Cancers

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17 pages, 2952 KiB

Open AccessArticle

Negative Control of Cell Migration by Rac1b in Highly Metastatic Pancreatic Cancer Cells Is Mediated by Sequential Induction of Nonactivated Smad3 and Biglycan

by Hannah Otterbein, Hendrik Lehnert and Hendrik Ungefroren

Cancers 2019, 11(12), 1959; https://doi.org/10.3390/cancers11121959 - 6 Dec 2019

Cited by 14 | Viewed by 3914

Abstract

Expression of the small GTPase, Ras-related C3 botulinum toxin substrate 1B (RAC1B), a RAC1-related member of the Rho GTPase family, in tumor tissues of pancreatic ductal adenocarcinoma (PDAC) has been shown previously to correlate positively with patient survival, but the underlying mechanism(s) and [...] Read more.

Expression of the small GTPase, Ras-related C3 botulinum toxin substrate 1B (RAC1B), a RAC1-related member of the Rho GTPase family, in tumor tissues of pancreatic ductal adenocarcinoma (PDAC) has been shown previously to correlate positively with patient survival, but the underlying mechanism(s) and the target genes involved have remained elusive. Screening of a panel of established PDAC-derived cell lines by immunoblotting indicated that both RAC1B and Mothers against decapentaplegic homolog 3 (SMAD3) were more abundantly expressed in poorly metastatic and well-differentiated lines as opposed to highly metastatic, poorly differentiated ones. Both siRNA-mediated RAC1B knockdown in the transforming growth factor (TGF)-β-sensitive PDAC-derived cell lines, Panc1 and PaCa3, or CRISPR/Cas-mediated knockout of exon 3b of RAC1 in Panc1 cells resulted in a dramatic decrease in the expression of SMAD3. Unexpectedly, the knockdown of SMAD3 reproduced the promigratory activity of a RAC1B knockdown in Panc1 and PaCa3, but not in TGF-β-resistant BxPC3 and Capan1 cells, while forced expression of SMAD3 alone was able to mimic the antimigratory effect of ectopic RAC1B overexpression in Panc1 cells. Moreover, overexpression of SMAD3 was able to rescue Panc1 cells from the RAC1B knockdown-induced increase in cell migration, while knockdown of SMAD3 prevented the RAC1B overexpression-induced decrease in cell migration. Using pharmacological and dominant-negative inhibition of SMAD3 C-terminal phosphorylation, we further show that the migration-inhibiting effect of SMAD3 is independent of its activation by TGF-β. Finally, we provide evidence that the antimigratory program of RAC1B-SMAD3 in Panc1 cells is executed through upregulation of the migration and TGF-β inhibitor, biglycan (BGN). Together, our data suggest that a RAC1B-SMAD3-BGN axis negatively controls cell migration and that SMAD3 can induce antimigratory genes, i.e., BGN independent of its role as a signal transducer for TGF-β. Therefore, targeting this novel pathway for activation is a potential therapeutic strategy in highly metastatic PDAC to interfere with invasion and metastasis. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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15 pages, 4206 KiB

Open AccessArticle

Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation

by Ilaria Casari, Alice Domenichini, Simona Sestito, Emily Capone, Gianluca Sala, Simona Rapposelli and Marco Falasca

Cancers 2019, 11(11), 1695; https://doi.org/10.3390/cancers11111695 - 31 Oct 2019

Cited by 7 | Viewed by 4012

Abstract

Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, [...] Read more.

Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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10 pages, 1882 KiB

Open AccessArticle

Nomogram for Predicting Survival in Patients Treated with Liposomal Irinotecan Plus Fluorouracil and Leucovorin in Metastatic Pancreatic Cancer

by Li-Tzong Chen, Teresa Macarulla, Jean-Frédéric Blanc, Beloo Mirakhur, Floris A. de Jong, Bruce Belanger, Tanios Bekaii-Saab and Jens T. Siveke

Cancers 2019, 11(8), 1068; https://doi.org/10.3390/cancers11081068 - 28 Jul 2019

Cited by 19 | Viewed by 4213

Abstract

NAPOLI-1 (NCT01494506) was a phase III study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This post hoc analysis of NAPOLI-1 aimed to develop a predictive nomogram for overall survival (OS) [...] Read more.

NAPOLI-1 (NCT01494506) was a phase III study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This post hoc analysis of NAPOLI-1 aimed to develop a predictive nomogram for overall survival (OS) at 6 and 12 months. Analyses were derived from all patients in NAPOLI-1 randomized to receive nal-IRI+5-FU/LV, nal-IRI monotherapy, or 5-FU/LV combination therapy. OS was associated with baseline factors using univariate and multivariable Cox analyses. A predictive nomogram was derived and validated using a concordance index and calibration plots. The univariate analyses identified 21 independent factors that contributed to OS, with eight factors significantly associated with OS. The Karnofsky Performance Score contributed the largest number of points (100), followed by presence of liver metastasis (98) and randomization to nal-IRI+5-FU/LV (96). The other baseline factors showing effects were albumin (g/dL), neutrophil/lymphocyte ratio, carbohydrate antigen 19-9 (U/mL), disease stage at diagnosis, and body mass index (kg/m²). The nomogram was used to predict the 6- and 12-month survival probability. The mean absolute errors between the observed and predicted probabilities for OS at 3, 6, and 9 months were 0.07, 0.08, and 0.07, respectively. This nomogram, based on NAPOLI-1, provides additional insight to aid decision-making for patients with mPDAC after previous gemcitabine-based therapy. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 1971 KiB

Open AccessArticle

Neoadjuvant Treatment in Locally Advanced Pancreatic Cancer (LAPC) Patients with FOLFIRINOX or Gemcitabine NabPaclitaxel: A Single-Center Experience and a Literature Review

by Fabiana Napolitano, Luigi Formisano, Alessandro Giardino, Roberto Girelli, Alberto Servetto, Antonio Santaniello, Francesca Foschini, Roberta Marciano, Eleonora Mozzillo, Anna Chiara Carratù, Priscilla Cascetta, Pietro De Placido, Sabino De Placido and Roberto Bianco

Cancers 2019, 11(7), 981; https://doi.org/10.3390/cancers11070981 - 13 Jul 2019

Cited by 34 | Viewed by 4972

Abstract

The optimal therapeutic strategy for locally advanced pancreatic cancer patients (LAPC) has not yet been established. Our aim is to evaluate how surgery after neoadjuvant treatment with either FOLFIRINOX (FFN) or Gemcitabine-NabPaclitaxel (GemNab) affects the clinical outcome in these patients. LAPC patients treated [...] Read more.

The optimal therapeutic strategy for locally advanced pancreatic cancer patients (LAPC) has not yet been established. Our aim is to evaluate how surgery after neoadjuvant treatment with either FOLFIRINOX (FFN) or Gemcitabine-NabPaclitaxel (GemNab) affects the clinical outcome in these patients. LAPC patients treated at our institution were retrospectively analysed to reach this goal. The group characteristics were similar: 35 patients were treated with the FOLFIRINOX regimen and 21 patients with Gemcitabine Nab-Paclitaxel. The number of patients undergoing surgery was 14 in the FFN group (40%) and six in the GemNab group (28.6%). The median Disease-Free Survival (DFS) was 77.10 weeks in the FFN group and 58.65 weeks in the Gem Nab group (p = 0.625), while the median PFS in the unresected group was 49.4 weeks in the FFN group and 30.9 in the GemNab group (p = 0.0029, 95% CI 0.138–0.862, HR 0.345). The overall survival (OS) in the resected population needs a longer follow up to be completely assessed, while the median overall survival (mOS) in the FFN group was 72.10 weeks and 53.30 weeks for the GemNab group (p = 0.06) in the unresected population. Surgery is a valuable option for LAPC patients and it is able to induce a relevant survival advantage. FOLFIRINOX and Gem-NabPaclitaxel should be offered as first options to pancreatic cancer patients in the locally advanced setting. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 8384 KiB

Open AccessEditor’s ChoiceArticle

Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

by Antonella Argentiero, Simona De Summa, Roberta Di Fonte, Rosa Maria Iacobazzi, Letizia Porcelli, Matteo Da Vià, Oronzo Brunetti, Amalia Azzariti, Nicola Silvestris and Antonio Giovanni Solimando

Cancers 2019, 11(7), 942; https://doi.org/10.3390/cancers11070942 - 4 Jul 2019

Cited by 68 | Viewed by 5060

Abstract

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a [...] Read more.

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window. To this end, we provide an original bioinformatic dissection of the gene expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient’s derived samples indicated that WNT increased activation and a peculiar immune microenvironment identify subjects with nodal involvement. In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939—a specific WNT pathway inhibitor—has in re-educating a tumor-permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in node-positive disease. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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12 pages, 1660 KiB

Open AccessArticle

Early Tumor Shrinkage and Depth of Response Evaluation in Metastatic Pancreatic Cancer Treated with First Line Chemotherapy: An Observational Retrospective Cohort Study

by Caterina Vivaldi, Lorenzo Fornaro, Carla Cappelli, Irene Pecora, Silvia Catanese, Francesca Salani, Andrea Cacciato Insilla, Emanuele Kauffmann, Francescamaria Donati, Giulia Pasquini, Valentina Massa, Niccolò Napoli, Monica Lencioni, Piero Boraschi, Daniela Campani, Ugo Boggi, Davide Caramella, Alfredo Falcone and Enrico Vasile

Cancers 2019, 11(7), 939; https://doi.org/10.3390/cancers11070939 - 4 Jul 2019

Cited by 14 | Viewed by 3780

Abstract

Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were [...] Read more.

Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions’ longest diameters (SLD) after 6–8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group; p = 0.280). In the overall population, ETS was significantly associated with better PFS (8.0 vs. 4.8 months, p < 0.001) and OS (13.2 vs. 9.7 months, p = 0.001). Median DoR was −27.5% (−29.4% with FOLFOXIRI and −21.4% with GemNab, p = 0.016): DoR was significantly associated with better PFS (9.0 vs. 6.7 months, p < 0.001) and OS (14.3 vs. 11.1 months, p = 0.031). Multivariate analysis confirmed both ETS and DoR are independently associated with PFS and OS. In conclusion, our study added evidence on the role of ETS and DoR in the prediction of outcome of PC patients treated with first-line combination chemotherapy. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 3448 KiB

Open AccessArticle

Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

by Jiangang Zhao, Hans A. Schlößer, Zhefang Wang, Jie Qin, Jiahui Li, Felix Popp, Marie Christine Popp, Hakan Alakus, Seung-Hun Chon, Hinrich P. Hansen, Wolfram F. Neiss, Karl-Walter Jauch, Christiane J. Bruns and Yue Zhao

Cancers 2019, 11(6), 874; https://doi.org/10.3390/cancers11060874 - 22 Jun 2019

Cited by 97 | Viewed by 6710

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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15 pages, 4344 KiB

Open AccessArticle

Myoferlin Contributes to the Metastatic Phenotype of Pancreatic Cancer Cells by Enhancing Their Migratory Capacity through the Control of Oxidative Phosphorylation

by Gilles Rademaker, Brunella Costanza, Sandy Anania, Ferman Agirman, Naïma Maloujahmoum, Emmanuel Di Valentin, Jean Jacques Goval, Akeila Bellahcène, Vincenzo Castronovo and Olivier Peulen

Cancers 2019, 11(6), 853; https://doi.org/10.3390/cancers11060853 - 19 Jun 2019

Cited by 24 | Viewed by 4850

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with an overall survival of 5% and is the second cause of death by cancer, mainly linked to its high metastatic aggressiveness. Accordingly, understanding the mechanisms sustaining the PDAC metastatic phenotype remains a [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with an overall survival of 5% and is the second cause of death by cancer, mainly linked to its high metastatic aggressiveness. Accordingly, understanding the mechanisms sustaining the PDAC metastatic phenotype remains a priority. In this study, we generated and used a murine in vivo model to select clones from the human Panc-1 PDAC cell line that exhibit a high propensity to seed and metastasize into the liver. We showed that myoferlin, a protein previously reported to be overexpressed in PDAC, is significantly involved in the migratory abilities of the selected cells. We first report that highly metastatic Panc-1 clones expressed a significantly higher myoferlin level than the corresponding low metastatic ones. Using scratch wound and Boyden’s chamber assays, we show that cells expressing a high myoferlin level have higher migratory potential than cells characterized by a low myoferlin abundance. Moreover, we demonstrate that myoferlin silencing leads to a migration decrease associated with a reduction of mitochondrial respiration. Since mitochondrial oxidative phosphorylation has been shown to be implicated in the tumor progression and dissemination, our data identify myoferlin as a valid potential therapeutic target in PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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12 pages, 4080 KiB

Open AccessArticle

Non-Invasive Monitoring of Stromal Biophysics with Targeted Depletion of Hyaluronan in Pancreatic Ductal Adenocarcinoma

by Ezekiel Maloney, Christopher C. DuFort, Paolo P. Provenzano, Navid Farr, Markus A. Carlson, Ravneet Vohra, Joshua Park, Sunil R. Hingorani and Donghoon Lee

Cancers 2019, 11(6), 772; https://doi.org/10.3390/cancers11060772 - 4 Jun 2019

Cited by 20 | Viewed by 4083

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of small molecule [...] Read more.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of small molecule therapeutics. The targeted depletion of hyaluronan with a PEGylated recombinant human hyaluronidase (PEGPH20) lowers interstitial gel–fluid pressures and re-expands collapsed intratumoral vasculature, improving the delivery of concurrently administered agents. Here we report a non-invasive means of assessing biophysical responses to stromal intervention with quantitative multiparametric magnetic resonance imaging (MRI) at 14 Tesla (T). We found that spin-spin relaxation time T2 values and glycosaminoglycan chemical exchange saturation transfer (GagCEST) values decreased at 24 h, reflecting depletion of intratumoral HA content, and that these parameters recovered at 7 days concurrent with replenishment of intratumoral HA. This was also reflected in an increase in low-b apparent diffusion coefficient (ADC) at 24 h, consistent with improved tumor perfusion that again normalized at 7 days after treatment. Phantom imaging suggests that the GagCEST signal is driven by changes in HA versus other glycosaminoglycans. Thus, multiparametric magnetic resonance imaging (MRI) can be used as a non-invasive tool to assess therapeutic responses to targeted stromal therapy in PDA and likely other stroma-rich solid tumors that have high levels of hyaluronan and collagen. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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13 pages, 1229 KiB

Open AccessArticle

Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation

by Patrick Naumann, Jonathan Eberlein, Benjamin Farnia, Thilo Hackert, Jürgen Debus and Stephanie E. Combs

Cancers 2019, 11(5), 709; https://doi.org/10.3390/cancers11050709 - 23 May 2019

Cited by 33 | Viewed by 4014

Abstract

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with [...] Read more.

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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23 pages, 3897 KiB

Open AccessArticle

Role of c-MET Inhibitors in Overcoming Drug Resistance in Spheroid Models of Primary Human Pancreatic Cancer and Stellate Cells

by Omidreza Firuzi, Pei Pei Che, Btissame El Hassouni, Mark Buijs, Stefano Coppola, Matthias Löhr, Niccola Funel, Rainer Heuchel, Ilaria Carnevale, Thomas Schmidt, Giulia Mantini, Amir Avan, Luciano Saso, Godefridus J. Peters and Elisa Giovannetti

Cancers 2019, 11(5), 638; https://doi.org/10.3390/cancers11050638 - 8 May 2019

Cited by 62 | Viewed by 7402

Abstract

Pancreatic stellate cells (PSCs) are a key component of tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) and contribute to drug resistance. c-MET receptor tyrosine kinase activation plays an important role in tumorigenesis in different cancers including PDAC. In this study, effects of PSC [...] Read more.

Pancreatic stellate cells (PSCs) are a key component of tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) and contribute to drug resistance. c-MET receptor tyrosine kinase activation plays an important role in tumorigenesis in different cancers including PDAC. In this study, effects of PSC conditioned medium (PCM) on c-MET phosphorylation (by immunocytochemistry enzyme-linked immunosorbent assay (ELISA)) and drug response (by sulforhodamine B assay) were investigated in five primary PDAC cells. In novel 3D-spheroid co-cultures of cyan fluorescence protein (CFP)-firefly luciferase (Fluc)-expressing primary human PDAC cells and green fluorescence protein (GFP)-expressing immortalized PSCs, PDAC cell growth and chemosensitivity were examined by luciferase assay, while spheroids’ architecture was evaluated by confocal microscopy. The highest phospho-c-MET expression was detected in PDAC5 and its subclone sorted for “stage specific embryonic antigen-4” (PDAC5 (SSEA4)). PCM of cells pre-incubated with PDAC conditioned medium, containing increased hepatocyte growth factor (HGF) levels, made PDAC cells significantly more resistant to gemcitabine, but not to c-MET inhibitors. Hetero-spheroids containing both PSCs and PDAC5 (SSEA4) cells were more resistant to gemcitabine compared to PDAC5 (SSEA4) homo-spheroids. However, c-MET inhibitors (tivantinib, PHA-665752 and crizotinib) were equally effective in both spheroid models. Experiments with primary human PSCs confirmed the main findings. In conclusion, we developed spheroid models to evaluate PSC–PDAC reciprocal interaction, unraveling c-MET inhibition as an important therapeutic option against drug resistant PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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20 pages, 1333 KiB

Open AccessArticle

Use of Machine-Learning Algorithms in Intensified Preoperative Therapy of Pancreatic Cancer to Predict Individual Risk of Relapse

by Pablo Sala Elarre, Esther Oyaga-Iriarte, Kenneth H. Yu, Vicky Baudin, Leire Arbea Moreno, Omar Carranza, Ana Chopitea Ortega, Mariano Ponz-Sarvise, Luis D. Mejías Sosa, Fernando Rotellar Sastre, Blanca Larrea Leoz, Yohana Iragorri Barberena, Jose C. Subtil Iñigo, Alberto Benito Boíllos, Fernando Pardo and Javier Rodríguez Rodríguez

Cancers 2019, 11(5), 606; https://doi.org/10.3390/cancers11050606 - 30 Apr 2019

Cited by 22 | Viewed by 5625

Abstract

Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) [...] Read more.

Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse. Methods: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques. Results: A R0 resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56–0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset. Conclusion: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 2589 KiB

Open AccessArticle

Prognostic Nutritional Index after Chemoradiotherapy Was the Strongest Prognostic Predictor among Biological and Conditional Factors in Localized Pancreatic Ductal Adenocarcinoma Patients

by Ken Ichikawa, Shugo Mizuno, Aoi Hayasaki, Masashi Kishiwada, Takehiro Fujii, Yusuke Iizawa, Hiroyuki Kato, Akihiro Tanemura, Yasuhiro Murata, Yoshinori Azumi, Naohisa Kuriyama, Masanobu Usui, Hiroyuki Sakurai and Shuji Isaji

Cancers 2019, 11(4), 514; https://doi.org/10.3390/cancers11040514 - 10 Apr 2019

Cited by 18 | Viewed by 3492

Abstract

Background: In many malignancies, including pancreatic ductal adenocarcinoma (PDAC), host-related inflammatory/immunonutritional markers, such as the prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and C-reactive protein (CRP)/albumin ratio are reported to be prognostic factors. However, the prognostic influence of these factors [...] Read more.

Background: In many malignancies, including pancreatic ductal adenocarcinoma (PDAC), host-related inflammatory/immunonutritional markers, such as the prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and C-reactive protein (CRP)/albumin ratio are reported to be prognostic factors. However, the prognostic influence of these factors before and after chemoradiotherapy (CRT) has not been studied in PDAC patients. Methods: Of 261 consecutive PDAC patients who were scheduled for CRT with gemcitabine or S1 plus gemcitabine between February 2005 and December 2015, participants in this study were 176 who completed CRT and had full data available on inflammatory/immunonutritional markers as well as on anatomical and biological factors for the investigation of prognostic/predictive factors. Results: In multivariate analysis, the significant prognostic factors were RECIST classification, cT category, performance status, post-CRT carcinoembryonic antigen, post-CRT C-reactive protein/albumin ratio, post-CRT mGPS, and post-CRT PNI. Post-CRT PNI (cut-off value, 39) was the strongest host-related prognostic factor according to the p-value. In the patients who underwent resection after CRT, median survival time (MST) was significantly shorter in the 12 patients with low PNI (<39) than in the 97 with high PNI (≥39), at 15.5 months versus 27.2 months, respectively (p = 0.0016). In the patients who did not undergo resection, MST was only 8.9 months in those with low PNI and 12.3 months in those with high PNI (p < 0.0001), and thus was similar to that of the resected patients with low PNI. Conclusions: Post-CRT PNI was the strongest prognostic/predictive indicator among the independent biological and conditional prognostic factors in PDAC patients who underwent CRT. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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15 pages, 1635 KiB

Open AccessEditor’s ChoiceArticle

Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors

by David Jérémie Birnbaum, François Bertucci, Pascal Finetti, Daniel Birnbaum and Emilie Mamessier

Cancers 2019, 11(4), 497; https://doi.org/10.3390/cancers11040497 - 8 Apr 2019

Cited by 67 | Viewed by 8955

Abstract

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T [...] Read more.

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% vs. 17%, p = 0.002) or from the same molecular class (squamous subtype: 31% vs. 0%, p < 0.0001). Bailey’s molecular subtypes were differentially distributed within the two groups, with the immunogenic subtype being underrepresented in the “B/T” group (p = 0.005). Uni- and multivariate analyses indicated that PDAC anatomic location was an independent prognostic factor. Finally, the supervised analysis identified 334 genes differentially expressed. Genes upregulated in the “head” group suggested lymphocyte activation and pancreas exocrine functions. Genes upregulated in the “B/T” group were related to keratinocyte differentiation, in line with the enrichment for squamous phenotype. We identified a robust gene expression signature (GES) associated with B/T PDAC location, suggesting that head and B/T PDAC are different. This GES could serve as an indicator for differential therapeutic management based on PDAC location. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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17 pages, 2027 KiB

Open AccessEditor’s ChoiceArticle

CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer

by Letizia Porcelli, Rosa Maria Iacobazzi, Roberta Di Fonte, Simona Serratì, Angelica Intini, Antonio Giovanni Solimando, Oronzo Brunetti, Angela Calabrese, Francesco Leonetti, Amalia Azzariti and Nicola Silvestris

Cancers 2019, 11(3), 330; https://doi.org/10.3390/cancers11030330 - 7 Mar 2019

Cited by 77 | Viewed by 6778

Abstract

Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the [...] Read more.

Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs’ cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 1038 KiB

Open AccessArticle

Clinical Outcomes of Conversion Surgery after Neoadjuvant Chemotherapy in Patients with Borderline Resectable and Locally Advanced Unresectable Pancreatic Cancer: A Single-Center, Retrospective Analysis

by Changhoon Yoo, Sang Hyun Shin, Kyu-pyo Kim, Jae Ho Jeong, Heung-Moon Chang, Jun Ho Kang, Sang Soo Lee, Do Hyun Park, Tae Jun Song, Dong Wan Seo, Sung Koo Lee, Myung-Hwan Kim, Jin-hong Park, Dae Wook Hwang, Ki Byung Song, Jae Hoon Lee, Baek-Yeol Ryoo and Song Cheol Kim

Cancers 2019, 11(3), 278; https://doi.org/10.3390/cancers11030278 - 26 Feb 2019

Cited by 35 | Viewed by 4421

Abstract

The clinical benefit and potential risks of conversion surgery after neoadjuvant chemotherapy (NACT) have not been fully investigated in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Therefore, this has been evaluated in a retrospective, prospective cohort-based [...] Read more.

The clinical benefit and potential risks of conversion surgery after neoadjuvant chemotherapy (NACT) have not been fully investigated in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Therefore, this has been evaluated in a retrospective, prospective cohort-based analysis. Between October 2005 and April 2017, 135 patients (65 with BRPC and 70 with LAPC) received conversion surgery after NACT. Exploratory analysis to assess clinical outcomes in comparison with patients who underwent upfront surgery in the same time period (n = 359) was also conducted. NACT with gemcitabine-based regimens (including gemcitabine monotherapy, gemcitabine-capecitabine combination, and gemcitabine-erlotinib combination) was used in 69 patients (51%) and FOLFIRINOX in 66 patients (49%). The median overall survival (OS) and disease-free survival (DFS) from the time of surgery was 25.4 months (95% CI, 18.6–32.2 months) and 9.0 months (95% CI, 6.8–11.2 months), respectively. The median OS and progression-free survival from the initiation of NACT was 29.7 months (95% CI, 22.5–36.8 months) and 13.4 months (95% CI, 12.5–14.4 months), respectively. In the exploratory analysis, conversion surgery after NACT was associated with a better median OS and DFS than upfront surgery (vs. 17.1 months; 95% CI, 15.5–18.7 months; p = 0.001 and vs. 7.1 months; 95% CI, 6.4–7.8 months; p = 0.005, respectively). There was no difference in length of hospital stay between the two groups, and conversion surgery after NACT showed a significantly lower incidence of postoperative complications than upfront surgery (38% vs. 27%, p = 0.03). Conversion surgery after NACT is a feasible and effective therapeutic strategy for the treatment of patients with BRPC and LAPC. Further clinical trials investigating optimal therapeutic strategies for BRPC and LAPC are warranted. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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10 pages, 1764 KiB

Open AccessArticle

Preoperative Imaging Evaluation after Downstaging of Pancreatic Ductal Adenocarcinoma: A Multi-Center Study

by Alessandro Beleù, Angela Calabrese, Giulio Rizzo, Paola Capelli, Nicolò Bellini, Simona Caloggero, Roberto Calbi, Paolo Tinazzi Martini, Riccardo De Robertis, Giovanni Carbognin, Giovanni Marchegiani, Aldo Scarpa, Roberto Salvia, Claudio Bassi and Mirko D’Onofrio

Cancers 2019, 11(2), 267; https://doi.org/10.3390/cancers11020267 - 25 Feb 2019

Cited by 20 | Viewed by 4122

Abstract

Introduction: Evaluation of pancreatic ductal adenocarcinoma (PDAC) after chemoradiotherapy downstaging is challenging due to computed tomography (CT) overestimation of tumor extension and residual vascular involvement, limiting access to surgery to some patients with potentially resectable tumors. With this study, we wanted to assess [...] Read more.

Introduction: Evaluation of pancreatic ductal adenocarcinoma (PDAC) after chemoradiotherapy downstaging is challenging due to computed tomography (CT) overestimation of tumor extension and residual vascular involvement, limiting access to surgery to some patients with potentially resectable tumors. With this study, we wanted to assess which radiological findings are most reliable at pre-operative imaging in the evaluation of PDAC after chemoradiotherapy in order to achieve complete resection. Methods: We retrospectively enrolled 71 patients with locally advanced and borderline resectable PDAC who underwent neoadjuvant chemoradiotherapy. Pre-operative CT or magnetic resonance (MR) have been evaluated by three radiologists to assess major qualitative and quantitative parameters of lesions. Accuracy, sensitivity, and specificity compared to anatomopathological results were evaluated for each parameter. Cohen’s K-coefficient has been calculated to evaluate the inter-observer agreement (IOA). Both single and consensus lecture have been tested. Different dimensional cut-offs were tested to categorize tumors according to their major axis and to compare with anatomopathological diameter, tumor persistence, and margin infiltration. Results: A 25 mm cut-off was 67% sensitive, 90% specific, and 77% accurate in assessing real tumor dimension. 25 mm cut-off reported a 64% sensitivity, 78% specificity, and 69% accuracy in assessing R0 resection. Each 5 mm increment of major axis dimension there is an odds ratio (OR) 1.79 (95% CI 1.13–2.80, p = 0.012) for R+ resection. Imaging presence of the perivascular cuff is not associated with tumor persistence and resection margin infiltration (p = 0.362). Lesion enhancement and pattern homogeneity were not accurate in determining tumor persistence. IOA was generally poor to fair, except for >25 mm cut-off classification where IOA was moderate. Diagnostic accuracy is superior in consensus lecture rather than single lecture. Conclusion: Imaging methods tend to underestimate PDAC resectability after neoadjuvant-CRT. IOA is poor to fair in evaluating most of the qualitative parameters of downstaged pancreatic adenocarcinoma. Surgery should be considered for downstaged borderline resectable PDACs, independently from perivascular cuff presence, especially for tumors smaller than 25 mm. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 4346 KiB

Open AccessArticle

An Integrative Data Mining and Omics-Based Translational Model for the Identification and Validation of Oncogenic Biomarkers of Pancreatic Cancer

by Nguyen Phuoc Long, Kyung Hee Jung, Nguyen Hoang Anh, Hong Hua Yan, Tran Diem Nghi, Seongoh Park, Sang Jun Yoon, Jung Eun Min, Hyung Min Kim, Joo Han Lim, Joon Mee Kim, Johan Lim, Sanghyuk Lee, Soon-Sun Hong and Sung Won Kwon

Cancers 2019, 11(2), 155; https://doi.org/10.3390/cancers11020155 - 29 Jan 2019

Cited by 37 | Viewed by 6977

Abstract

Substantial alterations at the multi-omics level of pancreatic cancer (PC) impede the possibility to diagnose and treat patients in early stages. Herein, we conducted an integrative omics-based translational analysis, utilizing next-generation sequencing, transcriptome meta-analysis, and immunohistochemistry, combined with statistical learning, to validate multiplex [...] Read more.

Substantial alterations at the multi-omics level of pancreatic cancer (PC) impede the possibility to diagnose and treat patients in early stages. Herein, we conducted an integrative omics-based translational analysis, utilizing next-generation sequencing, transcriptome meta-analysis, and immunohistochemistry, combined with statistical learning, to validate multiplex biomarker candidates for the diagnosis, prognosis, and management of PC. Experiment-based validation was conducted and supportive evidence for the essentiality of the candidates in PC were found at gene expression or protein level by practical biochemical methods. Remarkably, the random forests (RF) model exhibited an excellent diagnostic performance and LAMC2, ANXA2, ADAM9, and APLP2 greatly influenced its decisions. An explanation approach for the RF model was successfully constructed. Moreover, protein expression of LAMC2, ANXA2, ADAM9, and APLP2 was found correlated and significantly higher in PC patients in independent cohorts. Survival analysis revealed that patients with high expression of ADAM9 (Hazard ratio (HR)_OS = 2.2, p-value < 0.001), ANXA2 (HR_OS = 2.1, p-value < 0.001), and LAMC2 (HR_DFS = 1.8, p-value = 0.012) exhibited poorer survival rates. In conclusion, we successfully explore hidden biological insights from large-scale omics data and suggest that LAMC2, ANXA2, ADAM9, and APLP2 are robust biomarkers for early diagnosis, prognosis, and management for PC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 1200 KiB

Open AccessArticle

Prognostic Factors for Advanced Pancreatic Cancer Treated with Gemcitabine Plus S-1: Retrospective Analysis and Development of a Prognostic Model

by Ching-Fu Chang, Pei-Wei Huang, Jen-Shi Chen, Yen-Yang Chen, Chang-Hsien Lu, Pei-Hung Chang, Yu-Shin Hung and Wen-Chi Chou

Cancers 2019, 11(1), 57; https://doi.org/10.3390/cancers11010057 - 9 Jan 2019

Cited by 13 | Viewed by 3725

Abstract

Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival [...] Read more.

Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival prediction in patients with APC, treated with GS. Records of 111 patients with newly diagnosed APC who received first-line palliative GS chemotherapy during 2010–2016 in Taiwan were analyzed retrospectively. Univariate and multivariate analyses were performed for the identification of prognostic factors. A prognostic model using prognosticators from the multivariate analysis was developed for survival prediction. The median overall survival (OS) for the cohort was 9.3 months (95% confidence interval [CI], 8.0–10.6). The prognostic model was constructed based on four independent prognosticators: performance status, tumor stage, pre-treatment albumin level, and neutrophil-to-lymphocyte ratio. Patients were categorized by tertiles into good, intermediate, and poor prognostic groups. The median OS values for each of these groups were 21.1 (95% CI, 8.2–33.9), 9.2 (95% CI, 8.3–10.1), and 5.8 months (95% CI, 4.4–7.1; log-rank p < 0.001), respectively. The bootstrapped corrected C-index of this model was 0.80 (95% CI, 0.71–0.89). The developed model was robust and could accurately predict survival in this population, and can assist clinicians and patients in survival discrimination and the determination of appropriate medical care goals. Additional research is needed to externally validate the model’s performance. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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16 pages, 3357 KiB

Open AccessArticle

Venous Thromboembolism in Asian Patients with Pancreatic Cancer Following Palliative Chemotherapy: Low Incidence but a Negative Prognosticator for Those with Early Onset

by Jen-Shi Chen, Chia-Yen Hung, Hung Chang, Chien-Ting Liu, Yen-Yang Chen, Chang-Hsien Lu, Pei-Hung Chang, Yu-Shin Hung and Wen-Chi Chou

Cancers 2018, 10(12), 501; https://doi.org/10.3390/cancers10120501 - 10 Dec 2018

Cited by 20 | Viewed by 3435

Abstract

Background: Few studies have reported the epidemiology and clinical outcome of venous thromboembolism (VTE) in Asian patients with pancreatic cancer. This study investigated the incidence, risk factors, and clinical outcome of VTE in patients with pancreatic cancer following palliative chemotherapy. Methods: The medical [...] Read more.

Background: Few studies have reported the epidemiology and clinical outcome of venous thromboembolism (VTE) in Asian patients with pancreatic cancer. This study investigated the incidence, risk factors, and clinical outcome of VTE in patients with pancreatic cancer following palliative chemotherapy. Methods: The medical records of 838 patients with newly diagnosed locally advanced or metastatic pancreatic cancer who underwent palliative chemotherapy between 2010 and 2016 at four institutes in Taiwan were retrospectively reviewed. The clinical characteristics of all patients were analyzed to identify independent predictors of VTE and their effects on survival outcome. Results: During the median follow-up period of 7.7 months (range, 0.6–55.6), VTE occurred in 67 (8.0%) of the 838 patients. Leukocyte count > 11,000/μL and presence of liver metastases were the independent predictors of VTE. Patients with VTE did not show significantly poorer survival outcomes than those without VTE. However, early-onset VTE that occurred within 1.5 months after chemotherapy initiation was an independent negative prognosticator for overall survival. Conclusion: VTE incidence was found to be lower in Asian patients with pancreatic cancer than in their Western counterparts. Early-onset VTE, but not late-onset VTE, is a negative prognosticator for survival outcomes. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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Review

Jump to: Research, Other

41 pages, 1859 KiB

Open AccessReview

Basics and Frontiers on Pancreatic Cancer for Radiation Oncology: Target Delineation, SBRT, SIB Technique, MRgRT, Particle Therapy, Immunotherapy and Clinical Guidelines

by Francesco Cellini, Alessandra Arcelli, Nicola Simoni, Luciana Caravatta, Milly Buwenge, Angela Calabrese, Oronzo Brunetti, Domenico Genovesi, Renzo Mazzarotto, Francesco Deodato, Gian Carlo Mattiucci, Nicola Silvestris, Vincenzo Valentini and Alessio Giuseppe Morganti

Cancers 2020, 12(7), 1729; https://doi.org/10.3390/cancers12071729 - 29 Jun 2020

Cited by 26 | Viewed by 5481

Abstract

Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment [...] Read more.

Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on (i) the current indications by the available national and international guidelines; (ii) the current standard indications for target volume delineation in radiotherapy (RT); (iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); (iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; (v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and (vi) a multimodal integration opportunity: the combination of RT with immunotherapy. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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28 pages, 385 KiB

Open AccessReview

Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up of Exocrine Pancreatic Ductal Adenocarcinoma: Evidence Evaluation and Recommendations by the Italian Association of Medical Oncology (AIOM)

by Nicola Silvestris, Oronzo Brunetti, Alessandro Bittoni, Ivana Cataldo, Domenico Corsi, Stefano Crippa, Mirko D’Onofrio, Michele Fiore, Elisa Giommoni, Michele Milella, Raffaele Pezzilli, Enrico Vasile and Michele Reni

Cancers 2020, 12(6), 1681; https://doi.org/10.3390/cancers12061681 - 24 Jun 2020

Cited by 23 | Viewed by 3343

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

16 pages, 1486 KiB

Open AccessReview

Pancreatic Enzyme Replacement Therapy in Pancreatic Cancer

by Raffaele Pezzilli, Riccardo Caccialanza, Gabriele Capurso, Oronzo Brunetti, Michele Milella and Massimo Falconi

Cancers 2020, 12(2), 275; https://doi.org/10.3390/cancers12020275 - 22 Jan 2020

Cited by 61 | Viewed by 8703

Abstract

Pancreatic cancer is an aggressive malignancy and the seventh leading cause of global cancer deaths in industrialised countries. More than 80% of patients suffer from significant weight loss at diagnosis and over time tend to develop severe cachexia. A major cause of weight [...] Read more.

Pancreatic cancer is an aggressive malignancy and the seventh leading cause of global cancer deaths in industrialised countries. More than 80% of patients suffer from significant weight loss at diagnosis and over time tend to develop severe cachexia. A major cause of weight loss is malnutrition. Patients may experience pancreatic exocrine insufficiency (PEI) before diagnosis, during nonsurgical treatment, and/or following surgery. PEI is difficult to diagnose because testing is cumbersome. Consequently, PEI is often detected clinically, especially in non-specialised centres, and treated empirically. In this position paper, we review the current literature on nutritional support and pancreatic enzyme replacement therapy (PERT) in patients with operable and non-operable pancreatic cancer. To increase awareness on the importance of PERT in pancreatic patients, we provide recommendations based on literature evidence, and when data were lacking, based on our own clinical experience. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 479 KiB

Open AccessReview

Systematic Review of Irreversible Electroporation Role in Management of Locally Advanced Pancreatic Cancer

by Stefano Lafranceschina, Oronzo Brunetti, Antonella Delvecchio, Maria Conticchio, Michele Ammendola, Giuseppe Currò, Tullio Piardi, Nicola de’Angelis, Nicola Silvestris and Riccardo Memeo

Cancers 2019, 11(11), 1718; https://doi.org/10.3390/cancers11111718 - 3 Nov 2019

Cited by 30 | Viewed by 3566

Abstract

Background: Ablative techniques provide in patients with locally advanced pancreatic cancer (LAPC) symptomatic relief, survival benefit and potential downsizing. Irreversible Electroporation (IRE) represents potentially an ideal solution as no thermal tissue damage occurs. The purpose of this review is to present an overview [...] Read more.

Background: Ablative techniques provide in patients with locally advanced pancreatic cancer (LAPC) symptomatic relief, survival benefit and potential downsizing. Irreversible Electroporation (IRE) represents potentially an ideal solution as no thermal tissue damage occurs. The purpose of this review is to present an overview on safety, feasibility, oncological results, survival and quality of life improvement obtained by IRE. Methods: A systematic search was performed in PubMed, regarding the use of IRE on PC in humans for studies published in English up to March 2019. Results: 15 original studies embodying 691 patients with unresectable LAPC who underwent IRE were included. As emerged, IRE works better on tumour sizes between 3–4 cm. Oncological results are promising: median OS from diagnosis or treatment up to 27 months. Two groups investigated borderline resectable tumours treated with IRE before resection with margin attenuation, whereas IRE has proved to be effective in pain control. Conclusions: Electroporation is bringing new hopes in LAPC management. The first aim of IRE is to offer a palliative treatment. Further efforts are needed for patient selection, as well as the use of IRE for ‘margin accentuation’ during surgical resection. Even if promising, IRE needs to be validated in large, randomized, prospective series. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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14 pages, 678 KiB

Open AccessReview

Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives

by Verena Martini, Sylvia Timme-Bronsert, Stefan Fichtner-Feigl, Jens Hoeppner and Birte Kulemann

Cancers 2019, 11(11), 1659; https://doi.org/10.3390/cancers11111659 - 26 Oct 2019

Cited by 54 | Viewed by 6137

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. [...] Read more.

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. In the last twenty years (1999–2019), 140 articles have contained the key words “Circulating tumor cells, pancreatic cancer, prognosis and diagnosis.” Articles were evaluated for the use of CTCs as prognostic markers and their correlation to survival in pancreatic ductal adenocarcinoma (PDAC). In the final selected 17 articles, the CTC detection rate varied greatly between different enrichment methodologies and ranged from 11% to 92%; the majority of studies used the antigen-dependent CellSearch^© system for CTC detection. Fifteen of the reviewed studies showed a correlation between CTC presence and a worse overall survival. The heterogeneity of CTC-detection methods and the lack of uniform results hinder a comparison of the evaluated studies. However, CTCs can be detected in pancreatic cancer and harbor a hope to serve as an early detection tool. Larger studies are needed to corroborate CTCs as valid biomarkers in pancreatic cancer. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 331 KiB

Open AccessReview

Is There a Standard Adjuvant Therapy for Resected Pancreatic Cancer?

by Elisabetta Fenocchio, Roberto Filippi, Pasquale Lombardi, Virginia Quarà, Michela Milanesio, Giacomo Aimar, Francesco Leone and Massimo Aglietta

Cancers 2019, 11(10), 1547; https://doi.org/10.3390/cancers11101547 - 12 Oct 2019

Cited by 11 | Viewed by 3629

Abstract

Surgical resection remains the only treatment that offers a potential chance of long-term survival. Unfortunately, about 80% of patients treated with curative intent will develop recurrence. Since 2001, adjuvant therapy with gemcitabine or 5-fluorouracyle was recommended. This approach allows a median overall survival [...] Read more.

Surgical resection remains the only treatment that offers a potential chance of long-term survival. Unfortunately, about 80% of patients treated with curative intent will develop recurrence. Since 2001, adjuvant therapy with gemcitabine or 5-fluorouracyle was recommended. This approach allows a median overall survival (OS) of around 23 months, and 5-year survival of 22%. In recent years, two phase-3 trials investigating new chemotherapy regimens resulted in considerably improved survival times. The doublet gemcitabine–capecitabine has shown improvement in OS from 25.5 to 28 months (p = 0.032) compared to gemcitabine, in the ESPAC-4 trial. Later, preliminary results of PRODIGE 24 trial presented at the 2018 ASCO meeting showed a superiority of a combination chemotherapy regimen with fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) when compared to gemcitabine alone, both in terms of median disease-free survival (21.6 vs. 12.8 months, p < 0.0001) and OS (54.4 vs. 35 months, p = 0.003). Contrary to chemotherapy, the role of adjuvant radiotherapy is still controversial, even in the case of R1 surgery. A randomized trial exploring the role of chemoradiotherapy in this setting is now ongoing in the US (RTOG-0848). Overall, the management of localized pancreatic adenocarcinoma is evolving. In this review, we summarize the current status and the most up-to-date developments in adjuvant treatment. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

26 pages, 707 KiB

Open AccessReview

EMT and Stemness—Key Players in Pancreatic Cancer Stem Cells

by Eva Rodriguez-Aznar, Lisa Wiesmüller, Bruno Sainz, Jr. and Patrick C. Hermann

Cancers 2019, 11(8), 1136; https://doi.org/10.3390/cancers11081136 - 8 Aug 2019

Cited by 81 | Viewed by 8819

Abstract

Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state [...] Read more.

Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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16 pages, 724 KiB

Open AccessReview

Surgery or Locoregional Approaches for Hepatic Oligometastatic Pancreatic Cancer: Myth, Hope, or Reality?

by Michele Ghidini, Angelica Petrillo, Massimiliano Salati, Shelize Khakoo, Antonio Varricchio, Gianluca Tomasello, Francesco Grossi and Fausto Petrelli

Cancers 2019, 11(8), 1095; https://doi.org/10.3390/cancers11081095 - 1 Aug 2019

Cited by 20 | Viewed by 5682

Abstract

Despite extensive research, pancreatic ductal adenocarcinoma (PDAC) remains a difficult-to-treat cancer associated with poor survival. Due to the known aggressive disease biology, palliative chemotherapy is the only routinely recommended treatment in the metastatic setting in patients with adequate performance status. However, in a [...] Read more.

Despite extensive research, pancreatic ductal adenocarcinoma (PDAC) remains a difficult-to-treat cancer associated with poor survival. Due to the known aggressive disease biology, palliative chemotherapy is the only routinely recommended treatment in the metastatic setting in patients with adequate performance status. However, in a subset of patients with oligometastatic disease, multimodality treatment with surgery and/or locoregional approaches may provide long-term disease control and prolong survival. In fact, in highly selected cases, median overall survival has been reported to extend to 56 months in patients treated with surgery. In particular, liver and extraregional nodal resections may provide long-term tumor control with acceptable morbidity. Current guidelines do not recommend surgery for patients with metastatic PDAC and, in the case of PDAC with oligometastases, there are no published randomized controlled trials regarding locoregional or surgical approaches. Here we review the literature on surgical and locoregional approaches including radiofrequency ablation, irreversible electroporation, and stereotactic body radiation, and focus on patients with hepatic oligometastatic pancreatic cancer. We provide a summary regarding survival outcomes, morbidity and mortality and discuss selection criteria that may be useful to predict the best outcomes for such strategies. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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19 pages, 884 KiB

Open AccessReview

Omics Approaches in Pancreatic Adenocarcinoma

by Iranzu González-Borja, Antonio Viúdez, Saioa Goñi, Enrique Santamaria, Estefania Carrasco-García, Jairo Pérez-Sanz, Irene Hernández-García, Pablo Sala-Elarre, Virginia Arrazubi, Esther Oyaga-Iriarte, Ruth Zárate, Sara Arévalo, Onintza Sayar, Ruth Vera and Joaquin Fernández-Irigoyen

Cancers 2019, 11(8), 1052; https://doi.org/10.3390/cancers11081052 - 25 Jul 2019

Cited by 11 | Viewed by 5271

Abstract

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading [...] Read more.

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 933 KiB

Open AccessReview

Surgery for Recurrent Pancreatic Cancer: Is It Effective?

by Lucia Moletta, Simone Serafini, Michele Valmasoni, Elisa Sefora Pierobon, Alberto Ponzoni and Cosimo Sperti

Cancers 2019, 11(7), 991; https://doi.org/10.3390/cancers11070991 - 16 Jul 2019

Cited by 54 | Viewed by 6895

Abstract

Despite improvements to surgical procedures and novel combinations of drugs for adjuvant and neoadjuvant therapies for pancreatic adenocarcinoma, the recurrence rate after radical surgery is still high. Little is known about the role of surgery in the treatment of isolated recurrences of pancreatic [...] Read more.

Despite improvements to surgical procedures and novel combinations of drugs for adjuvant and neoadjuvant therapies for pancreatic adenocarcinoma, the recurrence rate after radical surgery is still high. Little is known about the role of surgery in the treatment of isolated recurrences of pancreatic cancer. The aim of this study was to review the current literature dealing with surgery for recurrent pancreatic cancer in order to examine its feasibility and effectiveness. An extensive literature review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and 14 articles dealing with re-resections for recurrent pancreatic adenocarcinoma were analyzed, focusing on the characteristics of the primary neoplasm and its recurrence, the surgical procedures used, and patient outcomes. Data were retrieved on a total of 301 patients. The interval between surgery for primary pancreatic cancer and the detection of a recurrence ranged from 2 to 120 months. The recurrence was local or regional in 230 patients, and distant in 71. The median overall survival was 68.9 months (range 3–152) after resection of the primary tumor, and 26.0 months (range 0–112) after surgery for recurrent disease. The disease-free interval after the resection of recurrences was 14.2 months (range 4–29). Although data analysis was performed on a heterogeneous and limited number of patients, some of these may benefit from surgery for isolated recurrence of pancreatic adenocarcinoma. Further studies are needed to identify these cases. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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17 pages, 486 KiB

Open AccessReview

Locally Advanced Pancreatic Cancer: Work-Up, Staging, and Local Intervention Strategies

by Eran van Veldhuisen, Claudia van den Oord, Lilly J. Brada, Marieke S. Walma, Jantien A. Vogel, Johanna W. Wilmink, Marco del Chiaro, Krijn P. van Lienden, Martijn R. Meijerink, Geertjan van Tienhoven, Thilo Hackert, Christopher L. Wolfgang, Hjalmar van Santvoort, Bas Groot Koerkamp, Olivier R. Busch, I. Quintus Molenaar, Casper H. van Eijck, Marc G. Besselink and the Dutch Pancreatic Cancer Group and International Collaborative Group on Locally Advanced Pancreatic Cancer

Cancers 2019, 11(7), 976; https://doi.org/10.3390/cancers11070976 - 12 Jul 2019

Cited by 63 | Viewed by 6249

Abstract

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel [...] Read more.

Locally advanced pancreatic cancer (LAPC) has several definitions but essentially is a nonmetastasized pancreatic cancer, in which upfront resection is considered not beneficial due to extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of FOLFIRINOX chemotherapy and gemcitabine-nab-paclitaxel (gem-nab) has had major implications for the management and outcome of patients with LAPC. After 4–6 months induction chemotherapy, the majority of patients have stable disease or even tumor-regression. Of these, 12 to 35% are successfully downstaged to resectable disease. Several studies have reported a 30–35 months overall survival after resection; although it currently remains unclear if this is a result of the resection or the good response to chemotherapy. Following chemotherapy, selection of patients for resection is difficult, as contrast-enhanced computed-tomography (CT) scan is unreliable in differentiating between viable tumor and fibrosis. In case a resection is not considered possible but stable disease is observed, local ablative techniques are being studied, such as irreversible electroporation, radiofrequency ablation, and stereotactic body radiation therapy. Pragmatic, multicenter, randomized studies will ultimately have to confirm the exact role of both surgical exploration and ablation in these patients. Since evidence-based guidelines for the management of LAPC are lacking, this review proposes a standardized approach for the treatment of LAPC based on the best available evidence. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 1821 KiB

Open AccessReview

Clinical Scenarios Emerging from Combined Immunophenotypic, Molecular and Morphologic Analysis of Pancreatic Cancer: The Good, the Bad and the Ugly Scenario

by Eva Karamitopoulou and Beat Gloor

Cancers 2019, 11(7), 968; https://doi.org/10.3390/cancers11070968 - 10 Jul 2019

Cited by 3 | Viewed by 3507

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with increasing incidence and dismal prognosis. The composition of the immune cell infiltrates in the tumor microenvironment (TME) and the dynamic interplay between cancer- and immune cells can influence and/or be influenced by tumor-intrinsic characteristics [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with increasing incidence and dismal prognosis. The composition of the immune cell infiltrates in the tumor microenvironment (TME) and the dynamic interplay between cancer- and immune cells can influence and/or be influenced by tumor-intrinsic characteristics like molecular profiles and tumor cell morphology. The combined analyses of pancreatic cancer by using morphologic, genetic, and immunologic features help us understand the significant heterogeneity of the TME and recognize the different mechanisms of immune evasion. Moreover, this information may lead to the identification of novel biomarkers for more precise patient stratification and therapy guidance. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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26 pages, 5570 KiB

Open AccessReview

Nerves and Pancreatic Cancer: New Insights into A Dangerous Relationship

by Giulia Gasparini, Marta Pellegatta, Stefano Crippa, Marco Schiavo Lena, Giulio Belfiori, Claudio Doglioni, Carla Taveggia and Massimo Falconi

Cancers 2019, 11(7), 893; https://doi.org/10.3390/cancers11070893 - 26 Jun 2019

Cited by 60 | Viewed by 7105

Abstract

Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer—particularly in pancreatic ductal adenocarcinoma (PDAC)—PNI has a prevalence between 70 and 100%, surpassing any [...] Read more.

Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer—particularly in pancreatic ductal adenocarcinoma (PDAC)—PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously (“present” or “absent”). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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23 pages, 1927 KiB

Open AccessReview

Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis

by Madelaine G. van Mackelenbergh, Charlotte I. Stroes, René Spijker, Casper H.J. van Eijck, Johanna W. Wilmink, Maarten F. Bijlsma and Hanneke W.M. van Laarhoven

Cancers 2019, 11(5), 588; https://doi.org/10.3390/cancers11050588 - 26 Apr 2019

Cited by 42 | Viewed by 7298

Abstract

The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for [...] Read more.

The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90–1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)^high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26–1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 766 KiB

Open AccessReview

Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis

by Sara Pusceddu, Michele Ghidini, Martina Torchio, Francesca Corti, Gianluca Tomasello, Monica Niger, Natalie Prinzi, Federico Nichetti, Andrea Coinu, Maria Di Bartolomeo, Mary Cabiddu, Rodolfo Passalacqua, Filippo de Braud and Fausto Petrelli

Cancers 2019, 11(4), 484; https://doi.org/10.3390/cancers11040484 - 5 Apr 2019

Cited by 81 | Viewed by 7386

Abstract

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX [...] Read more.

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08–2.22, p = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84–1.16; p = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71–1.1; p = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3–4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized “real world” studies to date has not provided evidence of a major benefit of one regimen over the other. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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18 pages, 490 KiB

Open AccessReview

Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies

by Tiziana Annese, Roberto Tamma, Simona Ruggieri and Domenico Ribatti

Cancers 2019, 11(3), 381; https://doi.org/10.3390/cancers11030381 - 18 Mar 2019

Cited by 78 | Viewed by 5736

Abstract

Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. [...] Read more.

Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. In this review article, after a brief introduction on pancreatic cancer classification and on angiogenesis mechanisms involved in its progression, the pre-clinical and clinical trials conducted in pancreatic cancer treatment using anti-angiogenic inhibitors will be described. Finally, we will discuss the anti-angiogenic therapy paradox between the advantage to abolish vessel supply to block tumor growth and the disadvantage due to reduction of drug delivery at the same time. The purpose is to identify new anti-angiogenic molecules that may enhance treatment regimen. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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14 pages, 1099 KiB

Open AccessReview

Cancer-Associated Fibroblasts’ Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma

by Mohammad Awaji and Rakesh K. Singh

Cancers 2019, 11(3), 290; https://doi.org/10.3390/cancers11030290 - 1 Mar 2019

Cited by 45 | Viewed by 6340

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier to hinder chemotherapy and actively contributes to tumor progression and metastasis. CAFs represent a multifunctional subset of PDAC microenvironment and contribute to tumor initiation and progression through ECM deposition and remodeling, as well as the secretion of paracrine factors. Attempts to resolve desmoplasia by targeting CAFs can render an adverse outcome, which is likely due to CAFs heterogeneity. Recent reports describe subsets of CAFs that assume more secretory functions, in addition to the typical myofibroblast phenotype. Here, we review the literature and describe the relationship between CAFs and inflammation and the role of the secretory-CAFs in PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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11 pages, 1349 KiB

Open AccessReview

Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition

by Rita T. Lawlor, Nicola Veronese, Alessia Nottegar, Giuseppe Malleo, Lee Smith, Jacopo Demurtas, Liang Cheng, Laura D. Wood, Nicola Silvestris, Roberto Salvia, Aldo Scarpa and Claudio Luchini

Cancers 2019, 11(1), 113; https://doi.org/10.3390/cancers11010113 - 19 Jan 2019

Cited by 50 | Viewed by 6115

Abstract

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested [...] Read more.

This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13–1.88, p = 0.004; HR, 2.65; 95% CI, 1.79–3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05–2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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21 pages, 260 KiB

Open AccessReview

Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients

by Fleur van der Sijde, Eveline E. Vietsch, Dana A. M. Mustafa, Marc G. Besselink, Bas Groot Koerkamp and Casper H. J. van Eijck

Cancers 2019, 11(1), 93; https://doi.org/10.3390/cancers11010093 - 15 Jan 2019

Cited by 25 | Viewed by 4073

Abstract

Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual [...] Read more.

Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual patients may not benefit from chemotherapy. Biomarkers are needed to predict who will benefit from chemotherapy and to monitor a patient’s response to chemotherapy. This review summarizes current research and future perspectives on circulating biomarkers for systemic chemotherapy response. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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9 pages, 1575 KiB

Open AccessCase Report

Molecular Characterization of a Long-Term Survivor Double Metastatic Non-Small Cell Lung Cancer and Pancreatic Ductal Adenocarcinoma Treated with Gefitinib in Combination with Gemcitabine Plus Nab-Paclitaxel and mFOLFOX6 as First and Second Line Therapy

by Oronzo Brunetti, Giuseppe Badalamenti, Simona De Summa, Angela Calabrese, Antonella Argentiero, Livia Fucci, Vito Longo, Domenico Galetta, Pia Maria Soccorsa Perrotti, Rosamaria Pinto, Daniela Petriella, Katia Danza, Stefania Tommasi, Francesco Leonetti and Nicola Silvestris

Cancers 2019, 11(6), 749; https://doi.org/10.3390/cancers11060749 - 29 May 2019

Cited by 3 | Viewed by 3558

Abstract

The management of multiple primary cancers, an event not so infrequent in oncology practice, is a critical issue due to the lack of literature. In this study, we reported the case of a patient with non-small cell metastatic lung cancer (NSCLC) and pancreatic [...] Read more.

The management of multiple primary cancers, an event not so infrequent in oncology practice, is a critical issue due to the lack of literature. In this study, we reported the case of a patient with non-small cell metastatic lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. It achieved a progression-free survival and a28-months overall survival (OS) for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapy treatmentsshowed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. It is interesting to note that two neoplasms shared a common mutation ofthe B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival rate. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a leading justification of the long survival of the patient considered in this report. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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