HCC) undergoing curative resection experience tumor recurrence. To examine the association between preoperative serum sorbitol dehydrogenase (SORD), a liver-derived enzyme that reflects liver damage, and recurrence of HCC after curative resection, 92 patients were randomly selected [...] Read more.

The majority of patients with hepatocellular carcinoma (HCC) undergoing curative resection experience tumor recurrence. To examine the association between preoperative serum sorbitol dehydrogenase (SORD), a liver-derived enzyme that reflects liver damage, and recurrence of HCC after curative resection, 92 patients were randomly selected who underwent curative resection for HCC between 2011 and 2012 from a prospective registry. Recurrence-free survival (RFS) was compared based on serum SORD levels. Cox proportional hazard models were used to investigate prognostic factors for RFS. During a median follow-up duration of 57.1 months, 43 patients experienced HCC recurrence. Patients with serum SORD ≥15 ng/mL (HR, 3.46; 95% CI, 1.76–6.81; p < 0.001) had worse RFS compared with patients with serum SORD <15 ng/mL. Serum AFP and SORD levels were two independent prognostic factors for RFS. When patients were stratified by baseline serum SORD and AFP levels, patients with serum AFP levels ≥400 ng/mL and serum SORD levels ≥15 ng/mL had a distinctly poor prognosis with the lowest RFS rates (HR, 22.08; 95% CI, 6.91–70.50; p < 0.001). Baseline serum SORD is an effective prognostic factor for HCC after resection. It may help guide patient selection for surgery, especially when combined with serum AFP levels. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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15 pages, 1838 KiB

Open AccessArticle

hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA

by Karen Aughton, Nils O. Elander, Anthony Evans, Richard Jackson, Fiona Campbell, Eithne Costello, Christopher M. Halloran, John R. Mackey, Andrew G. Scarfe, Juan W. Valle, Ross Carter, David Cunningham, Niall C. Tebbutt, David Goldstein, Jennifer Shannon, Bengt Glimelius, Thilo Hackert, Richard M. Charnley, Alan Anthoney, Markus M. Lerch, Julia Mayerle, Daniel H. Palmer, Markus W. Büchler, Paula Ghaneh, John P. Neoptolemos and William Greenhalf Show full author list Hide full author list

Cancers 2021, 13(22), 5758; https://doi.org/10.3390/cancers13225758 - 17 Nov 2021

Cited by 7 | Viewed by 3211

Abstract

Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a [...] Read more.

Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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16 pages, 1464 KiB

Open AccessArticle

Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma

by Kelley G. Núñez, Tyler Sandow, Daniel Fort, Jai Patel, Mina Hibino, Ian Carmody, Ari J. Cohen and Paul Thevenot

Cancers 2021, 13(19), 4765; https://doi.org/10.3390/cancers13194765 - 23 Sep 2021

Cited by 6 | Viewed by 2679

Abstract

The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, [...] Read more.

The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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20 pages, 3540 KiB

Open AccessArticle

Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer

by Shivan Sivakumar, Enas Abu-Shah, David J. Ahern, Edward H. Arbe-Barnes, Ashwin K. Jainarayanan, Nagina Mangal, Srikanth Reddy, Aniko Rendek, Alistair Easton, Elke Kurz, Michael Silva, Zahir Soonawalla, Lara R. Heij, Rachael Bashford-Rogers, Mark R. Middleton and Michael L. Dustin

Cancers 2021, 13(8), 1776; https://doi.org/10.3390/cancers13081776 - 8 Apr 2021

Cited by 21 | Viewed by 7939

Abstract

Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify [...] Read more.

Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8⁺ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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16 pages, 4358 KiB

Open AccessArticle

Neuroendocrine Neoplasms: Identification of Novel Metabolic Circuits of Potential Diagnostic Utility

by Beatriz Jiménez, Mei Ran Abellona U, Panagiotis Drymousis, Michael Kyriakides, Ashley K. Clift, Daniel S. K. Liu, Eleanor Rees, Elaine Holmes, Jeremy K. Nicholson, James M. Kinross and Andrea Frilling

Cancers 2021, 13(3), 374; https://doi.org/10.3390/cancers13030374 - 20 Jan 2021

Cited by 2 | Viewed by 2939

Abstract

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (¹H-NMR) [...] Read more.

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (¹H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker ¹H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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16 pages, 1612 KiB

Open AccessArticle

The Expression Profile and Textural Characteristics of C595-Reactive MUC1 in Pancreatic Ductal Adenocarcinoma for Targeted Radionuclide Therapy

by Ashleigh Hull, Yanrui Li, Dylan Bartholomeusz, William Hsieh, Samantha Escarbe, Andrew Ruszkiewicz and Eva Bezak

Cancers 2021, 13(1), 61; https://doi.org/10.3390/cancers13010061 - 28 Dec 2020

Cited by 4 | Viewed by 2966

Abstract

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide [...] Read more.

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5–93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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12 pages, 1190 KiB

Open AccessArticle

Severe Salmonella spp. or Campylobacter spp. Infection and the Risk of Biliary Tract Cancer: A Population-Based Study

by Elise de Savornin Lohman, Janneke Duijster, Bas Groot Koerkamp, Rachel van der Post, Eelco Franz, Lapo Mughini Gras and Philip de Reuver

Cancers 2020, 12(11), 3348; https://doi.org/10.3390/cancers12113348 - 12 Nov 2020

Cited by 5 | Viewed by 2433

Abstract

Salmonella spp. infection has shown to have oncogenic transformative effects and thereby increases the risk of certain cancers. For Campylobacter spp., similar effects have been demonstrated. Risk factor identification may allow for timely diagnosis and preventive treatment. To substantiate the oncogenic potential of [...] Read more.

Salmonella spp. infection has shown to have oncogenic transformative effects and thereby increases the risk of certain cancers. For Campylobacter spp., similar effects have been demonstrated. Risk factor identification may allow for timely diagnosis and preventive treatment. To substantiate the oncogenic potential of Salmonella and Campylobacter spp., this study compared the incidence of extrahepatic biliary tract cancer (BTC) in patients with diagnosed Salmonella or Campylobacter spp. infection with BTC incidence in the Netherlands. National infectious diseases surveillance records of patients diagnosed with a laboratory-confirmed Salmonella or Campylobacter spp. infection during 1999–2016 were linked to the Netherlands Cancer Registry. Incidence of BTC in Salmonella and Campylobacter spp. patients was compared to the incidence of BTC in the general population using Standardized Incidence Ratios (SIRs). In total, 16,252 patients were diagnosed with Salmonella spp. and 27,668 with Campylobacter spp. infection. Nine patients developed BTC at a median of 46 months (13–67) after Salmonella spp. infection and seven at a median of 60 months (18–138) after Campylobacter spp. infection. SIR of BTC in salmonellosis patients was 1.53 (95% CI 0.70–2.91). In patients aged <60 years, the SIR was 1.74 (95% CI 0.36–5.04). For campylobacteriosis patients, the SIR was 0.97 (95% CI 0.39–2.00). Even though Salmonella or Campylobacter spp. infection was not significantly associated with increased BTC risk in this cohort, it remains extremely important to study potential risk factors for cancer to facilitate screening and ultimately improve prognosis of cancer patients. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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14 pages, 3502 KiB

Open AccessArticle

Alpha-Fetoprotein, Protein Induced by Vitamin K Absence or Antagonist II and Glypican-3 for the Detection and Prediction of Hepatocellular Carcinoma in Patients with Cirrhosis of Viral Etiology

by Gian Paolo Caviglia, Michela Ciruolo, Maria Lorena Abate, Patrizia Carucci, Emanuela Rolle, Chiara Rosso, Antonella Olivero, Giulia Troshina, Alessandra Risso, Aurora Nicolosi, Davide Giuseppe Ribaldone, Angelo Armandi, Francesco Tandoi, Giorgio Maria Saracco, Elisabetta Bugianesi, Alessia Ciancio and Silvia Gaia

Cancers 2020, 12(11), 3218; https://doi.org/10.3390/cancers12113218 - 31 Oct 2020

Cited by 29 | Viewed by 2936

Abstract

International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) [...] Read more.

International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) and glypican-3 (GPC-3) diagnostic accuracy for HCC detection and prediction in patients with liver cirrhosis of viral etiology under surveillance. A total of 349 patients (200 cirrhosis and 149 HCC) were enrolled. The 200 patients with cirrhosis consisted of 114 patients still HCC-free after 36 months of follow-up and 86 patients that developed HCC after 13.8 (11.0–19.8) months. AFP, PIVKA-II and GPC-3 were measured in serum samples collected at tumor diagnosis in the 149 patients with HCC, and at the beginning of follow-up in the 200 patients with cirrhosis. The higher performance for HCC detection was observed for PIVKA-II (area under the curve (AUC) = 0.790), followed by AFP (AUC = 0.737) and GPC-3 (AUC = 0.637); the combination of AFP + PIVKA-II improved the diagnostic accuracy to AUC = 0.822. Serum PIVKA-II values, but not AFP and GPC-3, were significantly higher in the 86 cirrhotics that developed HCC compared with the 114 cirrhotics still HCC-free after 36 months of follow-up (p = 0.020). PIVKA-II ≥ 55 mAU/mL allowed to identify patients with cirrhosis at higher risk of HCC development (Log-rank test, p < 0.001; adjusted Hazard Ratio = 1.99, p = 0.001). In conclusion, the measurement of PIVKA-II in patients with cirrhosis may be useful to tailor personalized surveillance strategies. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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20 pages, 2276 KiB

Open AccessArticle

“Open Sesame?”: Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer

by Ornella Randazzo, Filippo Papini, Giulia Mantini, Alessandro Gregori, Barbara Parrino, Daniel S. K. Liu, Stella Cascioferro, Daniela Carbone, Godefridus J. Peters, Adam E. Frampton, Ingrid Garajova and Elisa Giovannetti

Cancers 2020, 12(11), 3206; https://doi.org/10.3390/cancers12113206 - 31 Oct 2020

Cited by 24 | Viewed by 4021

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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8 pages, 607 KiB

Open AccessCommunication

Predictive Values of Blood-Based RNA Signatures for the Gemcitabine Response in Advanced Pancreatic Cancer

by David Piquemal, Florian Noguier, Fabien Pierrat, Roman Bruno and Jerome Cros

Cancers 2020, 12(11), 3204; https://doi.org/10.3390/cancers12113204 - 30 Oct 2020

Cited by 4 | Viewed by 2683

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second cause of cancer death by 2022. For nearly 80% of patients, diagnosis occurs at an advanced, nonsurgical stage, making such patients incurable. Gemcitabine is still an important component in PDAC treatment and is [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second cause of cancer death by 2022. For nearly 80% of patients, diagnosis occurs at an advanced, nonsurgical stage, making such patients incurable. Gemcitabine is still an important component in PDAC treatment and is most often used as a backbone to test new targeted therapies and there is, to date, no routine biomarker to predict its efficacy. Samples from a phase III randomized trial were used to develop through a large approach based on blood-based liquid biopsy, transcriptome profiling, and machine learning, a nine gene predictive signature for gemcitabine sensitivity. Patients with a positive test (41.6%) had a significantly longer progression free survival (PFS) (3.8 months vs. 1.9 months p = 0.03) and a longer overall survival (OS) (14.5 months vs. 5.1, p < 0.0001). In multivariate analyses, this signature was independently associated with PFS (HR = 0.5 (0.28–0.9) p = 0.025) and OS (HR = 0.39 (0.21–0.7) p = 0.002). Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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17 pages, 6876 KiB

Open AccessArticle

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

by Masanori Oshi, Stephanie Newman, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Matthew H. G. Katz and Kazuaki Takabe

Cancers 2020, 12(10), 2871; https://doi.org/10.3390/cancers12102871 - 6 Oct 2020

Cited by 46 | Viewed by 3583

Abstract

Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene [...] Read more.

Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene set variation analysis using the Hallmark G2M checkpoint gene set was used as a score to analyze a total of 390 human pancreatic cancer patients from 3 cohorts (TCGA, GSE62452, GSE57495). High G2M score tumors enriched other cell proliferation genes sets as well as MKI67 expression, pathological grade, and proliferation score. Independent of other prognostic factors, G2M score was predictive of disease-specific survival in pancreatic cancer. High G2M tumor was associated with high mutation rate of KRAS and TP53 and significantly enriched these pathway gene sets, as well as high infiltration of Th2 cells. High G2M score consistently associated with worse overall survival in 3 cohorts, particularly in R1/2 resection, but not in R0. High G2M tumor in R1/2 highly enriched metabolic and cellular components’ gene sets compared to R0. To our knowledge, this is the first study to use gene set variation analysis as a score to examine the clinical relevancy of the G2M pathway in pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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12 pages, 2284 KiB

Open AccessArticle

Transcriptomic Profile of Lymphovascular Invasion, a Known Risk Factor of Pancreatic Ductal Adenocarcinoma Metastasis

by Hideo Takahashi, Eriko Katsuta, Li Yan, Yoshihisa Tokumaru, Matthew H.G. Katz and Kazuaki Takabe

Cancers 2020, 12(8), 2033; https://doi.org/10.3390/cancers12082033 - 24 Jul 2020

Cited by 31 | Viewed by 2878

Abstract

Lymphovascular invasion (LVI) is an aggressive pathologic feature and considered a risk factor for distant metastasis. We hypothesized that pancreatic ductal adenocarcinomas (PDACs) with LVI are associated with shorter survival, as well as aggressive cancer biology and lymphangiogenesis in transcriptomic analysis. Utilizing the [...] Read more.

Lymphovascular invasion (LVI) is an aggressive pathologic feature and considered a risk factor for distant metastasis. We hypothesized that pancreatic ductal adenocarcinomas (PDACs) with LVI are associated with shorter survival, as well as aggressive cancer biology and lymphangiogenesis in transcriptomic analysis. Utilizing the cancer genome atlas (TCGA)-PDAC cohort, we found that positive LVI was significantly associated with positive perineural invasion (PNI) (p = 0.023), and higher American Joint Committee on Cancer (AJCC) T (p = 0.017) and N (p < 0.001) categories. Furthermore, positive LVI was associated with shorter overall survival (OS) (p = 0.014) and was an independent risk factor of poor OS. Although there was no association between LVI status and lymphangiogenesis, epithelial-mesenchymal transition (EMT), or metastasis-related genes, Gene Set Enrichment Analysis revealed a strong association with cell-proliferation-related gene sets such as mitotic spindles (Normalized enrichment score (NES) = 1.76, p = 0.016) and G2/M checkpoints (NES = 1.75, p = 0.036), as well as with transforming growth factor beta (TGF-beta) signaling (NES = 1.61, p = 0.043), which is a known mechanism of metastasis in PDACs. In conclusion, positive LVI was an independent risk factor of poor OS in PDACs. We found that PDACs with LVI were possibly associated with accelerated cell proliferation and enhanced TGF-beta signaling independent of lymphangiogenesis. Transcriptomic profiling elucidates more precise tumor biology of LVI-positive PDACs. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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14 pages, 2295 KiB

Open AccessArticle

Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial)

by Ioana Riaño, Leticia Martín, Maria Varela, Trinidad Serrano, Oscar Núñez, Beatriz Mínguez, Pedro M. Rodrigues, Maria J. Perugorria, Jesus M. Banales and Juan I. Arenas

Cancers 2020, 12(7), 1900; https://doi.org/10.3390/cancers12071900 - 14 Jul 2020

Cited by 16 | Viewed by 2987

Abstract

Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced [...] Read more.

Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced hepatocellular carcinoma (aHCC). A total of 31 patients were randomized. Median OS did not differ between both groups (12.4 months for the sorafenib + pravastatin group vs. 11.6 months for the control group). Of note, however, the radiological TTP was higher in patients treated with sorafenib + pravastatin than in the control group (9.9 months vs. 3.2 months; p = 0.008). Considering all the study population, the presence of portal vein thrombosis (PVT) was associated with worse OS, being lower in patients with PVT compared to patients without PVT (6.3 months vs. 14.8 months; p = 0.026). Data also showed a decrease in OS in patients with vascular invasion (VI) compared to patients who did not present it (6.3 months vs. 14.8 months; p = 0.041). The group of patients without dermatological events (DE) showed lower OS (6.9 months vs. 14.5 months; p = 0.049). In conclusion, combination of sorafenib + pravastatin was safe and well-tolerated, prolonging the TTP of patients with aHCC but not improving the OS compared to sorafenib + placebo. The absence of PVT and VI and the development of DE are positive prognostic factors of sorafenib response. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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17 pages, 2158 KiB

Open AccessArticle

A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma

by Rocio I. R. Macias, Luis Muñoz-Bellvís, Anabel Sánchez-Martín, Enara Arretxe, Ibon Martínez-Arranz, Ainhoa Lapitz, M. Laura Gutiérrez, Adelaida La Casta, Cristina Alonso, Luis M. González, Matias A. Avila, Maria L. Martinez-Chantar, Rui E. Castro, Luis Bujanda, Jesus M. Banales and Jose J. G. Marin

Cancers 2020, 12(6), 1433; https://doi.org/10.3390/cancers12061433 - 31 May 2020

Cited by 23 | Viewed by 3729

Abstract

The diagnosis of adenocarcinomas located in the pancreas head, i.e., distal cholangiocarcinoma (dCCA) and pancreatic ductal adenocarcinoma (PDAC), constitutes a clinical challenge because they share many symptoms, are not easily distinguishable using imaging techniques and accurate biomarkers are not available. Searching for biomarkers [...] Read more.

The diagnosis of adenocarcinomas located in the pancreas head, i.e., distal cholangiocarcinoma (dCCA) and pancreatic ductal adenocarcinoma (PDAC), constitutes a clinical challenge because they share many symptoms, are not easily distinguishable using imaging techniques and accurate biomarkers are not available. Searching for biomarkers with potential usefulness in the differential diagnosis of these tumors, we have determined serum metabolomic profiles in healthy controls and patients with dCCA, PDAC or benign pancreatic diseases (BPD). Ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis was performed in serum samples from dCCA (n = 34), PDAC (n = 38), BPD (n = 42) and control (n = 25) individuals, divided into discovery and validation cohorts. This approach permitted 484 metabolites to be determined, mainly lipids and amino acids. The analysis of the results led to the proposal of a logistic regression model able to discriminate patients with dCCA and PDAC (AUC value of 0.888) based on the combination of serum levels of nine metabolites (acylcarnitine AC(16:0), ceramide Cer(d18:1/24:0), phosphatidylcholines PC(20:0/0:0) and PC(O-16:0/20:3), lysophosphatidylcholines PC(20:0/0:0) and PC(0:0/20:0), lysophosphatidylethanolamine PE(P-18:2/0:0), and sphingomyelins SM(d18:2/22:0) and SM(d18:2/23:0)) and CA 19-9. In conclusion, we propose a novel specific panel of serum metabolites that can help in the differential diagnosis of dCCA and PDAC. Further validation of their clinical usefulness in prospective studies is required. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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13 pages, 1281 KiB

Open AccessArticle

Trends in Treatment and Survival of Gallbladder Cancer in the Netherlands; Identifying Gaps and Opportunities from a Nation-Wide Cohort

by Elise de Savornin Lohman, Tessa de Bitter, Rob Verhoeven, Lydia van der Geest, Jeroen Hagendoorn, Nadia Haj Mohammad, Freek Daams, Heinz-Josef Klümpen, Thomas van Gulik, Joris Erdmann, Marieke de Boer, Frederik Hoogwater, Bas Groot Koerkamp, Andries Braat, Joanne Verheij, Iris Nagtegaal, Cornelis van Laarhoven, Peter van den Boezem, Rachel van der Post and Philip de Reuver

Cancers 2020, 12(4), 918; https://doi.org/10.3390/cancers12040918 - 9 Apr 2020

Cited by 22 | Viewed by 3369

Abstract

Gallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using population-based data from a low-incidence country. GBC patients diagnosed between 2005 and 2016 with GBC [...] Read more.

Gallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using population-based data from a low-incidence country. GBC patients diagnosed between 2005 and 2016 with GBC were identified from the Netherlands Cancer Registry. Patients were grouped according to time period (2005–2009/2010–2016) and disease stage. Trends in treatment and overall survival (OS) were analyzed. In total 1834 patients were included: 661 (36%) patients with resected, 278 (15%) with non-resected non-metastatic, and 895 (49%) with metastatic GBC. Use of radical versus simple cholecystectomy (12% vs. 26%, p < 0.001) in early (pT1b/T2) GBC increased. More patients with metastatic GBC received chemotherapy (11% vs. 29%, p < 0.001). OS improved from 4.8 months (2005–2009) to 6.1 months (2010–2016) (p = 0.012). Median OS increased over time (2005–2009 vs. 2010–2016) in resected (19.4 to 26.8 months, p = 0.038) and metastatic (2.3 vs. 3.4 months, p = 0.001) GBC but not in unresected, non-metastatic GBC. In early GBC, patients with radical cholecystectomy had a median OS of 76.7 compared to 18.4 months for simple cholecystectomy (p < 0.001). Palliative chemotherapy showed superior (p < 0.001) survival in metastatic (7.3 versus 2.1 months) and non-resected non-metastatic (7.7 versus 3.5 months) GBC. In conclusion, survival of GBC remains poor. Radical surgery and palliative chemotherapy appear to improve prognosis but remain under-utilized. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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Graphical abstract

17 pages, 3823 KiB

Open AccessArticle

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer

by Patricia García, Lorena Rosa, Sergio Vargas, Helga Weber, Jaime A. Espinoza, Felipe Suárez, Isabel Romero-Calvo, Nicole Elgueta, Vanessa Rivera, Bruno Nervi, Javiera Obreque, Pamela Leal, Eduardo Viñuela, Gloria Aguayo, Sabrina Muñiz, Alfredo Sagredo, Juan C. Roa and Carolina Bizama

Cancers 2020, 12(4), 778; https://doi.org/10.3390/cancers12040778 - 25 Mar 2020

Cited by 22 | Viewed by 4478

Abstract

Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not [...] Read more.

Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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31 pages, 4959 KiB

Open AccessArticle

An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

by Grasieli de Oliveira, Paula Paccielli Freire, Sarah Santiloni Cury, Diogo de Moraes, Jakeline Santos Oliveira, Maeli Dal-Pai-Silva, Patrícia Pintor do Reis and Robson Francisco Carvalho

Cancers 2020, 12(3), 716; https://doi.org/10.3390/cancers12030716 - 18 Mar 2020

Cited by 22 | Viewed by 6400

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is extremely aggressive, has an unfavorable prognosis, and there are no biomarkers for early detection of the disease or identification of individuals at high risk for morbidity or mortality. The cellular and molecular complexity of PDAC leads to inconsistences [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is extremely aggressive, has an unfavorable prognosis, and there are no biomarkers for early detection of the disease or identification of individuals at high risk for morbidity or mortality. The cellular and molecular complexity of PDAC leads to inconsistences in clinical validations of many proteins that have been evaluated as prognostic biomarkers of the disease. The tumor secretome, a potential source of biomarkers in PDAC, plays a crucial role in cell proliferation and metastasis, as well as in resistance to treatments, which together contribute to a worse clinical outcome. The massive amount of proteomic data from pancreatic cancer that has been generated from previous studies can be integrated and explored to uncover secreted proteins relevant to the diagnosis and prognosis of the disease. The present study aimed to perform an integrated meta-analysis of PDAC proteome and secretome public data to identify potential biomarkers of the disease. Our meta-analysis combined mass spectrometry data obtained from two systematic reviews of the pancreatic cancer literature, which independently selected 20 studies of the secretome and 35 of the proteome. Next, we predicted the secreted proteins using seven in silico tools or databases, which identified 39 secreted proteins shared between the secretome and proteome data. Notably, the expression of 31 genes of these secretome-related proteins was upregulated in PDAC samples from The Cancer Genome Atlas (TCGA) when compared to control samples from TCGA and The Genotype-Tissue Expression (GTEx). The prognostic value of these 39 secreted proteins in predicting survival outcome was confirmed using gene expression data from four PDAC datasets (validation set). The gene expression of these secreted proteins was able to distinguish high- and low-survival patients in nine additional tumor types from TCGA, demonstrating that deregulation of these secreted proteins may also contribute to the prognosis in multiple cancers types. Finally, we compared the prognostic value of the identified secreted proteins in PDAC biomarkers studies from the literature. This analysis revealed that our gene signature performed equally well or better than the signatures from these previous studies. In conclusion, our integrated meta-analysis of PDAC proteome and secretome identified 39 secreted proteins as potential biomarkers, and the tumor gene expression profile of these proteins in patients with PDAC is associated with worse overall survival. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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10 pages, 1880 KiB

Open AccessArticle

hENT1 Testing in Pancreatic Ductal Adenocarcinoma: Are We Ready? A Multimodal Evaluation of hENT1 Status

by Jerome Raffenne, Remy Nicolle, Francesco Puleo, Delphine Le Corre, Camille Boyez, Raphael Marechal, Jean François Emile, Peter Demetter, Armelle Bardier, Pierre Laurent-Puig, Louis de Mestier, Valerie Paradis, Anne Couvelard, Jean Luc VanLathem, John R. MacKey, Jean-Baptiste Bachet, Magali Svrcek and Jerome Cros

Cancers 2019, 11(11), 1808; https://doi.org/10.3390/cancers11111808 - 18 Nov 2019

Cited by 26 | Viewed by 3102

Abstract

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports [...] Read more.

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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Review

Jump to: Research, Other

25 pages, 1030 KiB

Open AccessReview

Next-Generation Biomarkers for Cholangiocarcinoma

by Pedro M. Rodrigues, Arndt Vogel, Marco Arrese, Domingo C. Balderramo, Juan W. Valle and Jesus M. Banales

Cancers 2021, 13(13), 3222; https://doi.org/10.3390/cancers13133222 - 28 Jun 2021

Cited by 23 | Viewed by 3806

Abstract

The increasing mortality rates of cholangiocarcinoma (CCA) registered during the last decades are, at least in part, a result of the lack of accurate non-invasive biomarkers for early disease diagnosis, making the identification of patients who might benefit from potentially curative approaches (i.e., [...] Read more.

The increasing mortality rates of cholangiocarcinoma (CCA) registered during the last decades are, at least in part, a result of the lack of accurate non-invasive biomarkers for early disease diagnosis, making the identification of patients who might benefit from potentially curative approaches (i.e., surgery) extremely challenging. The obscure CCA pathogenesis and associated etiological factors, as well as the lack of symptoms in patients with early tumor stages, highly compromises CCA identification and to predict tumor development in at-risk populations. Currently, CCA diagnosis is accomplished by the combination of clinical/biochemical features, radiological imaging and non-specific serum tumor biomarkers, although a tumor biopsy is still needed to confirm disease diagnosis. Furthermore, prognostic and predictive biomarkers are still lacking and urgently needed. During the recent years, high-throughput omics-based approaches have identified novel circulating biomarkers (diagnostic and prognostic) that might be included in large, international validation studies in the near future. In this review, we summarize and discuss the most recent advances in the field of biomarker discovery in CCA, providing new insights and future research directions. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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25 pages, 1164 KiB

Open AccessReview

Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer—A Comprehensive Review

by Greta Brezgyte, Vinay Shah, Daria Jach and Tatjana Crnogorac-Jurcevic

Cancers 2021, 13(11), 2722; https://doi.org/10.3390/cancers13112722 - 31 May 2021

Cited by 26 | Viewed by 4828

Abstract

Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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13 pages, 1800 KiB

Open AccessEditor’s ChoiceReview

Serum Biomarkers for the Prediction of Hepatocellular Carcinoma

by José D. Debes, Pablo A. Romagnoli, Jhon Prieto, Marco Arrese, Angelo Z. Mattos, André Boonstra and on behalf of the ESCALON Consortium

Cancers 2021, 13(7), 1681; https://doi.org/10.3390/cancers13071681 - 2 Apr 2021

Cited by 43 | Viewed by 10436

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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17 pages, 518 KiB

Open AccessReview

Diagnostic, Predictive and Prognostic Molecular Biomarkers in Pancreatic Cancer: An Overview for Clinicians

by Dimitrios Giannis, Dimitrios Moris and Andrew S. Barbas

Cancers 2021, 13(5), 1071; https://doi.org/10.3390/cancers13051071 - 3 Mar 2021

Cited by 19 | Viewed by 3939

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and is associated with aggressive tumor behavior and poor prognosis. Most patients with PDAC present with an advanced disease stage and treatment-resistant tumors. The lack of noninvasive tests for PDAC diagnosis and survival [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and is associated with aggressive tumor behavior and poor prognosis. Most patients with PDAC present with an advanced disease stage and treatment-resistant tumors. The lack of noninvasive tests for PDAC diagnosis and survival prediction mandates the identification of novel biomarkers. The early identification of high-risk patients and patients with PDAC is of utmost importance. In addition, the identification of molecules that are associated with tumor biology, aggressiveness, and metastatic potential is crucial to predict survival and to provide patients with personalized treatment regimens. In this review, we summarize the current literature and focus on newer biomarkers, which are continuously added to the armamentarium of PDAC screening, predictive tools, and prognostic tools. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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16 pages, 549 KiB

Open AccessReview

Circulating Cell-Free Tumour DNA for Early Detection of Pancreatic Cancer

by Jedrzej J. Jaworski, Robert D. Morgan and Shivan Sivakumar

Cancers 2020, 12(12), 3704; https://doi.org/10.3390/cancers12123704 - 9 Dec 2020

Cited by 18 | Viewed by 3747

Abstract

Pancreatic cancer is a lethal disease, with mortality rates negatively associated with the stage at which the disease is detected. Early detection is therefore critical to improving survival outcomes. A recent focus of research for early detection is the use of circulating cell-free [...] Read more.

Pancreatic cancer is a lethal disease, with mortality rates negatively associated with the stage at which the disease is detected. Early detection is therefore critical to improving survival outcomes. A recent focus of research for early detection is the use of circulating cell-free tumour DNA (ctDNA). The detection of ctDNA offers potential as a relatively non-invasive method of diagnosing pancreatic cancer by using genetic sequencing technology to detect tumour-specific mutational signatures in blood samples before symptoms manifest. These technologies are limited by a number of factors that lower sensitivity and specificity, including low levels of detectable ctDNA in early stage disease and contamination with non-cancer circulating cell-free DNA. However, genetic and epigenetic analysis of ctDNA in combination with other standard diagnostic tests may improve early detection rates. In this review, we evaluate the genetic and epigenetic methods under investigation in diagnosing pancreatic cancer and provide a perspective for future developments. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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24 pages, 772 KiB

Open AccessReview

Current and New Biomarkers for Early Detection, Prognostic Stratification, and Management of Gallbladder Cancer Patients

by Patricia García, Angela Lamarca, Javier Díaz, Enrique Carrera, Juan Carlos Roa and on behalf of the European-Latin American ESCALON Consortium

Cancers 2020, 12(12), 3670; https://doi.org/10.3390/cancers12123670 - 7 Dec 2020

Cited by 16 | Viewed by 7641

Abstract

Gallbladder cancer (GBC) is an aggressive disease that shows evident geographic variation and is characterized by a poor prognosis, mainly due to the late diagnosis and ineffective treatment. Genetic variants associated with GBC susceptibility, including polymorphisms within the toll-like receptors TLR2 and TLR4 [...] Read more.

Gallbladder cancer (GBC) is an aggressive disease that shows evident geographic variation and is characterized by a poor prognosis, mainly due to the late diagnosis and ineffective treatment. Genetic variants associated with GBC susceptibility, including polymorphisms within the toll-like receptors TLR2 and TLR4, the cytochrome P450 1A1 (CYP1A1), and the ATP-binding cassette (ABC) transporter ABCG8 genes, represent promising biomarkers for the stratification of patients at higher risk of GBC; thus, showing potential to prioritize cholecystectomy, particularly considering that early diagnosis is difficult due to the absence of specific signs and symptoms. Similarly, our better understanding of the gallbladder carcinogenic processes has led to identify several cellular and molecular events that may influence patient management, including HER2 aberrations, high tumor mutational burden, microsatellite instability, among others. Despite these reports on interesting and promising markers for risk assessment, diagnosis, and prognosis; there is an unmet need for reliable and validated biomarkers that can improve the management of GBC patients and support clinical decision-making. This review article examines the most potentially significant biomarkers of susceptibility, diagnosis, prognosis, and therapy selection for GBC patients, highlighting the need to find and validate existing and new molecular biomarkers to improve patient outcomes. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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17 pages, 947 KiB

Open AccessReview

Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options

by Nicola Personeni, Ana Lleo, Tiziana Pressiani, Francesca Colapietro, Mark Robert Openshaw, Chara Stavraka, Athanasios Pouptsis, David James Pinato and Lorenza Rimassa

Cancers 2020, 12(11), 3370; https://doi.org/10.3390/cancers12113370 - 13 Nov 2020

Cited by 31 | Viewed by 7830

Abstract

Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both [...] Read more.

Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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29 pages, 1035 KiB

Open AccessReview

The Role of Circular RNAs in Pancreatic Ductal Adenocarcinoma and Biliary-Tract Cancers

by Christopher Limb, Daniel S. K. Liu, Morten T. Veno, Eleanor Rees, Jonathan Krell, Izhar N. Bagwan, Elisa Giovannetti, Hardev Pandha, Oliver Strobel, Timothy A. Rockall and Adam E. Frampton

Cancers 2020, 12(11), 3250; https://doi.org/10.3390/cancers12113250 - 4 Nov 2020

Cited by 23 | Viewed by 3632

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific [...] Read more.

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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21 pages, 728 KiB

Open AccessReview

Recent Discoveries of Diagnostic, Prognostic and Predictive Biomarkers for Pancreatic Cancer

by Andrii Khomiak, Marius Brunner, Maximilian Kordes, Stina Lindblad, Rainer Christoph Miksch, Daniel Öhlund and Ivonne Regel

Cancers 2020, 12(11), 3234; https://doi.org/10.3390/cancers12113234 - 2 Nov 2020

Cited by 42 | Viewed by 8808

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis that is frequently diagnosed at an advanced stage. Although less common than other malignant diseases, it currently ranks as the fourth most common cause of cancer-related death in the European Union [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis that is frequently diagnosed at an advanced stage. Although less common than other malignant diseases, it currently ranks as the fourth most common cause of cancer-related death in the European Union with a five-year survival rate of below 9%. Surgical resection, followed by adjuvant chemotherapy, remains the only potentially curative treatment but only a minority of patients is diagnosed with locally resectable, non-metastatic disease. Patients with advanced disease are treated with chemotherapy but high rates of treatment resistance and unfavorable side-effect profiles of some of the used regimens remain major challenges. Biomarkers reflect pathophysiological or physiological processes linked to a disease and can be used as diagnostic, prognostic and predictive tools. Thus, accurate biomarkers can allow for better patient stratification and guide therapy choices. Currently, the only broadly used biomarker for PDAC, CA 19-9, has multiple limitations and the need for novel biomarkers is urgent. In this review, we highlight the current situation, recent discoveries and developments in the field of biomarkers of PDAC and their potential clinical applications. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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19 pages, 2675 KiB

Open AccessReview

Size-Exclusion Chromatography as a Technique for the Investigation of Novel Extracellular Vesicles in Cancer

by Daniel S. K. Liu, Flora M. Upton, Eleanor Rees, Christopher Limb, Long R. Jiao, Jonathan Krell and Adam E. Frampton

Cancers 2020, 12(11), 3156; https://doi.org/10.3390/cancers12113156 - 27 Oct 2020

Cited by 26 | Viewed by 4877

Abstract

Cancer cells release extracellular vesicles, which are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. Size-exclusion chromatography (SEC) is an increasingly popular technique, which has been rediscovered for the purposes of extracellular vesicle (EV) isolation and purification [...] Read more.

Cancer cells release extracellular vesicles, which are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. Size-exclusion chromatography (SEC) is an increasingly popular technique, which has been rediscovered for the purposes of extracellular vesicle (EV) isolation and purification from diverse biofluids. A systematic review was undertaken to identify all papers that described size exclusion as their primary EV isolation method in cancer research. In all, 37 papers were identified and discussed, which showcases the breadth of applications in which EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. EVs isolated using SEC are able to identify cancer cells, highlight active pathways in tumourigenesis, clinically distinguish cohorts, and remain functionally active for further experiments. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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11 pages, 3828 KiB

Open AccessSystematic Review

Prognostic Factors in Patients with Breast Cancer Liver Metastases Undergoing Liver Resection: Systematic Review and Meta-Analysis

by Federica Galiandro, Salvatore Agnes, Giovanni Moschetta, Armando Orlandi, George Clarke, Emilio Bria, Gianluca Franceschini, Giorgio Treglia and Francesco Giovinazzo

Cancers 2022, 14(7), 1691; https://doi.org/10.3390/cancers14071691 - 26 Mar 2022

Cited by 5 | Viewed by 2639

Abstract

Background: The role of surgical resection of liver metastases in patients with breast cancer liver metastasis (BCLM) remains controversial. A systematic review and meta-analysis of prognostic factors related to survival after BCLM resection was performed. Methods: An electronic search of relevant publications was [...] Read more.

Background: The role of surgical resection of liver metastases in patients with breast cancer liver metastasis (BCLM) remains controversial. A systematic review and meta-analysis of prognostic factors related to survival after BCLM resection was performed. Methods: An electronic search of relevant publications was performed. Pooled outcome measures were expressed as hazard ratios (HRs), including 95% confidence interval values (95% CIs), and calculated through a random-effects model. Heterogeneity was tested through the I² index. Results: Thirty-five publications reported analyses on prognostic factors and survival. A total of 2782 patients who underwent liver resection for BCLM were included. Positive axillary lymph nodes at breast cancer diagnosis were an unfavorable survival factor (HR 1.74, 95% CI 1.25 to 2.41, I² = 0%). Cumulative predictive factor HRs (multiple liver metastases, size of the metastases, short interval between primary tumor and onset of liver disease) related to the BCLM pattern were 1.32 (95% CI 1.17 to 1.48, I² = 71%) and 1.51 (95% CI 1.15 to 1.98, I² = 76%) for surgical and pathological features (resection margin and presence of extrahepatic disease), respectively. Conclusion: Resection of BCLM may provide a survival benefit for selected patients. For better long-term results, surgical selection should consider both primary tumor and BCLM features such as negative axillary lymph nodes at breast resection, a single hepatic lesion, a time longer than 24 months between breast and hepatic diagnosis, and a realizable R0 liver resection. However, the high heterogeneity among studies suggests the need for an RCT to validate the present findings. Full article

(This article belongs to the Special Issue Molecular Biomarkers and Precision Medicine for Pancreatic, Liver and Biliary Tract Cancers)

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