Journal of Clinical Medicine

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14 pages, 1894 KiB

Open AccessArticle

Preoperative Clinical and Computed Tomography (CT)-Based Nomogram to Predict Oncologic Outcomes in Patients with Pancreatic Head Cancer Resected with Curative Intent: A Retrospective Study

by Shin Hye Hwang, Ha Yan Kim, Eun Ju Lee, Ho Kyoung Hwang, Mi-Suk Park, Myeong-jin Kim, Woo Jung Lee, Yong Eun Chung and Chang Moo Kang

J. Clin. Med. 2019, 8(10), 1749; https://doi.org/10.3390/jcm8101749 - 21 Oct 2019

Cited by 8 | Viewed by 2614

Abstract

Background: Currently, proposed nomograms are mainly based on post-operative histopathology. The purpose of this study was to identify preoperative computed tomography (CT) and clinical information that allow prediction of disease-free (DFS) and overall survival (OS) of patients surgically treated for pancreatic head cancer. [...] Read more.

Background: Currently, proposed nomograms are mainly based on post-operative histopathology. The purpose of this study was to identify preoperative computed tomography (CT) and clinical information that allow prediction of disease-free (DFS) and overall survival (OS) of patients surgically treated for pancreatic head cancer. Methods: A total of 136 patients who underwent curative-intent surgery were retrospectively reviewed. Based on results from multivariate Cox regression analysis, a prediction model was constructed with preoperative CT features and clinical information. Overall performance of the nomogram was calculated by Harrell’s C-index. Results: Symptoms at diagnosis, preoperative serum CA 19-9 ≥ 34 U/mL, and four imaging features (necrosis (DFS, P = 0.066; OS, P = 0.002), possible venous invasion (DFS, P = 0.150, OS, P = 0.055), suspected metastatic regional lymph node (DFS, P = 0.001; OS, P = 0.099), and associated pancreatitis or pseudocyst (DFS, P = 0.013; OS, P = 0.041)) were included to build the nomogram. The c-statistics for the discrimination power of the proposed nomogram was 0.6496 for DFS and 0.6746 for OS. Conclusion: A nomogram derived from preoperative CT and clinical information could estimate the risk of recurrence and all-cause death after curative-intent surgery for radiologically resectable pancreatic head cancer. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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14 pages, 3299 KiB

Open AccessArticle

Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for the Diagnosis of Pancreatic Tumors

by Yung-Yeh Su, Yi-Sheng Liu, Ying-Jui Chao, Nai-Jung Chiang, Chia-Jui Yen and Hong-Ming Tsai

J. Clin. Med. 2019, 8(10), 1633; https://doi.org/10.3390/jcm8101633 - 05 Oct 2019

Cited by 4 | Viewed by 6377

Abstract

Endoscopic, ultrasound-guided tissue acquisition (EUS-TA) with rapid on-site evaluation is recommended as a first choice in the diagnosis of pancreatic lesions. Since EUS facilities and rapid on-site evaluation are not widely available, even in medical centers, an alternative for precise diagnoses of pancreatic [...] Read more.

Endoscopic, ultrasound-guided tissue acquisition (EUS-TA) with rapid on-site evaluation is recommended as a first choice in the diagnosis of pancreatic lesions. Since EUS facilities and rapid on-site evaluation are not widely available, even in medical centers, an alternative for precise diagnoses of pancreatic tumor is warranted. The percutaneous computed tomography-guided, core needle biopsy (CT-CNB) is a commonly applicable method for biopsies. Our institute has developed a fat-transversing approach for pancreatic biopsies which is able to approach most tumors in the pancreas without penetrating organs or vessels. Herein, we report a 15-year experiment of pancreatic tumor coaxial CT-CNB in 420 patients. The success rate of tissue yielding by the technique was 99.3%. The overall sensitivity, specificity, and accuracy were 93.2%, 100%, and 93.4%, respectively. The diagnostic accuracy could be increased to 96.4% in 2016–2018 (after the learning curve period). The overall complication rate was 8.6%. Neither life-threatening major complications, nor seeding through the biopsy tract, were observed. Our study supported the hypothesis that CT-CNB could be a complementary option for diagnostic tissue acquisition in patients with unresectable or metastatic pancreatic tumors when EUS-TA is either unsuitable or unavailable. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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10 pages, 867 KiB

Open AccessArticle

Lung Metastases in Patients with Stage IV Pancreatic Cancer: Prevalence, Risk Factors, and Survival Impact

by Keng-Hao Liu, Chia-Yen Hung, Shu-Wen Hsueh, Pei-Hung Chang, Yen-Yang Chen, Chang-Hsien Lu, Ping-Tsung Chen, Kun-Yun Yeh, Pei-Wei Huang, Ngan-Ming Tsang, Yu-Shin Hung and Wen-Chi Chou

J. Clin. Med. 2019, 8(9), 1402; https://doi.org/10.3390/jcm8091402 - 06 Sep 2019

Cited by 18 | Viewed by 2883

Abstract

The aim of this study was to evaluate the prevalence, the clinicopathological variables associated with probability of lung metastases, and the impact of lung metastases on survival outcome in patients with stage IV pancreatic cancer (PC) treated with palliative chemotherapy. A total of [...] Read more.

The aim of this study was to evaluate the prevalence, the clinicopathological variables associated with probability of lung metastases, and the impact of lung metastases on survival outcome in patients with stage IV pancreatic cancer (PC) treated with palliative chemotherapy. A total of 654 patients with stage IV PC who underwent palliative chemotherapy from 2010–2016 were retrospectively enrolled in this study. Possible clinical variables associated with lung metastases and survival outcome were examined by univariate and multivariate analysis. Lung metastases were detected in 15.0% (3.4% with isolated lung metastases and 11.6% with synchronic metastases to lung and other organs). Female gender, poorly differentiated tumor grade, and large primary tumor size were independent risk factor in multivariate analysis. The median overall survival (OS) time was 6.5 months in the entire cohort, while the median OS was 11.8, 6.9, 7.7, 10.1, and 5.0 months for patients with isolated lung, isolated liver, isolated peritoneum, isolated distant lymph nodes, and multiple sites metastases, respectively. Isolated lung metastases were a better prognosticator for OS in univariate and multivariate analysis. This study utilized real-world clinical practice data to assess the prevalence, risk factors, and survival impact of lung metastases in patients with stage IV pancreatic cancer. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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14 pages, 2722 KiB

Open AccessArticle

Postoperative Imaging and Tumor Marker Surveillance in Resected Pancreatic Cancer

by Hsu Wu, Jhe-Cyuan Guo, Shih-Hung Yang, Yu-Wen Tien and Sung-Hsin Kuo

J. Clin. Med. 2019, 8(8), 1115; https://doi.org/10.3390/jcm8081115 - 27 Jul 2019

Cited by 6 | Viewed by 3203

Abstract

Background: Pancreatic cancer is a catastrophic disease with high recurrence and death rates, even in early stages. Early detection and early treatment improve survival in many cancer types but have not yet been clearly documented to do so in pancreatic cancer. In [...] Read more.

Background: Pancreatic cancer is a catastrophic disease with high recurrence and death rates, even in early stages. Early detection and early treatment improve survival in many cancer types but have not yet been clearly documented to do so in pancreatic cancer. In this study, we assessed the benefit on survival resulting from different patterns of surveillance in daily practice after curative surgery of early pancreatic cancer. Methods: Patients with pancreatic ductal adenocarcinoma who had received curative surgery between January 2000 and December 2013 at our institute were retrospectively reviewed. Patients were classified into one of four groups, based on surveillance strategy: the symptom group, the imaging group, the marker group (carbohydrate antigen 19-9 and/or carcinoembryonic antigen), and the intense group (both imaging and tumor marker assessment). Overall survival (OS), relapse-free survival (RFS), and post-recurrence overall survival (PROS) were evaluated. Results: One hundred and eighty-one patients with documented recurrence or metastasis were included in our analysis. The median OS for patients in the symptom group, imaging group, marker group, and intense group were 21.4 months, 13.9 months, 20.5 months, and 16.5 months, respectively (p = 0.670). Surveillance with imaging, tumor markers, or both was not an independent risk factor for OS in univariate and multivariate analyses. There was no significant difference in median RFS (symptom group, 11.7 months; imaging group, 6.3 months; marker group, 9.3 months; intense group, 6.9 months; p = 0.259) or median PROS (symptom group, 6.9 months; imaging group, 7.5 months; marker group, 5.0 months; intense group, 7.8 months; p = 0.953) between the four groups. Multivariate analyses identified poor Eastern Cooperative Oncology Group Performance Status (ECOG PS) (≥1), primary tumor site (tail), and tumor grade (poor differentiation) were poor prognostic factors for OS. Conclusions: Surveillance with regular imaging, tumor marker, or both was not an independent risk factor for OS of pancreatic cancer patients who undergo curative tumor resection. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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10 pages, 859 KiB

Open AccessArticle

Second-Line Gemcitabine Plus Nab-Paclitaxel for Patients with Unresectable Advanced Pancreatic Cancer after First-Line FOLFIRINOX Failure

by Naoki Mita, Takuji Iwashita, Shinya Uemura, Kensaku Yoshida, Yuhei Iwasa, Nobuhiro Ando, Keisuke Iwata, Mitsuru Okuno, Tsuyoshi Mukai and Masahito Shimizu

J. Clin. Med. 2019, 8(6), 761; https://doi.org/10.3390/jcm8060761 - 29 May 2019

Cited by 33 | Viewed by 4654

Abstract

FOLFIRINOX (FX) and gemcitabine (GEM) plus nab-paclitaxel (GnP) have been reported as effective regimens for unresectable advanced pancreatic cancer (APC). FX may be more effective but is also associated with more adverse events (AEs). Therefore, first-line treatment with FX followed by second-line GnP [...] Read more.

FOLFIRINOX (FX) and gemcitabine (GEM) plus nab-paclitaxel (GnP) have been reported as effective regimens for unresectable advanced pancreatic cancer (APC). FX may be more effective but is also associated with more adverse events (AEs). Therefore, first-line treatment with FX followed by second-line GnP may be appropriate. Aims: To assess the safety and efficacy of second-line GnP for patients with APC after first-line FX failure. Methods: This study was a multicenter prospective phase II study evaluating second-line GnP in patients with APC after failed first-line FX. The primary endpoint was response rate (RR), and the secondary endpoints were overall survival (OS), progression free survival (PFS), and the frequency and degree of adverse events (AEs). Results: Thirty patients (14 male; median age, 64 years) were enrolled. The RR was 13.3%, with a median follow-up time of 9.3 months. The median OS and PFS were 7.6 and 3.8 months, respectively. From the beginning of first-line treatment, the median OS and PFS were 14.2 and 9.3 months, respectively. Grade 3 or 4 AEs were seen in 70% of patients. Conclusion: Second-line GnP after FX failure for patients with APC could be more effective than GEM alone. Further comparison studies are warranted. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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14 pages, 730 KiB

Open AccessArticle

XPO1 Expression Is a Poor-Prognosis Marker in Pancreatic Adenocarcinoma

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

J. Clin. Med. 2019, 8(5), 596; https://doi.org/10.3390/jcm8050596 - 30 Apr 2019

Cited by 23 | Viewed by 3412

Abstract

Pancreatic adenocarcinoma (PAC) is one of the most aggressive human cancers and new systemic therapies are urgently needed. Exportin-1 (XPO1), which is a member of the importin-β superfamily of karyopherins, is the major exporter of many tumor suppressor proteins that are involved in [...] Read more.

Pancreatic adenocarcinoma (PAC) is one of the most aggressive human cancers and new systemic therapies are urgently needed. Exportin-1 (XPO1), which is a member of the importin-β superfamily of karyopherins, is the major exporter of many tumor suppressor proteins that are involved in the progression of PAC. Promising pre-clinical data using XPO1 inhibitors have been reported in PAC, but very few data are available regarding XPO1 expression in clinical samples. Retrospectively, we analyzed XPO1 mRNA expression in 741 pancreatic samples, including 95 normal, 73 metastatic and 573 primary cancers samples, and searched for correlations with clinicopathological and molecular data, including overall survival. XPO1 expression was heterogeneous across the samples, higher in metastatic samples than in the primary tumors, and higher in primaries than in the normal samples. “XPO1-high” tumors were associated with positive pathological lymph node status and aggressive molecular subtypes. They were also associated with shorter overall survival in both uni- and multivariate analyses. Supervised analysis between the “XPO1-high” and “XPO1-low” tumors identified a robust 268-gene signature, whereby ontology analysis suggested increased XPO1 activity in the “XPO1-high” tumors. XPO1 expression refines the prognostication in PAC and higher expression exists in secondary versus primary tumors, which supports the development of XPO1 inhibitors in this so-lethal disease. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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18 pages, 5177 KiB

Open AccessArticle

Elevated Serum Interleukin-8 Level Correlates with Cancer-Related Cachexia and Sarcopenia: An Indicator for Pancreatic Cancer Outcomes

by Ya-Chin Hou, Chih-Jung Wang, Ying-Jui Chao, Hao-Yun Chen, Hao-Chen Wang, Hui-Ling Tung, Jung-Ting Lin and Yan-Shen Shan

J. Clin. Med. 2018, 7(12), 502; https://doi.org/10.3390/jcm7120502 - 01 Dec 2018

Cited by 65 | Viewed by 5516

Abstract

Cancer cachexia (CC), characterized by body weight loss and sarcopenia, contributes to over 20% of all cancer-related death. Approximately 80% of pancreatic cancer (PC) patients develop CC during disease progression. Pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, have [...] Read more.

Cancer cachexia (CC), characterized by body weight loss and sarcopenia, contributes to over 20% of all cancer-related death. Approximately 80% of pancreatic cancer (PC) patients develop CC during disease progression. Pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, have been correlated with CC; however, its prognostic significance remains unclear. In this study, serum levels of the CC-related cytokines were determined in normal donors and PC patients. IL-8 expression was assessed in PC tissue microarrays. The correlation of levels of each cytokine with disease progression, weight loss, and sarcopenia was calculated. The relationships among the baseline variables, CC, and IL-8 expression with disease progression were examined using univariate and multivariate analyses. Of these mentioned cytokines, only serum IL-8 level was elevated in the locally advanced group (n = 55) compared with the normal (n = 17) and resected groups (n = 55). Serum IL-8 level was positively correlated with CC status, weight loss, sarcopenia, but was negatively correlated with total psoas area (TPA). IL-8 expression in tissue samples was also positively associated with weight loss. Furthermore, serum IL-8 level was an independent predictor of survival. In conclusion, elevated serum IL-8 level significantly correlates with CC and sarcopenia and can be used as a prognostic indicator in PC. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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13 pages, 465 KiB

Open AccessArticle

The Combination of MiRNA-196b, LCN2, and TIMP1 is a Potential Set of Circulating Biomarkers for Screening Individuals at Risk for Familial Pancreatic Cancer

by Detlef K. Bartsch, Norman Gercke, Konstantin Strauch, Ronja Wieboldt, Elvira Matthäi, Vinona Wagner, Susanne Rospleszcz, Agnes Schäfer, Frederike S. Franke, Ioannis Mintziras, Christian Bauer, Tobias Grote, Jens Figiel, Pietro Di Fazio, Andreas Burchert, Silke Reinartz, Elke Pogge von Strandmann, Günter Klöppel and Emily P. Slater

J. Clin. Med. 2018, 7(10), 295; https://doi.org/10.3390/jcm7100295 - 20 Sep 2018

Cited by 30 | Viewed by 4618

Abstract

Individuals at risk (IAR) of familial pancreatic cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were [...] Read more.

Individuals at risk (IAR) of familial pancreatic cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were analyzed in 218 individuals with sporadic pancreatic ductal adenocarcinoma (PDAC, n = 50), FPC (n = 20), chronic pancreatitis (n = 10), IAR with relevant precursor lesions (n = 11) or non-relevant lesions (n = 5), 20 controls, and IAR with (n = 51) or without (n = 51) lesions on pancreatic imaging. In addition, corresponding duodenal juice samples were analyzed for Glypican-1 (n = 144) enrichment and KRAS mutations (n = 123). The panel miR-196b/LCN2/TIMP1 could distinguish high-grade lesions and stage I PDAC from controls with absolute specificity and sensitivity. In contrast, Glypican-1 enrichment in serum exosomes and duodenal juice was not diagnostic. KRAS mutations in duodenal juice were detected in 9 of 12 patients with PDAC and only 4 of 9 IAR with relevant precursor lesions. IAR with lesions on imaging had elevated miR-196b/LCN2/TIMP1 levels (p = 0.0007) and KRAS mutations in duodenal juice (p = 0.0004) significantly more often than IAR without imaging lesions. The combination miR-196b/LCN2/TIMP1 might be a promising biomarker set for the detection of high-grade PDAC precursor lesions in IAR of FPC families. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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Review

Jump to: Research

13 pages, 1809 KiB

Open AccessReview

Molecular Subtyping and Precision Medicine for Pancreatic Cancer

by Fieke E. M. Froeling, Raffaella Casolino, Antonio Pea, Andrew V. Biankin, David K. Chang and on behalf of Precision-Panc

J. Clin. Med. 2021, 10(1), 149; https://doi.org/10.3390/jcm10010149 - 04 Jan 2021

Cited by 28 | Viewed by 4875

Abstract

Substantial progress in recent years has dramatically increased our knowledge of the molecular basis of cancer, revealing new potential therapeutic targets and paving the way for effective personalised medicine for the treatment of many tumour types. However, pancreatic cancer has been lagging behind [...] Read more.

Substantial progress in recent years has dramatically increased our knowledge of the molecular basis of cancer, revealing new potential therapeutic targets and paving the way for effective personalised medicine for the treatment of many tumour types. However, pancreatic cancer has been lagging behind in this success and continues to be one of the most lethal solid malignancies. Its molecular heterogeneity and the unselected design of the majority of clinical trials to date can in part explain the reason for our failure to make a significant change in the survival outcomes for patients with pancreatic cancer. A changing paradigm in drug development is required to validate the new molecular taxonomy and to rapidly translate preclinical discovery into clinical trials. Here, we review the molecular subtyping of pancreatic cancer, the challenges in identifying effective treatment regimens according to defined low-prevalence molecular subgroups and we illustrate a new model of translational therapeutic development that was established in the U.K. (Precision-Panc) as a potentially effective solution to improve outcomes for patients with pancreatic cancer. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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18 pages, 5112 KiB

Open AccessReview

Conversion Surgery for Advanced Pancreatic Cancer

by Thomas Hank and Oliver Strobel

J. Clin. Med. 2019, 8(11), 1945; https://doi.org/10.3390/jcm8111945 - 12 Nov 2019

Cited by 19 | Viewed by 3539

Abstract

While primarily unresectable locally advanced pancreatic cancer (LAPC) used to be an indication for palliative therapy, a strategy of neoadjuvant therapy (NAT) and conversion surgery is being increasingly used after more effective chemotherapy regimens have become available for pancreatic ductal adenocarcinoma. While high-level [...] Read more.

While primarily unresectable locally advanced pancreatic cancer (LAPC) used to be an indication for palliative therapy, a strategy of neoadjuvant therapy (NAT) and conversion surgery is being increasingly used after more effective chemotherapy regimens have become available for pancreatic ductal adenocarcinoma. While high-level evidence from prospective studies is still sparse, several large retrospective studies have recently reported their experience with NAT and conversion surgery for LAPC. This review aims to provide a current overview about different NAT regimens, conversion rates, survival outcomes and determinants of post-resection outcomes, as well as surgical strategies in the context of conversion surgery after NAT. FOLFIRINOX is the predominant regimen used and associated with the highest reported conversion rates. Conversion rates considerably vary between less than 5% and more than half of the study population with heterogeneous long-term outcomes, owing to a lack of intention-to-treat analyses in most studies and a high heterogeneity in resectability criteria, treatment strategies, and reporting among studies. Since radiological criteria of local resectability are no longer applicable after NAT, patients without progressive disease should undergo surgical exploration. Surgery after NAT has to be aimed at local radicality around the peripancreatic vessels and should be performed in expert centers. Future studies in this rapidly evolving field need to be prospective, analyze intention-to-treat populations, report stringent and objective inclusion criteria and criteria for resection. Innovative regimens for NAT in combination with a radical surgical approach hold high promise for patients with LAPC in the future. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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13 pages, 275 KiB

Open AccessReview

Are We Sure that Adjuvant Chemotherapy is the Best Approach for Resectable Pancreatic Cancer? Are We in the Era of Neoadjuvant Treatment? A Review of Current Literature

by Ester Oneda and Alberto Zaniboni

J. Clin. Med. 2019, 8(11), 1922; https://doi.org/10.3390/jcm8111922 - 08 Nov 2019

Cited by 23 | Viewed by 2873

Abstract

The outcome of pancreatic cancer is poor, with a 9% 5-year survival rate. Current treatment recommendations in the 10%–20% of patients who present with resectable disease support upfront resection followed by adjuvant therapy. Until now, only early complete surgical (R0) resection and adjuvant [...] Read more.

The outcome of pancreatic cancer is poor, with a 9% 5-year survival rate. Current treatment recommendations in the 10%–20% of patients who present with resectable disease support upfront resection followed by adjuvant therapy. Until now, only early complete surgical (R0) resection and adjuvant chemotherapy (AC) with either FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or nab-paclitaxel plus gemcitabine have been shown to prolong the survival. However, up to 30% of patients do not receive adjuvant therapy because of the development of early recurrence, postoperative complications, comorbidities, and reduced performance status. The aims of neoadjuvant chemotherapy (NAC) are to identify rapidly progressing patients to avoid futile surgery, eliminate micrometastases, increase the feasibility of R0 resection, and ensure the completion of multimodal treatment. Neoadjuvant treatments are effective, but there is no consensus on their use in resectable pancreatic cancer (RPC) because of its lack of a survival benefit over adjuvant therapy. In this review, we analyze the advantages and disadvantages of the two therapeutic approaches in RPC. We need studies that compare the two approaches and can identify the appropriate sequence of adjuvant therapy after neoadjuvant treatment and surgery. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

10 pages, 767 KiB

Open AccessReview

Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune “Defects” in the Tumor Microenvironment

by Sireesha Upadhrasta and Lei Zheng

J. Clin. Med. 2019, 8(9), 1472; https://doi.org/10.3390/jcm8091472 - 16 Sep 2019

Cited by 51 | Viewed by 3997

Abstract

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed [...] Read more.

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed with the treatment of pancreatic cancer and all other immunogenic “cold” tumors. This prompts the need for a better understanding of the complexity of the cold tumor microenvironment (TME) of pancreatic cancer and what are truly the “defects” in the TME making the cancer unresponsive to immune checkpoint inhibitors. Here we discuss four major immune defects that can be recognized in pancreatic cancer, including lack of high-quality effector intratumoral T cells, heterogeneous dense stroma as a barrier to effector immune cells infiltrating into the tumor, immunosuppressive tumor microenvironment, and failure of the T cells to accomplish tumor elimination. We also discuss potential strategies for pancreatic cancer treatment that work by correcting these immune defects. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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16 pages, 736 KiB

Open AccessReview

Environmental Risk Factors of Pancreatic Cancer

by Hui-Jen Tsai and Jeffrey S. Chang

J. Clin. Med. 2019, 8(9), 1427; https://doi.org/10.3390/jcm8091427 - 10 Sep 2019

Cited by 33 | Viewed by 5109

Abstract

Despite the advancement in medical knowledge that has improved the survival rate of many cancers, the survival rate of pancreatic cancer has remained dismal with a five-year survival rate of only 9%. The poor survival of pancreatic cancer emphasizes the urgent need to [...] Read more.

Despite the advancement in medical knowledge that has improved the survival rate of many cancers, the survival rate of pancreatic cancer has remained dismal with a five-year survival rate of only 9%. The poor survival of pancreatic cancer emphasizes the urgent need to identify the causes or the risk factors of pancreatic cancer in order to establish effective preventive strategies. This review summarizes the current evidence regarding the environmental (non-genetic, including lifestyle, and clinical factors) risk factors of pancreatic cancer. Based on the current evidence, the established risk factors of pancreatic cancer are cigarette smoking, chronic diabetes, and obesity. Other strong risk factors include low consumption of fruits and vegetables, excess consumption of alcohol, poor oral hygiene, and the lack of allergy history. In the future, more studies are needed to identify additional risk factors of pancreatic cancer, especially the modifiable risk factors that could be included in a public health campaign to educate the public in order to reduce the incidence of pancreatic cancer. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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25 pages, 2529 KiB

Open AccessReview

The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

by Ching-Chieh Weng, Yu-Chun Lin and Kuang-Hung Cheng

J. Clin. Med. 2019, 8(9), 1369; https://doi.org/10.3390/jcm8091369 - 02 Sep 2019

Cited by 7 | Viewed by 3857

Abstract

Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival. Reflecting on the history of failed clinical trials, genetically engineered mouse models (GEMMs) in oncology research provides the inspiration to discover new treatments [...] Read more.

Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival. Reflecting on the history of failed clinical trials, genetically engineered mouse models (GEMMs) in oncology research provides the inspiration to discover new treatments for pancreatic cancer that come from better knowledge of pathogenesis mechanisms, not only of the derangements in and consequently acquired capabilities of the cancer cells, but also in the aberrant microenvironment that becomes established to support, sustain, and enhance neoplastic progression. On the other hand, the existing mutational profile of pancreatic cancer guides our understanding of the disease, but leaves many important questions of pancreatic cancer biology unanswered. Over the past decade, a series of transgenic and gene knockout mouse modes have been produced that develop pancreatic cancers with features reflective of metastatic pancreatic ductal adenocarcinoma (PDAC) in humans. Animal models of PDAC are likely to be essential to understanding the genetics and biology of the disease and may provide the foundation for advances in early diagnosis and treatment. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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13 pages, 1440 KiB

Open AccessReview

Contemporary Review of Borderline Resectable Pancreatic Ductal Adenocarcinoma

by Morgan Bonds and Flavio G. Rocha

J. Clin. Med. 2019, 8(8), 1205; https://doi.org/10.3390/jcm8081205 - 12 Aug 2019

Cited by 8 | Viewed by 3138

Abstract

Borderline resectable pancreatic adenocarcinoma (PDAC) presents challenges in definition and treatment. Many different definitions exist for this disease. Some are based on anatomy alone, while others include factors such as disease biology and patient performance status. Regardless of definition, evidence suggests that borderline [...] Read more.

Borderline resectable pancreatic adenocarcinoma (PDAC) presents challenges in definition and treatment. Many different definitions exist for this disease. Some are based on anatomy alone, while others include factors such as disease biology and patient performance status. Regardless of definition, evidence suggests that borderline resectable PDAC is a systemic disease at the time of diagnosis. There is high-level evidence to support the use of neoadjuvant systemic therapy in these cases. Evidence to support the use of radiation therapy is ongoing. There are ongoing trials investigating the available neoadjuvant therapies for borderline resectable PDAC that may provide clarity in the future. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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22 pages, 2222 KiB

Open AccessReview

New Era of Endoscopic Ultrasound-Guided Tissue Acquisition: Next-Generation Sequencing by Endoscopic Ultrasound-Guided Sampling for Pancreatic Cancer

by Hiroshi Imaoka, Mitsuhito Sasaki, Yusuke Hashimoto, Kazuo Watanabe and Masafumi Ikeda

J. Clin. Med. 2019, 8(8), 1173; https://doi.org/10.3390/jcm8081173 - 05 Aug 2019

Cited by 27 | Viewed by 4881

Abstract

Pancreatic cancer is a lethal cancer with an increasing incidence. Despite improvements in chemotherapy, patients with pancreatic cancer continue to face poor prognoses. Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is the primary method for obtaining tissue samples of pancreatic cancer. Due to advancements in [...] Read more.

Pancreatic cancer is a lethal cancer with an increasing incidence. Despite improvements in chemotherapy, patients with pancreatic cancer continue to face poor prognoses. Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is the primary method for obtaining tissue samples of pancreatic cancer. Due to advancements in next-generation sequencing (NGS) technologies, multiple parallel sequencing can be applied to EUS-TA samples. Genomic biomarkers for therapeutic stratification in pancreatic cancer are still lacking, however, NGS can unveil potential predictive genomic biomarkers of treatment response. Thus, the importance of NGS using EUS-TA samples is becoming recognized. In this review, we discuss the recent advances in EUS-TA application for NGS of pancreatic cancer. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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12 pages, 233 KiB

Open AccessReview

Paradigm Shifting of Systemic Chemotherapy for Unresectable Pancreatic Cancer in Japan

by Junji Furuse

J. Clin. Med. 2019, 8(8), 1170; https://doi.org/10.3390/jcm8081170 - 04 Aug 2019

Cited by 3 | Viewed by 3169

Abstract

Systemic chemotherapy plays an important role in the treatment of pancreatic cancer, to improve the survival of patients with pancreatic cancer. Unresectable pancreatic cancer can be classified into three categories: metastatic, locally advanced, and hereditary pancreatic cancers. Furthermore, the second-line chemotherapy is required [...] Read more.

Systemic chemotherapy plays an important role in the treatment of pancreatic cancer, to improve the survival of patients with pancreatic cancer. Unresectable pancreatic cancer can be classified into three categories: metastatic, locally advanced, and hereditary pancreatic cancers. Furthermore, the second-line chemotherapy is required to prolong the survival. The combined regimens of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GEM plus nab-PTX) have been recognized as the standard of care for advanced pancreatic cancer. However, the consensus of selection of the first-line chemotherapy still remains. Randomized controlled trials (RCTs) between FOLFIRINOX and GEM plus nab-PTX are ongoing for locally advanced and metastatic disease in Japan, respectively. Hereditary pancreatic cancer, especially associated with BRCA mutations, is responsive to platinum-containing regimens and/or poly (ADP-ribose) polymerase (PARP) inhibitors. It is becoming more important to examine the presence/absence of BRCA mutations to select the appropriate treatment strategy for individual patients. Although some S-1-based regimens have been investigated in the second-line treatment after GEM-based chemotherapy in Japan, no regime demonstrated survival benefit. Nanoliposomal irinotecan (nal-IRI) plus FF has been established as the standard of care in the second-line treatment in a global phase III trial (NAPOLI-1). A randomized phase II trial comparing FF plus nal-IRI with FF alone was also conducted in Japan to examine the efficacy and safety of the FF plus nal-IRI in Japanese patients. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

14 pages, 2112 KiB

Open AccessReview

Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication

by Yu-Hsuan Hung, Ming-Chuan Hsu, Li-Tzong Chen, Wen-Chun Hung and Mei-Ren Pan

J. Clin. Med. 2019, 8(6), 903; https://doi.org/10.3390/jcm8060903 - 24 Jun 2019

Cited by 16 | Viewed by 4880

Abstract

The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms [...] Read more.

The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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24 pages, 3556 KiB

Open AccessReview

Next Viable Routes to Targeting Pancreatic Cancer Stemness: Learning from Clinical Setbacks

by Kelvin K. Tsai, Tze-Sian Chan and Yuval Shaked

J. Clin. Med. 2019, 8(5), 702; https://doi.org/10.3390/jcm8050702 - 17 May 2019

Cited by 13 | Viewed by 3571

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating and highly aggressive malignancy. Existing therapeutic strategies only provide a small survival benefit in patients with PDAC. Laboratory and clinical research have identified various populations of stem-cell-like cancer cells or cancer stem cells (CSCs) as the [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating and highly aggressive malignancy. Existing therapeutic strategies only provide a small survival benefit in patients with PDAC. Laboratory and clinical research have identified various populations of stem-cell-like cancer cells or cancer stem cells (CSCs) as the driving force of PDAC progression, treatment-resistance, and metastasis. Whilst a number of therapeutics aiming at inhibiting or killing CSCs have been developed over the past decade, a series of notable clinical trial setbacks have led to their deprioritization from the pipelines, triggering efforts to refine the current CSC model and exploit alternative therapeutic strategies. This review describes the current and the evolving models of pancreatic CSCs (panCSCs) and the potential factors that hamper the clinical development of panCSC-targeted therapies, emphasizing the heterogeneity, the plasticity, and the non-binary pattern of cancer stemness, as well as the desmoplastic stroma impeding drug penetration. We summarized novel and promising therapeutic strategies implicated by the works of our groups and others’ that may overcome these hurdles and have shown efficacies in preclinical models of PDAC, emphasizing the unique advantages of targeting the stroma-engendered panCSC-niches and metronomic chemotherapy. Finally, we proposed feasible clinical trial strategies and biomarkers that can guide the next-generation clinical trials. Full article

(This article belongs to the Special Issue Current Standards and New Innovative Approaches for Treatment of Pancreatic Cancer)

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