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1
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Bangolo AI, Trivedi C, Jani I, Pender S, Khalid H, Alqinai B, Intisar A, Randhawa K, Moore J, De Deugd N, Faisal S, Suresh SB, Gopani P, Nagesh VK, Proverbs-Singh T, Weissman S. Impact of gut microbiome in the development and treatment of pancreatic cancer: Newer insights. World J Gastroenterol 2023; 29:3984-3998. [PMID: 37476590 PMCID: PMC10354587 DOI: 10.3748/wjg.v29.i25.3984] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 05/24/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
The gut microbiome plays an important role in the variation of pharmacologic response. This aspect is especially important in the era of precision medicine, where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy. The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research. Pancreatic adenocarcinoma (PAC) has a poor prognosis even in those with potentially resectable disease, and treatment options are very limited. Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs, in the treatment of PAC. A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC. This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.
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Affiliation(s)
- Ayrton I Bangolo
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Chinmay Trivedi
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Ishan Jani
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Silvanna Pender
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Hirra Khalid
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Budoor Alqinai
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Alina Intisar
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Karamvir Randhawa
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Joseph Moore
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Nicoleta De Deugd
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shaji Faisal
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Suchith Boodgere Suresh
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Parva Gopani
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Vignesh K Nagesh
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Tracy Proverbs-Singh
- Department of Gastrointestinal Malignancies, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Simcha Weissman
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
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Halle-Smith JM, Powell-Brett SF, Hall LA, Duggan SN, Griffin O, Phillips ME, Roberts KJ. Recent Advances in Pancreatic Ductal Adenocarcinoma: Strategies to Optimise the Perioperative Nutritional Status in Pancreatoduodenectomy Patients. Cancers (Basel) 2023; 15:cancers15092466. [PMID: 37173931 PMCID: PMC10177139 DOI: 10.3390/cancers15092466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy for which the mainstay of treatment is surgical resection, followed by adjuvant chemotherapy. Patients with PDAC are disproportionately affected by malnutrition, which increases the rate of perioperative morbidity and mortality, as well as reducing the chance of completing adjuvant chemotherapy. This review presents the current evidence for pre-, intra-, and post-operative strategies to improve the nutritional status of PDAC patients. Such preoperative strategies include accurate assessment of nutritional status, diagnosis and appropriate treatment of pancreatic exocrine insufficiency, and prehabilitation. Postoperative interventions include accurate monitoring of nutritional intake and proactive use of supplementary feeding methods, as required. There is early evidence to suggest that perioperative supplementation with immunonutrition and probiotics may be beneficial, but further study and understanding of the underlying mechanism of action are required.
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Affiliation(s)
- James M Halle-Smith
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK
| | - Sarah F Powell-Brett
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK
| | - Lewis A Hall
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK
| | - Sinead N Duggan
- Department of Surgery, Trinity College Dublin, University of Dublin, Tallaght University Hospital, D24 NR0A Dublin, Ireland
| | - Oonagh Griffin
- Department of Nutrition and Dietetics, St. Vincent's University Hospital, D04 T6F4 Dublin, Ireland
| | - Mary E Phillips
- Department of Nutrition and Dietetics, Royal Surrey County Hospital, Guildford GU2 7XX, UK
| | - Keith J Roberts
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK
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KARAYİĞİT A, ÖZDEMİR DB, DİZEN H, ÜNAL B. Factors independently associated with prognosis in patients operated for pancreatic cancer: Assessing the role of various parameters including red cell distribution width, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. JOURNAL OF HEALTH SCIENCES AND MEDICINE 2022. [DOI: 10.32322/jhsm.1137856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Objective: We aimed to assess whether, among other parameters, preoperative red cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) values were associated with prognosis in patients operated for pancreatic cancer (PC).
Material and Method: This retrospective cohort was conducted from February 1, 2016 to February 1, 2021 at the general surgery department of a university hospital in Turkey. A total of 75 patients histologically diagnosed with PC who had undergone surgery were included in the study.
Results: The PLR values of patients with poorly differentiated and undifferentiated tumors were found to be higher than those with moderately and highly differentiated tumors. Also, there was a significant relationship between PLR values and the length of hospital stay. PLR values increased as the length of hospital stay increased. There was a statistically significant positive correlation between CA 19-9 levels and NLR and PLR. High total bilirubin level was related with increased risk of death, while adjuvant chemotherapy recipients had 4.049-fold lower risk of death than those without adjuvant chemotherapy.
Conclusion: Our results indicate that preoperative NLR, PLR and RDW cannot be used as prognostic indicators of mortality in patients with operated PC, but high PLR appears to be associated with lower level of tumor differentiation and prolonged hospital stay. We also found that high total bilirubin was a poor prognostic factor, while adjuvant chemotherapy was a good prognostic factor. Further multicenter, prospective studies with larger sample sizes will help to verify these results.
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Affiliation(s)
- Ahmet KARAYİĞİT
- ADANA ŞEHİR EĞİTİM VE ARAŞTIRMA HASTANESİ, CERRAHİ ONKOLOJİ KLİNİĞİ
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Agarwal D, Covarrubias-Zambrano O, Bossmann SH, Natarajan B. Early Detection of Pancreatic Cancers Using Liquid Biopsies and Hierarchical Decision Structure. IEEE JOURNAL OF TRANSLATIONAL ENGINEERING IN HEALTH AND MEDICINE 2022; 10:4300208. [PMID: 35937463 PMCID: PMC9342860 DOI: 10.1109/jtehm.2022.3186836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/30/2022] [Accepted: 06/23/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE Pancreatic cancer (PC) is a silent killer, because its detection is difficult and to date no effective treatment has been developed. In the US, the current 5-year survival rate of 11%. Therefore, PC has to be detected as early as possible. METHODS AND PROCEDURES In this work, we have combined the use of ultrasensitive nanobiosensors for protease/arginase detection with information fusion based hierarchical decision structure to detect PC at the localized stage by means of a simple Liquid Biopsy. The problem of early-stage detection of pancreatic cancer is modelled as a multi-class classification problem. We propose a Hard Hierarchical Decision Structure (HDS) along with appropriate feature engineering steps to improve the performance of conventional multi-class classification approaches. Further, a Soft Hierarchical Decision Structure (SDS) is developed to additionally provide confidences of predicted labels in the form of class probability values. These frameworks overcome the limitations of existing research studies that employ simple biostatistical tools and do not effectively exploit the information provided by ultrasensitive protease/arginase analyses. RESULTS The experimental results demonstrate that an overall mean classification accuracy of around 92% is obtained using the proposed approach, as opposed to 75% with conventional multi-class classification approaches. This illustrates that the proposed HDS framework outperforms traditional classification techniques for early-stage PC detection. CONCLUSION Although this study is only based on 31 pancreatic cancer patients and a healthy control group of 48 human subjects, it has enabled combining Liquid Biopsies and Machine Learning methodologies to reach the goal of earliest PC detection. The provision of both decision labels (via HDS) as well as class probabilities (via SDS) helps clinicians identify instances where statistical model-based predictions lack confidence. This further aids in determining if more tests are required for better diagnosis. Such a strategy makes the output of our decision model more interpretable and can assist with the diagnostic procedure. CLINICAL IMPACT With further validation, the proposed framework can be employed as a decision support tool for the clinicians to help in detection of pancreatic cancer at early stages.
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Affiliation(s)
- Deepesh Agarwal
- Department of Electrical and Computer EngineeringKansas State UniversityManhattanKS66506USA
| | | | - Stefan H. Bossmann
- Department of Cancer BiologyThe University of Kansas Medical CenterKansas CityKS66160USA
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Luu AM, Braumann C, Belyaev O, Janot-Matuschek M, Rudolf H, Praktiknjo M, Uhl W. Long-term survival after pancreaticoduodenectomy in patients with ductal adenocarcinoma of the pancreatic head. Hepatobiliary Pancreat Dis Int 2021; 20:271-278. [PMID: 33349608 DOI: 10.1016/j.hbpd.2020.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 12/02/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all malignant tumors due to unavailable screening methods, late diagnosis with a low proportion of resectable tumors and resistance to systemic treatment. Complete tumor resection remains the cornerstone of modern multimodal strategies aiming at long-term survival. This study was performed to investigate the overall rate of long-term survival (LTS) and its contributing factors. METHODS This was a retrospective single-center analysis of consecutive patients undergoing pancreaticoduodenectomy (PD) for PDAC between 2007 and 2014 at the St. Josef Hospital, Ruhr University Bochum, Germany. Clinical and laboratory parameters were assessed and evaluated for prediction of LTS with Cox regression analysis. RESULTS The overall rate of LTS after PD for PDAC was 20.4% (34/167). Median survival was 24 months regardless of adjuvant treatment. Carbohydrate antigen 19-9 levels, tumor grade, lymph vessel invasion, perineural invasion and reduced general condition were significantly associated with LTS in univariate analysis (P < 0.05). Serum levels of carbohydrate antigen 19-9, American Joint Committee on Cancer stage, tumor grade, abdominal pain, male, exocrine pancreatic insufficiency and duration of postoperative hospital stay were independent predictors of cancer survival in multivariable analysis. CONCLUSIONS Cancer related characteristics are associated with LTS in multimodally treated patients after curative PDAC surgery.
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Affiliation(s)
- Andreas Minh Luu
- Department of General and Visceral Surgery, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, Bochum 44791, Germany.
| | - Chris Braumann
- Department of General and Visceral Surgery, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, Bochum 44791, Germany
| | - Orlin Belyaev
- Department of General and Visceral Surgery, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, Bochum 44791, Germany
| | - Monika Janot-Matuschek
- Department of General and Visceral Surgery, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, Bochum 44791, Germany
| | - Henrik Rudolf
- Department of Medical Informatics, Biometry and Epidemiology, Ruhr University Bochum, Universitaetsstrasse 105, Bochum 44789, Germany
| | - Michael Praktiknjo
- Department of Internal Medicine, University of Bonn, Venusberg-Campus 1, Bonn 53127, Germany
| | - Waldemar Uhl
- Department of General and Visceral Surgery, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, Bochum 44791, Germany
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Li Y, Tian M, Zhou Y, Tan F, Liu W, Zhao L, Perez D, Song X, Wang D, Nitschke C, Pei Q, Güngör C. A novel risk-scoring system conducing to chemotherapy decision for patients with pancreatic ductal adenocarcinoma after pancreatectomy. J Cancer 2021; 12:4433-4442. [PMID: 34093844 PMCID: PMC8176415 DOI: 10.7150/jca.57768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 04/28/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Chemotherapy is suggested to use in all stages of pancreatic cancer. Is it reasonable to recommend chemotherapy for all PDAC patients? It is necessary to distinguish low-risk PDAC patients underwent pancreatectomy, who may not lose survival time due to missed chemotherapy and not need to endure pain, nausea, tiredness, drowsiness, and breath shortness caused by chemotherapy. Methods: Nomograms were constructed with basis from the multivariate Cox regression analysis. X-tile software was utilized to perform risk stratification. Survival curves were used to display the effect of chemotherapy in different risk-stratification. Results: All of the significant variables were used to create the nomograms for overall survival (OS). The total risk score of each patient was calculated by summing the scores related to each variable. X-tile software was utilized to classify patients into high-risk (score >283), median-risk (197
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Affiliation(s)
- Yuqiang Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mengxiang Tian
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Zhou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Fengbo Tan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wenxue Liu
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Lilan Zhao
- Department of Thoracic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Daniel Perez
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Xiangping Song
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Nitschke
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Qian Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Cenap Güngör
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Zhang Y, Xu G, Chen M, Wei Q, Zhou T, Chen Z, Shen M, Wang P. Stage IA Patients With Pancreatic Ductal Adenocarcinoma Cannot Benefit From Chemotherapy: A Propensity Score Matching Study. Front Oncol 2020; 10:1018. [PMID: 32766130 PMCID: PMC7379031 DOI: 10.3389/fonc.2020.01018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose: Adjuvant chemotherapy following resection is recommended by clinical practice guidelines for all patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the efficacy of adjuvant chemotherapy among the staging groups of the American Joint Committee on Cancer (AJCC) for PDAC. Patients and Methods: This retrospective cohort analysis was performed by the Surveillance Epidemiology and End Results (SEER) (2004–2015) database and multi-institutional dataset (2010–2018). Baseline clinicopathologic characteristics of PDAC patients, including age, gender, ethnicity, marital status, education level, county income level, county unemployed rate, insurance status, grade, stage, chemotherapy, and radiotherapy, were collected. Overall survival (OS) was analyzed using the Kaplan–Meier method. The SEER and multi-institutional data were adjusted with 1:1 ratio propensity score matching (PSM). Results: In total, 6,274 and 1,361 PDAC patients were included from the SEER database and multi-institutional dataset, respectively. Regardless of the count of resected lymph nodes, adjuvant chemotherapy prolonged the long-term OS time for stage IB, IIA, IIB, and III patients in both SEER and multi-institutional cohorts. Nevertheless, adjuvant chemotherapy did not provide additional clinical benefits even after a PSM adjustment for stage IA patients in both SEER and multi-institutional cohorts. Conclusion: Adjuvant chemotherapy improved the long-term survival of stage IB, IIA, IIB, and III PDAC patients; however, it demonstrated no survival benefit in stage IA PDAC patients. Thus, adjuvant chemotherapy should not be recommended for stage IA PDAC patients. These would significantly reduce the economic burden of society and improve the life quality of stage IA PDAC patients.
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Affiliation(s)
- Yuchao Zhang
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Gang Xu
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Maozhen Chen
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Qian Wei
- Department of Breast Surgery, XuZhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, China
| | - Tengteng Zhou
- Department of Breast Surgery, Xuzhou Maternal and Child Health Hospital, Xuzhou, China
| | - Ziliang Chen
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Mingyang Shen
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Ping Wang
- Vascular Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
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Parmar A, Chaves-Porras J, Saluja R, Perry K, Rahmadian AP, Santos SD, Ko YJ, Berry S, Doherty M, Chan KKW. Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis. Crit Rev Oncol Hematol 2019; 145:102817. [PMID: 31955005 DOI: 10.1016/j.critrevonc.2019.102817] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 09/30/2019] [Accepted: 10/02/2019] [Indexed: 02/07/2023] Open
Abstract
Adjuvant chemotherapy has significantly improved outcomes following surgical resection for pancreatic adenocarcinoma; however, the optimal adjuvant strategy remains unclear. This systematic review and network meta-analysis was conducted to provide indirect comparative evidence across adjuvant chemotherapies. Electronic searches of EMBASE, MEDLINE, Cochrane and ASCO databases were conducted to identify eligible randomized controlled trials (RCT). Direct pairwise meta-analysis was conducted for disease-free survival (DFS), overall-survival (OS) and adverse events (AE). Network meta-analysis of DFS and OS was conducted to evaluate indirect comparisons. Ten publications of eleven RCT met eligibility criteria. Indirect DFS comparison demonstrated superiority of mFOLFIRINOX versus gemcitabine-capecitabine, gemcitabine-erlotinib and gemcitabine-nab-paclitaxel. S-1 demonstrated a DFS benefit versus gemcitabine-capecitabine, gemcitabine-erlotinib, gemcitabine-nab-paclitaxel. OS benefits were demonstrated for mFOLFIRINOX verus gemcitabine-erlotinib and for S-1 versus gemcitabine-based combination with erlotinib, capecitabine and nab-paclitaxel. In conclusion, mFOLFIRINOX is the preferred approach for adjuvant therapy. For mFOLFIRINOX-ineligible patients no additional benefit is seen with gemcitabine-nab-paclitaxel.
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Affiliation(s)
- Ambica Parmar
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Jorge Chaves-Porras
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Ronak Saluja
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Kaitlyn Perry
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Amanda P Rahmadian
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | | | - Yoo-Joung Ko
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Scott Berry
- Kingston Health Sciences Centre, Queen's University, Kingston, ON, Canada
| | - Mark Doherty
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Kelvin K W Chan
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Canadian Centre for Applied Research in Cancer Control, Toronto, ON, Canada.
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Fenocchio E, Filippi R, Lombardi P, Quarà V, Milanesio M, Aimar G, Leone F, Aglietta M. Is There a Standard Adjuvant Therapy for Resected Pancreatic Cancer? Cancers (Basel) 2019; 11:E1547. [PMID: 31614884 PMCID: PMC6826876 DOI: 10.3390/cancers11101547] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/07/2019] [Accepted: 10/11/2019] [Indexed: 12/19/2022] Open
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 (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.
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Affiliation(s)
- Elisabetta Fenocchio
- Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
| | - Roberto Filippi
- Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
| | - Pasquale Lombardi
- Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
| | - Virginia Quarà
- Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
| | - Michela Milanesio
- Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
| | - Giacomo Aimar
- Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
| | - Francesco Leone
- Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
- Department of Oncology, Azienda Sanitaria Locale di Biella, 13875 Ponderano (BI), Italy.
| | - Massimo Aglietta
- Department of Oncology, University of Turin Medical School, Strada Provinciale 142, km 3.95, 10060 Candiolo (TO), Italy.
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Treatment of hepatic pancreatic ductal adenocarcinoma metastases with high-dose-rate image-guided interstitial brachytherapy: a single center experience. J Contemp Brachytherapy 2019; 11:329-336. [PMID: 31523233 PMCID: PMC6737574 DOI: 10.5114/jcb.2019.87269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/23/2019] [Indexed: 01/05/2023] Open
Abstract
Purpose To evaluate the efficacy and safety of image-guided (computed tomography/magnetic resonance imaging – CT/MRI) high-dose-rate (HDR) interstitial brachytherapy (iBT) as a salvage maneuver for the treatment of hepatic metastases originating from hepatic pancreatic ductal adenocarcinoma (PDAC). PDAC metastases present a major and unresolved problem, and any surgical approach or local therapeutic intervention remains extremely controversial. Material and methods A cumulative number of 45 hepatic PDAC metastases in 16 patients were treated and retrospectively analyzed. Synchronous metastatic spread was observed in five patients, metachronous in eleven. 14 patients had resection of the pancreatic primary prior to iBT: eight Whipple/PPPD and six distal pancreatectomy procedures. The hepatic metastases were progressing under chemotherapy, thus iBT was applied as a salvage maneuver with the intention of local tumor control and prolonged survival. iBT is applied interstitially, with temporarily introduced 192Ir source in a single fraction HDR irradiation regime to eradicate vital tumor cells. Response to treatment was assessed clinically with CT/MRI every three months. Results Local tumor control was achieved in 87% of all treated metastases. The median diameter of the irradiated lesions was 2.2 cm (range, 1-11.2 cm), the median irradiation dose was 21 Gy (range, 5-29.1 Gy). Median progression-free survival (PFS) after iBT was 3.4 months (range, 1.5-19.6 months), the median overall survival (OS) after iBT was 8.9 months (range, 3.1-29.3 months). Three major complications (CTCAE grade 3) occurred following iBT: three cases of liver abscess, which were successfully resolved with drainage and antibiotics. Conclusions Overall, iBT is a safe procedure, which enables excellent rates of local tumor control and presents a viable anti-neoplastic treatment option as a salvage therapy for metastatic PDAC patients.
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Shen P, Huang KJ, Zhang CZ, Xiao L, Zhang T. Surgery with adjuvant or neoadjuvant treatment vs surgery alone for resectable pancreatic cancer: A network meta-analysis. World J Meta-Anal 2019; 7:309-322. [DOI: 10.13105/wjma.v7.i6.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/04/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most common and lethal malignancies worldwide. The common treatment options for resectable pancreatic cancer include surgery alone, neoadjuvant chemotherapy (CT), neoadjuvant chemoradiotherapy (CRT), adjuvant CT, and adjuvant CRT. However, the optimal treatment is still controversial.
AIM To identify the most effective approach for pancreatic cancer using network meta-analysis.
METHODS Eligible studies were searched from PubMed, MEDLINE, EMBASE, Cochrane database, and Google scholar. We searched and included randomized controlled trials reporting on neoadjuvant and adjuvant therapies. For direct comparisons, standard pairwise meta-analysis was performed using the inverse variance DerSimonian-Laird random-effects model. For indirect comparisons, Bayesian network meta-analysis was used to combine direct and indirect evidence. We used relative hazard ratios (HRs) to estimate death difference of different treatments, and relative odds ratios (ORs) for toxic effects. Treatment effects were ranked based on their efficacy for improving survival or reducing toxicity using rankogram. The quality of evidence of estimates from direct comparison and network meta-analysis was evaluated following the GRADE approach.
RESULTS We included 13 high quality trials with 1591 participants in this network meta-analysis. Compared with surgery alone [pooled HR = 0.7, 95% confidence interval (CI): 0.62-0.79] and surgery with adjuvant CRT (pooled HR = 0.6, 95%CI: 0.54-0.72), surgery with adjuvant CT had a higher rate of overall survival. In contrast, standard pairwise meta-analysis showed a statistically significant survival advantage of surgery with adjuvant CT compared with surgery alone (pooled HR = 0.75, 95%CI: 0.63-0.89; P < 0.001). Rankogram showed that surgery with adjuvant CT was most likely to rank the best in terms of overall survival (probability: 94.2%), followed by surgery alone (probability: 5.8%). No significant differences in overall toxicity or haematological toxicity were found between all the therapies. High quality evidence supported surgery with adjuvant CT over surgery alone for increasing overall survival. Moderate quality evidence supported surgery with adjuvant CT over surgery with adjuvant CRT for increasing overall survival.
CONCLUSION Surgery with adjuvant CT prolongs overall survival compared with surgery alone and surgery with adjuvant CRT, suggesting surgery with adjuvant CT is the optimal treatment for resectable pancreatic cancer.
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Affiliation(s)
- Pu Shen
- Department of Anesthesia, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Kai-Jun Huang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Chuan-Zhao Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Li Xiao
- Department of Anesthesia, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Tao Zhang
- Department of Anesthesia, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
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12
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Fitzgerald TL, Hunter L, Mosquera C, Jindal C, Biswas T, Zervos E, Efird JT. A simple matrix to predict treatment success and long-term survival among patients undergoing pancreatectomy. HPB (Oxford) 2019; 21:204-211. [PMID: 30087052 DOI: 10.1016/j.hpb.2018.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 05/16/2018] [Accepted: 07/09/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND A more accurate measure of long-term survival among patients who have undergone a successful resection for pancreatic adenocarcinoma may be computed by accounting for time already survived during the initial treatment window. METHODS Patients diagnosed with pancreatic adenocarcinoma, from 2004 through 2013, were identified from the American College of Surgeons National Cancer Database (NCDB). A risk-stratification matrix was constructed including age, histopathologic factors and the use of adjuvant therapy, given successful treatment and survival at 3-month following diagnosis. RESULTS A total of 25,897 patients (50% male, 53% >65 years of age) presented with stage I-III pancreatic cancer. The majority of patients had tumors >2 cm size (82%), grade I/II (65%), lymphatic invasion (LI) (66%), and negative margins (76%). A survival advantage for adjuvant therapy was observed among all patients, independent of their risk-profile. For example, a patient ≤65 years of age, with early stage cancer (size ≤2 cm, grade I/II, -ve LI, -ve margins) who received adjuvant therapy had a 62% probability of being alive beyond three years (95%CI = 59%-66%). In contrast, the survival probability decreased to 53% (95%CI = 59%-66%) without adjuvant therapy. CONCLUSIONS These results provide surgeons and patients with more accurate information regarding long-term survival, as well as the benefit of opting for adjuvant therapy after successful pancreatic surgery.
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Affiliation(s)
| | - Lucas Hunter
- Department of Surgical Oncology, Brody School of Medicine, Greenville, NC, USA
| | - Catalina Mosquera
- Department of Surgical Oncology, Brody School of Medicine, Greenville, NC, USA; Vidant Cancer Care, Greenville, NC, USA
| | - Charulata Jindal
- Centre for Clinical Epidemiology and Biostatistics (CCEB), School of Medicine and Public Health, The University of Newcastle (UoN), Newcastle, 2308, Australia
| | - Tithi Biswas
- Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | | | - Jimmy T Efird
- Centre for Clinical Epidemiology and Biostatistics (CCEB), School of Medicine and Public Health, The University of Newcastle (UoN), Newcastle, 2308, Australia.
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13
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Huang L, Jansen L, Balavarca Y, van der Geest L, Lemmens V, Van Eycken L, De Schutter H, Johannesen TB, Primic-Žakelj M, Zadnik V, Mägi M, Pulte D, Schrotz-King P, Brenner H. Nonsurgical therapies for resected and unresected pancreatic cancer in Europe and USA in 2003-2014: a large international population-based study. Int J Cancer 2018; 143:3227-3239. [DOI: 10.1002/ijc.31628] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 04/21/2018] [Accepted: 05/17/2018] [Indexed: 01/01/2023]
Affiliation(s)
- Lei Huang
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
- Medical Faculty Heidelberg; Heidelberg University; Heidelberg Germany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Yesilda Balavarca
- Division of Preventive Oncology; German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT); Heidelberg Germany
| | - Lydia van der Geest
- Netherlands Cancer Registry (NCR), The Netherlands Comprehensive Cancer Organization (IKNL); Utrecht The Netherlands
| | - Valery Lemmens
- Netherlands Cancer Registry (NCR), The Netherlands Comprehensive Cancer Organization (IKNL); Utrecht The Netherlands
| | | | | | - Tom B. Johannesen
- Registry Department; The Cancer Registry of Norway (CRN); Oslo Norway
| | - Maja Primic-Žakelj
- Epidemiology and Cancer Registry; Institute of Oncology Ljubljana; Ljubljana Slovenia
| | - Vesna Zadnik
- Epidemiology and Cancer Registry; Institute of Oncology Ljubljana; Ljubljana Slovenia
| | - Margit Mägi
- Estonian Cancer Registry; National Institute for Health Development; Tallinn Estonia
| | - Dianne Pulte
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - Petra Schrotz-King
- Division of Preventive Oncology; German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT); Heidelberg Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ); Heidelberg Germany
- Division of Preventive Oncology; German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT); Heidelberg Germany
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14
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Kalubowilage M, Covarrubias-Zambrano O, Malalasekera AP, Wendel SO, Wang H, Yapa AS, Chlebanowski L, Toledo Y, Ortega R, Janik KE, Shrestha TB, Culbertson CT, Kasi A, Williamson S, Troyer DL, Bossmann SH. Early detection of pancreatic cancers in liquid biopsies by ultrasensitive fluorescence nanobiosensors. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 14:1823-1832. [PMID: 29782949 DOI: 10.1016/j.nano.2018.04.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/19/2018] [Accepted: 04/24/2018] [Indexed: 01/15/2023]
Abstract
Numerous proteases, such as matrix metalloproteinases (MMPs), cathepsins (CTS), and urokinase plasminogen activator (UpA), are dysfunctional (that is, over- or under-expressed) in solid tumors, when compared to healthy human subjects. This offers the opportunity to detect early tumors by liquid biopsies. This approach is of particular advantage for the early detection of pancreatic cancer, which is a "silent killer". We have developed fluorescence nanobiosensors for ultrasensitive (sub-femtomolar) arginase and protease detection, consisting of water-dispersible Fe/Fe3O4 core/shell nanoparticles and two tethered fluorescent dyes: TCPP (Tetrakis(4-carboxyphenyl)porphyrin) and cyanine 5.5. Upon posttranslational modification or enzymatic cleavage, the fluorescence of TCPP increases, which enables the detection of proteases at sub-femtomolar activities utilizing conventional plate readers. We have identified an enzymatic signature for the detection of pancreatic adenocarcinomas in serum, consisting of arginase, matrix metalloproteinase-1, -3, and - 9, cathepsin-B and -E, urokinase plasminogen activator, and neutrophil elastase, which is a potential game-changer.
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Affiliation(s)
| | | | | | - Sebastian O Wendel
- Department of Chemistry, Kansas State University, Manhattan, KS, USA; Department of Anatomy & Physiology, Kansas State University, Manhattan, KS, USA
| | - Hongwang Wang
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | - Asanka S Yapa
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | | | - Yubisela Toledo
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | - Raquel Ortega
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | - Katharine E Janik
- Department of Chemistry, Kansas State University, Manhattan, KS, USA
| | - Tej B Shrestha
- Department of Anatomy & Physiology, Kansas State University, Manhattan, KS, USA
| | | | - Anup Kasi
- University of Kansas Medical School, Kansas City, KS, USA
| | | | - Deryl L Troyer
- Department of Anatomy & Physiology, Kansas State University, Manhattan, KS, USA
| | - Stefan H Bossmann
- Department of Chemistry, Kansas State University, Manhattan, KS, USA.
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15
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Yu C, Chen S, Guo Y, Sun C. Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway. Am J Cancer Res 2018; 8:3224-3236. [PMID: 29930725 PMCID: PMC6010981 DOI: 10.7150/thno.23259] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 03/31/2018] [Indexed: 12/16/2022] Open
Abstract
Background: Drug resistance is well known as a major obstacle for cancer recurrence and treatment failure, leading to poor survival in pancreatic cancer, which is a highly aggressive tumor. Identifying effective strategies to overcome drug resistance would have a significant clinical impact for patients with pancreatic cancer. Methods: The protein and mRNA expression of TRIM31 in pancreatic cancer cell lines and patient tissues were determined using Real-time PCR and Western blot, respectively. 89 human pancreatic cancer tissue samples were analyzed by IHC to investigate the association between TRIM31 expression and the clinicopathological characteristics of pancreatic cancer patients. Functional assays, such as MTT, FACS, and Tunel assay used to determine the oncogenic role of TRIM31 in human pancreatic cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of TRIM31 promotes chemoresistance in pancreatic cancer cells. Results: The expression of TRIM31was markedly upregulated in pancreatic cancer cell lines and tissues, and high TRIM31 expression was associated with an aggressive phenotype and poor prognosis with pancreatic cancer patients. TRIM31 overexpression confers gemcitabine resistance on pancreatic cancer cells; however, inhibition of TRIM31 sensitized pancreatic cancer cell lines to gemcitabine cytotoxicity both in vitro and in vivo. Additionally, TRIM31 upregulated the levels of nuclear p65 by promoting K63-linked polyubiquitination of tumor necrosis factor receptor-associated factor 2 (TRAF2) and sustained the activation of nuclear transcription factor kappa B (NF-κB) in pancreatic cancer cells. Conclusions: Our findings provided evidence that TRIM31 is a potential therapeutic target for patients with pancreatic cancer. Targeting TRIM31 signaling may be a promising strategy to enhance gemcitabine response during pancreatic cancer chemo-resistance.
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16
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Li Z, Zou X, Zhu H, Chen M, Zhao Y. Inhibitory effect of baicalein combined with gemcitabine in human pancreatic cancer cell lines. Oncol Lett 2018; 15:5459-5464. [PMID: 29552186 PMCID: PMC5840621 DOI: 10.3892/ol.2018.8043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 11/02/2017] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is an aggressive disease with a particularly poor prognosis contributing to a substantial percentage of cancer-associated mortality rates. In the present study, the combination treatment of baicalein (BAI) and gemcitabine (GEM) was investigated to examine whether it inhibited the growth of the human CFPAC-1 pancreatic cancer cell line in vitro and in vivo. The cytotoxic interactions between BAI and GEM in human pancreatic cancer cell lines were determined using MTT assays, and the effect of the two agents on apoptosis was detected using Hoechst 33258 staining and annexin V/7-AAD. The protein levels of Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3, poly ADP ribose polymerase (PARP) and survivin were detected using western blot analysis. Furthermore, the expression levels of Bax, Bcl-2, caspase-3 and survivin in tumor tissues were detected using immunohistochemistry. The results demonstrated that following GEM treatment, the growth of CFPAC-1 cells and xenografts in nude mice were inhibited, and the expression levels of Bcl-2 and survivin were downregulated, whilst the expression levels of Bax, caspase-3 and PARP were upregulated. These effects were enhanced with the use of BAI in combination with GEM. The mechanism underlying the anti-tumor effect of BAI combined with GEM may be associated with the induction of cell apoptosis and the inhibition of proliferation. To the best of our knowledge, this is the first evidence of the efficacy of BAI against pancreatic cancer and may provide the potential clinical evidence for the use of this drug combination for the treatment of patients with pancreatic cancer.
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Affiliation(s)
- Zhenlei Li
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, P.R. China
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, P.R. China.,Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Hao Zhu
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Min Chen
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Yan Zhao
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
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17
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Deplanque G, Demartines N. Pancreatic cancer: are more chemotherapy and surgery needed? Lancet 2017; 389:985-986. [PMID: 28129986 DOI: 10.1016/s0140-6736(17)30126-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 11/30/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Gaël Deplanque
- Service d'Oncologie, Hôpital Riviera-Chablais, 1800 Vevey, Switzerland.
| | - Nicolas Demartines
- Service de Chirurgie Viscérale, Centre Hospitalier Universitaire Vaudois CHUV, 1011 Lausanne, Switzerland
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18
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Nayar P, Chandak A, Gupta N, Yu F, Qiu F, Ganti AK, Are C. Postoperative mortality following multi-modality therapy for pancreatic cancer: Analysis of the SEER-Medicare data. J Surg Oncol 2017; 115:158-163. [PMID: 28133817 DOI: 10.1002/jso.24472] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVES The objective of this study was to examine post-operative mortality for elderly pancreatic cancer patients treated with multi-modality therapy. METHODS Surveillance Epidemiology and End Results (SEER) Medicare linked data were used to examine differences in mortality between patients who underwent pancreatectomy alone and those who had early (within 12 weeks) and late (after 12 weeks) adjuvant therapy (chemotherapy and/or radiotherapy). RESULTS Among 4,105 patients who underwent pancreatectomy between 1991 and 2008, 1-year mortality (Odds Ratio [OR] = 0.71; P-value = 0.000; 95% Confidence Interval [CI]: 0.60-0.85) and 6-month mortality (OR = 0.44; P-value = 0.000; 95%CI: 0.35-0.53) following pancreatectomy were significantly lower in the group that underwent pancreatectomy with early adjuvant therapy. Late adjuvant therapy group also had lower 1 year (OR = 0.51; P-value = 0.000; 95%CI: 0.43-0.61) and 6 months (OR = 0.14; P-value = 0.000; 95%CI: 0.10-0.17) mortality, compared to surgery alone. CONCLUSIONS Post-operative outcomes were better for patients treated with surgery with adjuvant therapy, with the late adjuvant therapy group having the best outcomes (lowest odds of 6 month and 1-year mortality following surgery). J. Surg. Oncol. 2017;115:158-163. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Preethy Nayar
- Department of Health Services Research and Administration, University of Nebraska Medical Center, Omaha, Nebraska
| | - Aastha Chandak
- Department of Health Services Research and Administration, University of Nebraska Medical Center, Omaha, Nebraska
| | - Niodita Gupta
- Department of Health Services Research and Administration, University of Nebraska Medical Center, Omaha, Nebraska
| | - Fang Yu
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska
| | - Fang Qiu
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska
| | - Apar Kishor Ganti
- Division of Oncology-Hematology, VA-NWIHCS and University of Nebraska Medical Center, Omaha, Nebraska
| | - Chandrakanth Are
- Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska
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19
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Zhou Y, Song A, Wu L, Si X, Li Y. Second pancreatectomy for recurrent pancreatic ductal adenocarcinoma in the remnant pancreas: A pooled analysis. Pancreatology 2016; 16:1124-1128. [PMID: 27717684 DOI: 10.1016/j.pan.2016.09.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 09/13/2016] [Accepted: 09/29/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aim of this study was to examine the outcomes of second pancreatectomy for the treatment of recurrent pancreatic ductal adenocarcinoma (PDAC) in the remnant pancreas. METHOD Search of the PubMed database was undertaken to identify relevant English language studies. Pooled individually data were examined for clinical outcomes after second pancreatectomy for recurrent PDAC. RESULTS A total of 19 articles involving 55 patients were eligible for inclusion. The median disease-free interval after initial resection was 33 (range 7-143) months. Of the 55 patients reported, 52 (94.5%) patients underwent completion total pancreatectomy in the second operation for recurrences, including 15 patients who developed recurrences more than 5 years after the initial operation. There was no perioperative death. The 1-, 3- and 5-year overall survival rate after the second pancreatectomy was 82.2%, 49.2% and 40.6% respectively. CONCLUSION Second pancreatectomy for recurrent PDAC can be performed safely with long-term survival in selected patients.
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Affiliation(s)
- Yanming Zhou
- Department of Hepatobiliary & Pancreatovascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, China; Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Ailing Song
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Lupeng Wu
- Department of Hepatobiliary & Pancreatovascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Xiaoying Si
- Department of Hepatobiliary & Pancreatovascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.
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20
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Riediger H, Kulemann B, Wittel U, Adam U, Sick O, Neeff H, Höppner J, Hopt UT, Makowiec F. Prognostic Role of Log Odds of Lymph Nodes After Resection of Pancreatic Head Cancer. J Gastrointest Surg 2016; 20:1707-15. [PMID: 27384432 DOI: 10.1007/s11605-016-3200-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/23/2016] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Nodal status is a strong prognostic factor after resection of pancreatic cancer. The lymph node ratio (LNR) has been shown to be superior to the pN status in several studies. The role of log odds of the ratio between positive and negative nodes (LODDS) as a suggested new indicator of prognosis, however, has been hardly evaluated in pancreatic cancer. METHODS Prognostic factors for overall survival after resection for cancer of the pancreatic head were evaluated in 409 patients from two institutions (prospectively maintained databases). The lymph node status, LNR, and LODDS were separately analyzed and independently compared in multivariate survival analysis. RESULTS The median numbers of examined and positive lymph nodes were 16 and 2, respectively. Actuarial 3- and 5-year survival rates were 29 and 16 %. All three classifications of nodal disease significantly predicted survival in the entire group (n = 409), in patients with free resection margins (n = 297), and in patients with <12 examined nodes. In multivariate analysis, however, both LNR and LODDS were equally superior to the nodal status. In node-negative patients (n = 110), LODDS could not identify subgroups with different prognosis. CONCLUSION Both LNR and LODDS are superior to the classical nodal status in predicting prognosis in resected pancreatic cancer. However, LODDS has not shown any advantage over LNR in our series, neither in the entire patient group nor in the subgroups with free margins, negative nodes or a low number of examined nodes. Therefore, the use of LODDS to predict the outcome after resection of pancreatic head cancer cannot be recommended.
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Affiliation(s)
- Hartwig Riediger
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany.,Department of Surgery, Vivantes-Humboldt-Klinikum, Berlin, Germany
| | - Birte Kulemann
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany
| | - Uwe Wittel
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany
| | - Ulrich Adam
- Department of Surgery, Vivantes-Humboldt-Klinikum, Berlin, Germany
| | - Olivia Sick
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany
| | - Hannes Neeff
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany
| | - Jens Höppner
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany
| | - Ulrich T Hopt
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany
| | - Frank Makowiec
- Department of Surgery, University of Freiburg, Hugstetterstrasse 55, D-79106, Freiburg, Germany.
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21
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Abstract
Background: Pancreatic adenocarcinoma is associated with a very poor prognosis, with a 5 year survival of ∼7.2%. Vitamin D has long been evaluated for benefit as a protective agent and treatment for malignancies. Although cancer incidence and outcomes have been tied to vitamin D levels, there is no clear evidence that supplementation of vitamin D improves outcome in pancreatic cancer to date. Case Presentation: We present a patient who errantly took supratherapeutic doses of vitamin D 50,000 U daily, achieving a serum 25(OH)D level of more than 150 mg/mL, with no appreciable side effects. Conclusion: Her disease was stable for 8 months off of conventional treatment, although it is unclear whether this was related to vitamin D supplementation.
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Affiliation(s)
- Timothy L. Cannon
- Inova Schar Cancer Institute, Fairfax, Virginia
- Address correspondence to: Timothy L. Cannon, MD, Inova Schar Cancer Institute, 8505 Arlington Blvd., Suite 100, Fairfax, VA 22031,
| | - Joel Ford
- Inova Medical Center, Falls Church, Virginia
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22
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GONG JUN, TULI RICHARD, SHINDE ARVIND, HENDIFAR ANDREWE. Meta-analyses of treatment standards for pancreatic cancer. Mol Clin Oncol 2016; 4:315-325. [PMID: 26998283 PMCID: PMC4774516 DOI: 10.3892/mco.2015.716] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 11/23/2015] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is the most lethal common cancer with an estimated 5-year survival rate of 6-7% (across all stages). The only potential curative therapy is surgical resection in those with localized disease. Adjuvant (postoperative) therapy confers a survival advantage over postoperative observation alone. Neoadjuvant (preoperative) therapy offers the potential to downstage initially unresectable tumors for resection, sterilize resection margins and decrease locoregional recurrence, and identify a subset of patients with aggressive disease for whom surgery will not be beneficial. Induction chemotherapy followed by consolidation chemoradiation is another recommended approach in those with locally advanced disease. For those who cannot be downstaged, cannot tolerate surgery, or were diagnosed with metastatic disease, treatment remains palliative with chemotherapy being a critical component of this approach. Recently, intensive combination chemotherapy has been shown to improve survival rates in comparison to gemcitabine alone in advanced disease. The past few decades have afforded an accumulation of high-level evidence regarding neoadjuvant, adjuvant and palliative therapies in pancreatic cancer. There are numerous reviews discussing recent retrospective studies, prospective studies and randomized controlled trials in each of these areas. However, reviews of optimal and recommended treatment strategies across all stages of pancreatic cancer that focus on the highest levels of hierarchical evidence, such as meta-analyses, are limited. The discussion of novel therapeutics is beyond the scope of this review. However, an extensive and the most current collection of meta-analyses of first-line systemic and locoregional treatment options for all stages of pancreatic cancer to date has been accumulated.
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Affiliation(s)
- JUN GONG
- Department of Internal Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - RICHARD TULI
- Department of Radiation Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - ARVIND SHINDE
- Department of Hematology and Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - ANDREW E. HENDIFAR
- Gastrointestinal and Neuroendocrine Malignancies, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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23
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Abstract
Gemcitabine (GEM) is an approved treatment for unresectable pancreatic cancer; however, its role in treating resected pancreatic cancer is less clear. The aim of this study was to investigate the evidence of the role of adjuvant GEM therapy on survival in resected pancreatic cancer. Four phase III randomized trials of adjuvant GEM in patients with resected pancreatic cancer were identified and the hazard ratio (HR) for overall survival were used in this meta-analysis; 2 studies compared GEM treatment with best supportive care and 2 studies with 5-fluorouracil/folinic acid therapy. The pooled data (n=2017 patients) indicated that the overall survival data were homogenous among the studies (Q=4.371; I=31.37%; P=0. 224). The combined HR significantly favors GEM over the other treatments. The overall HR was 0.88 (range, 0. 720 to 0.940; P=0.014). The results indicate that GEM prolongs overall survival compared with other treatments after the resection of pancreatic cancer.
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Xiang J, Liu L, Wang W, Xu H, Wu C, Xu J, Liu C, Long J, Ni Q, Yu X. Metabolic tumor burden: a new promising way to reach precise personalized therapy in PDAC. Cancer Lett 2015; 359:165-168. [PMID: 25617800 DOI: 10.1016/j.canlet.2015.01.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 01/18/2015] [Accepted: 01/19/2015] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is currently one of the deadliest solid malignancies and pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. In the past decade, diagnostics and surgical techniques for PDAC have been evolving steadily; however, clinical outcomes of patients with PDAC have shown little, if any, improvement. Subgroup classification based on accurate prediction of prognosis in patients with pancreatic cancer is important for treatment selection and clinical decision-making. The traditional method to evaluate prognosis relies on the TNM staging system, but it may not reflect the true status of every patient due to individual biological differences. Metabolomics is a field of study that involves the identification and quantification of metabolites present in a biological system. Analysis of metabolic differences between cancerous and noncancerous tissues can provide novel insights into tumor biology that are closely associated with disease prognosis and diagnosis. Therefore, evaluation of metabolic tumor burden may improve the accuracy of the clinical decision-making process, thereby facilitating optimization of the treatment strategies for pancreatic cancer.
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Affiliation(s)
- Jinfeng Xiang
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wenquan Wang
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Huaxiang Xu
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Chuntao Wu
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin Xu
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Chen Liu
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Long
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Quanxing Ni
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic and Hepatobiliary Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
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Hidalgo M, Cascinu S, Kleeff J, Labianca R, Löhr JM, Neoptolemos J, Real FX, Van Laethem JL, Heinemann V. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015; 15:8-18. [PMID: 25547205 DOI: 10.1016/j.pan.2014.10.001] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 10/01/2014] [Accepted: 10/03/2014] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease.
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Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
| | - Stefano Cascinu
- Department of Medical Oncology, University of Ancona, Ancona, Italy
| | - Jörg Kleeff
- Department of General Surgery, Technische Universität München, Munich, Germany
| | | | - J-Matthias Löhr
- Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - John Neoptolemos
- National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Cancer Research UK Liverpool Clinical Trials Unit Director, University of Liverpool and Royal Liverpool University Hospital, Liverpool, UK
| | - Francisco X Real
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid and Universitat Pompeu Fabra, Barcelona, Spain
| | - Jean-Luc Van Laethem
- Department of Gastroenterology-GI Cancer Unit, Erasme University Hospital, Brussels, Belgium
| | - Volker Heinemann
- Comprehensive Cancer Centre Munich, Klinikum der Universität München, Munich, Germany
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Sun J, Kim DH, Guo Y, Teng Z, Li Y, Zheng L, Zhang Z, Larson AC, Lu G. A c(RGDfE) conjugated multi-functional nanomedicine delivery system for targeted pancreatic cancer therapy. J Mater Chem B 2014; 3:1049-1058. [PMID: 32261983 DOI: 10.1039/c4tb01402b] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Pancreatic cancer is one of the five most lethal malignancies and has a poor prognosis due to its abundant stromal barriers and lack of effective available therapies. Although gemcitabine has been used as a standard therapy for several decades, there has been little progress in the improvement of the 5 year survive rate due to the low targeting efficiency for pancreatic cancer cells. To achieve a targeted delivery of gemcitabine to pancreatic cancer cells, we have developed a c(RGDfE) [cyclic (Arg-Gly-Asp-d-Phe-Glu)] conjugated multi-functional nanomedicine delivery system composed of a magnetic core and mesoporous silica shell. These magnetic mesoporous nanoparticles demonstrated sufficient relaxivity properties for detection with magnetic resonance imaging (MRI). These c(RGDfE) peptide conjugated magnetic mesoporous silica nanoparticles [c(RGDfE)-pMMSNs] can target pancreatic cancer cells and increase cellular uptake in human pancreatic cancer cell lines that overexpress integrin ανβ3. Gemcitabine loaded c(RGDfE)-pMMSNs were most efficiently targeted to pancreatic cancer cells (BxPC-3). Growth inhibition of the BxPC-3 cell line was achieved in a time dependent manner consistent with observed drug release behavior. Intracellular targeted gemcitabine delivery using c(RGDfE)-pMMSNs offers a promising approach for the treatment of pancreatic cancer.
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Affiliation(s)
- Jing Sun
- Department of Medical Imaging, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, P.R. China.
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Jones OP, Melling JD, Ghaneh P. Adjuvant therapy in pancreatic cancer. World J Gastroenterol 2014; 20:14733-46. [PMID: 25356036 PMCID: PMC4209539 DOI: 10.3748/wjg.v20.i40.14733] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/29/2014] [Accepted: 05/25/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains one of the leading causes of cancer related death worldwide with an overall five-year survival of less than 5%. Potentially curative surgery, which alone can improve 5-year survival to 10%, is an option for only 10%-20% of patients at presentation owing to local invasion of the tumour or metastatic disease. Adjuvant chemotherapy has been shown to improve 5-year survival to 20%-25% but conflicting evidence remains with regards to chemoradiation. In this article we review the current evidence available from published randomised trials and discuss ongoing phase III trials in relation to adjuvant therapy in pancreatic cancer.
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Rossi ML, Rehman AA, Gondi CS. Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 2014; 20:11142-11159. [PMID: 25170201 PMCID: PMC4145755 DOI: 10.3748/wjg.v20.i32.11142] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/11/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.
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29
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Sultana A, Jackson RJ, Cox T, Palmer D, Neoptolemos J, Ghaneh P. Chemotherapy, radiotherapy, chemoradiotherapy and combination therapy in localised and locally advanced pancreatic cancer. Hippokratia 2014. [DOI: 10.1002/14651858.cd011044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Asma Sultana
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
| | - Richard J Jackson
- Liverpool University; North West Surgical Trials Centre; Brownlow Street Liverpool UK L69 3GL
| | - Trevor Cox
- University of Liverpool; Liverpool Cancer Research UK Cancer Trials Unit; Liverpool UK
| | - Daniel Palmer
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
| | - John Neoptolemos
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
| | - Paula Ghaneh
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
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Maity G, Mehta S, Haque I, Dhar K, Sarkar S, Banerjee SK, Banerjee S. Pancreatic tumor cell secreted CCN1/Cyr61 promotes endothelial cell migration and aberrant neovascularization. Sci Rep 2014; 4:4995. [PMID: 24833309 PMCID: PMC4023131 DOI: 10.1038/srep04995] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 04/29/2014] [Indexed: 12/22/2022] Open
Abstract
The complex signaling networks between cancer cells and adjacent endothelial cells make it challenging to unravel how cancer cells send extracellular messages to promote aberrant vascularization or tumor angiogenesis. Here, in vitro and in vivo models show that pancreatic cancer cell generated unique microenvironments can underlie endothelial cell migration and tumor angiogenesis. Mechanistically, we find that pancreatic cancer cell secreted CCN1/Cyr61 matricellular protein rewires the microenvironment to promote endothelial cell migration and tumor angiogenesis. This event can be overcome by Sonic Hedgehog (SHh) antibody treatment. Collectively, these studies identify a novel CCN1 signaling program in pancreatic cancer cells which activates SHh through autocrine-paracrine circuits to promote endothelial cell migration and tumor angiogenesis and suggests that CCN1 signaling of pancreatic cancer cells is vital for the regulation of tumor angiogenesis. Thus CCN1 signaling could be an ideal target for tumor vascular disruption in pancreatic cancer.
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Affiliation(s)
- Gargi Maity
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas [3]
| | - Smita Mehta
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2]
| | - Inamul Haque
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas
| | - Kakali Dhar
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2]
| | - Sandipto Sarkar
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Sushanta K Banerjee
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas [3] Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas [4] Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas
| | - Snigdha Banerjee
- 1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas
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Ke K, Chen W, Chen Y. Standard and extended lymphadenectomy for adenocarcinoma of the pancreatic head: a meta-analysis and systematic review. J Gastroenterol Hepatol 2014; 29:453-62. [PMID: 24164704 DOI: 10.1111/jgh.12393] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Although some retrospective studies have recommended that pancreaticoduodenectomy with extended lymphadenectomy might improve the survival of patients with adenocarcinoma of the head of the pancreas, the procedure remains controversial. METHODS Using PubMed, EMBASE, and The Cochrane Library databases, a systematic literature review was performed to identify randomized, controlled trials comparing standard and extended lymphadenectomy in pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. RESULTS Four trials including 423 patients satisfied the inclusion criteria. Extended lymphadenectomy failed to improve the overall survival of patients with adenocarcinoma of the head of the pancreas (hazard ratio 1.09; 95% confidence interval 0.84-1.41; P = 0.51). Additionally, postoperative mortality and morbidity were comparable between the standard and extended groups, while extended lymphadenectomy was associated with poor quality of life within 1 year after the operation. CONCLUSIONS Extended lymphadenectomy do not benefit overall survival. Considering the poor quality of life associated with extended lymphadenectomy, pancreaticoduodenectomy with standard lymphadenectomy is suitable for patients with adenocarcinoma of the head of the pancreas.
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Affiliation(s)
- Kun Ke
- Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China; Fujian Institute of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
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Sohal DPS, Walsh RM, Ramanathan RK, Khorana AA. Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy. J Natl Cancer Inst 2014; 106:dju011. [PMID: 24563516 DOI: 10.1093/jnci/dju011] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pancreatic adenocarcinoma, even when resectable, remains highly lethal. Although surgical outcomes have improved considerably, median overall survival after surgery and adjuvant therapy such as single-agent gemcitabine remains less than 2 years. We discuss preclinical and clinical data supporting the contention that even early-stage pancreatic cancer is a systemic disease. Autopsy series reveal that 70% to 85% of patients die of systemic recurrence, rather than local disease, after pancreatic cancer resection. Preclinical studies using genomics and mouse models reveal evidence of metastatic spread even before histopathologic evidence of a pancreatic tumor. Analogous to breast cancer, we propose that the Halstedian approach of treating pancreatic cancer as a local, surgical problem should be replaced by Fisher's alternative hypothesis of cancer as a systemic disease. Newer multiagent chemotherapy regimens have shown meaningful response rates and improvement in overall survival in the metastatic setting and, for the first time, offer investigators an opportunity to use effective systemic therapy. We emphasize that a surgery-first approach is not resonant with our current understanding of pancreatic adenocarcinoma biology and that an upfront systemic approach for even resectable pancreatic cancer warrants testing in clinical trials.
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Affiliation(s)
- Davendra P S Sohal
- Affiliations of authors: Taussig Cancer Institute and Lerner College of Medicine (DPSS, AAK) and Digestive Disease Institute and Lerner College of Medicine (RMW), Cleveland Clinic, Cleveland, OH; Virgina G. Piper Cancer Center, Translational Genomics Research Institute, Scottsdale, AZ (RKR)
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Barugola G, Partelli S, Crippa S, Butturini G, Salvia R, Sartori N, Bassi C, Falconi M, Pederzoli P. Time trends in the treatment and prognosis of resectable pancreatic cancer in a large tertiary referral centre. HPB (Oxford) 2013; 15:958-64. [PMID: 23490217 PMCID: PMC3843614 DOI: 10.1111/hpb.12073] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 01/16/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Mortality in pancreatic cancer has remained unchanged over the last 20-30 years. The aim of the present study was to analyse survival trends in a selected population of patients submitted to resection for pancreatic cancer at a single institution. METHODS Included were 544 patients who underwent pancreatectomy for pancreatic cancer between 1990 and 2009. Patients were categorized into two subgroups according to the decade in which resection was performed (1990-1999 and 2000-2009). Predictors of survival were analysed using univariate and multivariate analyses. RESULTS Totals of 114 (21%) and 430 (79%) resections were carried out during the periods 1990-1999 and 2000-2009, respectively (P < 0.0001). Hospital length of stay (16 days versus 10 days; P < 0.001) and postoperative mortality (3% versus 1%; P = 0.160) decreased over time. Median disease-specific survival significantly increased from 16 months in the first period to 29 months in the second period (P < 0.001). Following multivariate analysis, poorly differentiated tumour [hazard ratio (HR) 3.1, P < 0.001], lymph node metastases (HR = 1.9, P < 0.001), macroscopically positive margin (R2) resection (HR = 3.2, P < 0.0001), no adjuvant therapy (HR = 1.6, P < 0.001) and resection performed in the period 1990-1999 (HR = 2.18, P < 0.001) were significant independent predictors of a poor outcome. CONCLUSIONS Longterm survival after surgery for pancreatic cancer significantly improved over the period under study. Better patient selection and the routine use of adjuvant therapy may account for this improvement.
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Burkhart RA, Pineda DM, Chand SN, Romeo C, Londin ER, Karoly ED, Cozzitorto JA, Rigoutsos I, Yeo CJ, Brody JR, Winter JM. HuR is a post-transcriptional regulator of core metabolic enzymes in pancreatic cancer. RNA Biol 2013; 10:1312-23. [PMID: 23807417 DOI: 10.4161/rna.25274] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNA-binding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein-immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment.
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Affiliation(s)
- Richard A Burkhart
- Department of Surgery; Jefferson Pancreas, Biliary and Related Cancer Center; Philadelphia, PA USA
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35
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Should the portal vein be routinely resected during pancreaticoduodenectomy for adenocarcinoma? Ann Surg 2013; 257:726-30. [PMID: 22968078 DOI: 10.1097/sla.0b013e318269d23c] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION In pancreatic adenocarcinoma (PA), a margin negative resection (R0) is critical for long-term survival. BACKGROUND Although pancreaticoduodenectomy (PD) with en-bloc portal vein/superior mesenteric vein (PV/SMV) resection is used in patients with venous involvement by tumor, its utility in patients with no venous involvement is unknown. This study examines survival in patients with no venous involvement who had PD with PV/SMV resection. METHODS From 2000 to 2010, 34 patients had PD with PV/SMV resection for resectable PA on preoperative staging. Fifteen patients (44%) had histological venous involvement and 19 (56%) had no histological involvement (-PV/SMV group). We matched 1:1 the -PV/SMV group (n = 19) with 19 contemporaneous PA patients who had a standard PD (control group) for age, tumor stage, tumor size, lymph node invasion, lymph node ratio, perineural invasion, margins status, and carbohydrate antigen 19-9 (CA 19-9) levels. RESULTS No differences were noted between the -PV/SMV group (n = 19) and the matched control group (n = 19) in morbidity, mortality, reoperation rate, or length of hospital stay. Median survival (42 months vs. 22 months, P = 0.02) and overall 3-year survival (60% vs. 31%, P = 0.03) were significantly longer in the -PV/SMV group compared with the control group. CONCLUSIONS Patients with PA and no venous involvement who had PD with PV/SMV resection had a significantly longer overall survival than patients in a matched control group who had PD without venous resection.
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van der Zee JA, Ten Hagen TLM, Hop WCJ, van Dekken H, Dicheva BM, Seynhaeve ALB, Koning GA, Eggermont AMM, van Eijck CHJ. Bcl-2 associated anthanogen-1 (Bag-1) expression and prognostic value in pancreatic head and periampullary cancer. Eur J Cancer 2012; 49:323-8. [PMID: 22939115 DOI: 10.1016/j.ejca.2012.07.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Accepted: 07/30/2012] [Indexed: 01/06/2023]
Abstract
The expression of anti-apoptosis gene Bcl-2 associated anthanogen-1 (Bag-1), has been associated with outcome in several cancer types, however its prognostic role in pancreatic cancer is unknown. Aim was therefore to evaluate expression of Bag-1 in two anatomically closely related however prognostically different tumours, pancreatic head- and periampullary cancer and correlate expression with outcome. Bag-1 protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 217 patients with microscopic radical resection (R0) of adenocarcinoma of the pancreatic head or periampullary region. Expression was assessed for associations with recurrence free- (RFS), cancer specific- (CSS), overall survival (OS) and conventional prognostic factors. Nuclear Bag-1 was present in 80% of tumours. In 40% Bag-1 resided in the cytosol, which was almost exclusively associated with nuclear expression. Nuclear Bag-1 protein was identified as an independent factor predicting a favourable outcome following radical resection of pancreatic head cancer. Eighteen percent of patients with nuclear Bag-1 were recurrence free and alive 5 years following surgery compared to none of the patients lacking expression. In periampullary cancer Bag-1 was not associated with outcome. In conclusion, Bag-1 was present in the majority of both pancreatic head- and periampullary cancers. However it was only identified as a discriminator of outcome in pancreatic head cancer.
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Affiliation(s)
- Jill A van der Zee
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.
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Tumour basement membrane laminin expression predicts outcome following curative resection of pancreatic head cancer. Br J Cancer 2012; 107:1153-8. [PMID: 22929879 PMCID: PMC3461165 DOI: 10.1038/bjc.2012.373] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Although widely fragmented BMs have been associated with adverse outcome in several cancer types, comparatively little is known with respect to its effect on the prognosis of pancreatic cancer. The aim of the current study was therefore to determine the prognostic value of tumour basement membrane (BM) continuity in two anatomically closely related, however, prognostically different tumours, pancreatic head- and periampullary cancer. Methods: Tumour BM continuity was determined by immunohistochemical staining of its two major components, laminin and collagen type IV. Associations were made with recurrence free survival (RFS), cancer-specific survival (CSS), overall survival (OS) and conventional prognostic factors. Results: Fifty-nine and 61% of pancreatic head and periampullary tumours, respectively, showed limited BM laminin expression. Whereas 43% and 41% of pancreatic head and periampullary cancers, respectively, showed limited BM collagen type IV expression. Limited BM laminin was associated with poor outcome following curative resection of pancreatic head cancer (P=0.034, 0.013 and 0.017 for RFS, CSS and OS, respectively). Two and a half times as many patients with ⩾25% BM laminin were recurrence free and alive 5 years following resection compared with those with limited BM laminin. Although staining patterns of both BM components were weakly correlated with each other, BM collagen type IV expression was not significantly associated with outcome in either tumour type. Conclusion: Discontinuous BMs, determined by laminin expression, are associated with poor outcome following curative resection of pancreatic head cancer.
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Rau BM, Moritz K, Schuschan S, Alsfasser G, Prall F, Klar E. R1 resection in pancreatic cancer has significant impact on long-term outcome in standardized pathology modified for routine use. Surgery 2012; 152:S103-11. [PMID: 22766366 DOI: 10.1016/j.surg.2012.05.015] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 05/11/2012] [Indexed: 01/10/2023]
Abstract
BACKGROUND The quality of a histopathologic workup after oncologic resection of pancreatic malignancies has changed the central role of surgery substantially for radical tumor clearance over the past years. The development of standardized protocols for pathologic workup increased the rate of R1 resections from around 20% up to 80%. In the present study, we investigated the incidence of R1 and its impact on survival after oncologic pancreatic resections using a standardized pathologic routine protocol. PATIENTS AND METHODS We performed 265 pancreatic resections from September 2003 to September 2010. Among 128 patients with malignant neoplasms, histology revealed ductal pancreatic adenocarcinoma in 97, ampullary cancer in 10, and distal bile duct cancer in 21 patients. Resected specimens were analyzed according to this improved standardized pathology protocol introduced in 2000. Follow-up data on overall and cancer-related survival, presence and site of tumor recurrence, and chemotherapy were obtained from 120 patients. RESULTS Pancreatic resection comprised a pylorus-preserving or classical pancreaticoduodenectomy in 112, a distal pancreatectomy in 8, and a total pancreatectomy in 7 patients. In the overall series, 56 (44%) were classified R1 resections and 68 (43%) R0 resections, 3 patients with R2 resections were excluded, leaving 125 patients for analysis. In pancreatic adenocarcinoma, the rate of R1 was 51% (48/94). R1 resection involved most frequently the circumferential margin in 86% (48/125) of the total group and in 92% (44/48) in pancreatic cancer. Follow-up was performed after a median of 17 months (range, 1-85) postoperatively. Cancer-related death rate in R0 and R1-resected patients was 60% and 83% (P < .02) in all cancers (n = 117) and 66% and 80% in patients with pancreatic adenocarcinoma (n = 88). Median tumor-related survival in R0 and R1 resections was 22 (range, 4-85) vs 14 months (range, 2-48) in all cancers (P < .002), and 19 (range, 4-85) vs 14 months (range, 2-48) in pancreatic adenocarcinoma (P < .04). Kaplan-Meier survival analysis revealed a survival benefit after R0 resection in both all cancers (P = .002) and pancreatic adenocarcinoma (P < .02). The pattern of tumor recurrence had a greater rate of regional metastases in the R1 group (P < .05). CONCLUSION Our 51% rate of R1 resections in ductal pancreatic carcinoma indicates a high quality standard of pathologic evaluation. The vast majority of R1 margins are located at the retroperitoneal dissection surface. Standardization of histopathologic analysis has a clinically relevant impact on survival after oncologic resection of pancreatic cancer and can be achieved by less extensive protocols.
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Affiliation(s)
- Bettina M Rau
- Department of General, Thoracic, Vascular, and Transplantation Surgery, University of Rostock, Germany.
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Lee SH, Kim H, Hwang JH, Lee HS, Cho JY, Yoon YS, Han HS. Breast cancer resistance protein expression is associated with early recurrence and decreased survival in resectable pancreatic cancer patients. Pathol Int 2012; 62:167-75. [PMID: 22360504 DOI: 10.1111/j.1440-1827.2011.02772.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismal even after complete resection, with most recurrences occurring within 1-2 years postoperatively. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been demonstrated to play major roles in multidrug resistance (MDR) of cancers. In this study, we evaluated the expression statuses and the clinical significance of MDR1 (ABCB1), MDR-associated proteins (MRPs/ABCC) 1, 2 and 3, and breast cancer resistance protein (BCRP/ABCG2) in 67 surgically resected PDACs by immunohistochemistry. MDR1, MRP1, MRP2, MRP3 and BCRP were expressed in 35 (52.2%), 56 (83.6%), 61 (91.0%), 49 (73.1%) and 49 (73.1%) out of 67 cases, respectively. The expression statuses of the MDR-related proteins were positively correlated with each other (P < 0.05). Tumors expressing MRP1 (P= 0.015), MRP2 (P= 0.022) and MRP3 (P < 0.001) demonstrated more frequent perineural invasion. MDR1 expression was significantly correlated with lymphatic invasion (P= 0.047). High BCRP expression in PDAC was a significant prognostic factor for early tumor recurrence (HR = 2.43, P= 0.003) and poor survival (HR = 2.63, P= 0.001). MDR-related proteins are frequently expressed in PDAC, and high BCRP expression is a significant independent predictor for early recurrence and poor survival. Immunohistochemical analysis for BCRP expression in PDAC may be a useful test in identifying a subgroup of patients with a poor prognosis.
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Affiliation(s)
- Sang Hyub Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea
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Perineural invasion and lymph node involvement as indicators of surgical outcome and pattern of recurrence in the setting of preoperative gemcitabine-based chemoradiation therapy for resectable pancreatic cancer. Ann Surg 2012; 255:95-102. [PMID: 22123160 DOI: 10.1097/sla.0b013e31823d813c] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To analyze the histopathological indicators significantly associated with surgical outcome and the pattern of recurrence in the setting of preoperative gemcitabine-based chemoradiation therapy (CRT) and subsequent pancreatectomy. BACKGROUND Clinicopathological assessment of the resected specimen is an indispensable tool for predicting patient prognosis and localizing high-risk sites for tumor relapse. This procedure is also essential for the establishment of efficient postoperative follow-up protocols in the setting of a preoperative CRT strategy. METHODS In a prospective phase II clinical trial at our hospital, 110 patients received preoperative CRT and subsequent resection. All 110 resected cases were included in this study. We employed disease-free survival (DFS) as a surgical outcome, and the pattern of recurrence was divided into 2 categories: (1) recurrence in the abdominal cavity (RAC), defined as either a locoregional or a peritoneal recurrence; or (2) distant recurrence (DR), defined as cancer recurrence in a distant organ. Clinicopathological variables were analyzed in association with DFS, RAC, and DR. RESULTS Positive nodal involvement and perineural invasion were independent factors that were significantly associated with an unfavorable DFS (P = 0.021 and P = 0.026, respectively). The presence of perineural invasion was the single independent variable significantly associated with an increased risk of RAC (P = 0.002), whereas the status of nodal involvement was the single independent variable significantly associated with an increased risk of DR (P = 0.013). CONCLUSIONS The status of nodal involvement and perineural invasion in resected specimens are significantly associated with DFS and clearly predict the pattern of recurrence in the setting of a preoperative gemcitabine-based CRT strategy. This study is registered at UMIN-CTR and carries the ID number UMIN000001804.
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Asuthkar S, Rao JS, Gondi CS. Drugs in preclinical and early-stage clinical development for pancreatic cancer. Expert Opin Investig Drugs 2012; 21:143-52. [PMID: 22217246 DOI: 10.1517/13543784.2012.651124] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the US and Europe, and the lethality of this cancer is demonstrated by the fact that the annual incidences are approximately equal to the annual deaths. Current therapy for PC is multimodal, involving surgery and chemotherapy. Clinical symptoms are unspecific, and consequently about 85% of patients with PC are diagnosed at advanced tumor stages without any surgical therapy options. Since the therapeutic rates for PC are so dismal, it is essential to review the clinical targets for diagnosis and treatment of this lethal cancer. AREAS COVERED In this review, we discuss potential treatment options for PC by identifying molecular targets including those involved in cell proliferation, survival, migration, invasion and angiogenesis. Targeting these molecules in combination with surgery could improve the clinical outcome for PC patients. EXPERT OPINION For a decade, gemcitabine has remained the single first-line chemotherapeutic agent for advanced adenocarcinoma of the pancreas; however, less than 25% of patients benefit from gemcitabine. The reason for frequent reoccurrence of PC after conventional methods such as surgery, radiation and/or chemotherapy is due to the lack of understanding of the basic underlying metabolic cause of the cancer and thus consequently remains uncorrected. Our understanding of drug resistance in PC is still not clear and may be answered by focusing on new useful biomarkers and their role in chemo- and radioresistance.
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Affiliation(s)
- Swapna Asuthkar
- University of Illinois College of Medicine, Cancer Biology and Pharmacology, One Illini Drive, Peoria, 61605, USA
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Abstract
Pancreatic cancer is a challenging malignancy to treat, as less than one-fifth of diagnosed cases are resectable, surgery is complex and postoperative recovery slow, treated patients tend to relapse and overall survival rates are low. It is one of the leading causes of cancer-related mortality. Adjuvant therapy has been employed in resectable disease, to target micrometastases and improve prognosis. Chemotherapy, chemoradiotherapy (chemoRT) and chemoradiotherapy (chemoRT) followed on by chemotherapy have been evaluated in randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 and CONKO-001 trials clearly established the survival advantage of adjuvant chemotherapy with 5 fluorouracil (5FU) plus folinic acid and gemcitabine respectively over no chemotherapy. The ESPAC-3 (version 2) trial demonstrated equivalence between 5FU plus folinic acid and gemcitabine in terms of survival parameters, though gemcitabine had a better toxicity profile. The results of these key studies, together with smaller ones have been subjected to meta-analyses, with confirmation of improved survival with adjuvant systemic chemotherapy. The EORTC-40891 and ESPAC-1 trials found no survival advantage with adjuvant chemoRT compared to observation, and this has been reflected in a subsequent meta-analysis. The popularisation of chemoRT, with follow on chemotherapy (versus observation) was based on the small underpowered GITSG trial. The ESPAC-1 trial was unable to find a survival benefit for chemoRT, with follow on chemotherapy compared to observation. The RTOG-9704 trial assessed chemoRT with follow on chemotherapy in both arms and found no difference between survival in the gemcitabine and 5FU arms. There has never been a published head-to-head randomised comparison of adjuvant chemotherapy to chemoRT, with follow on chemotherapy. Ongoing randomised trials are looking into adjuvant combination chemotherapy, chemotherapy with follow on chemoRT, and neoadjuvant therapy. Novel agents continue to be assessed in early phase trials with a major emphasis on predictive and prognostic biomarkers. Based on the available evidence, adjuvant chemotherapy with gemcitabine or 5FU/folinic acid is the current recommended gold standard in the management of resected pancreatic cancer.
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Affiliation(s)
- Asma Sultana
- Department of Molecular and Clinical Cancer Medicine Centre, University of Liverpool, Liverpool, L69 3GA, UK
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Winter JM, Tang LH, Klimstra DS, Brennan MF, Brody JR, Rocha FG, Jia X, Qin LX, D’Angelica MI, DeMatteo RP, Fong Y, Jarnagin WR, O’Reilly EM, Allen PJ. A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers. PLoS One 2012; 7:e40157. [PMID: 22792233 PMCID: PMC3391218 DOI: 10.1371/journal.pone.0040157] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 06/01/2012] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND One-fifth of patients with seemingly 'curable' pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed 'unresectable' by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ∼2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046). METHODS AND FINDINGS Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07). CONCLUSIONS MUC1 and MSLN were superior to pathologic features and other putative biomarkers as predicting survival group. Molecular assays comparing cancers from short and long survivors are an effective strategy to screen biomarkers and prioritize candidate cancer genes for diagnostic and therapeutic studies.
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Affiliation(s)
- Jordan M. Winter
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Laura H. Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - David S. Klimstra
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Murray F. Brennan
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Jonathan R. Brody
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Flavio G. Rocha
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington, United States of America
| | - Xiaoyu Jia
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Li-Xuan Qin
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Michael I. D’Angelica
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Ronald P. DeMatteo
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Yuman Fong
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - William R. Jarnagin
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington, United States of America
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Peter J. Allen
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
- * E-mail:
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Zhao M, Tominaga Y, Ohuchida K, Mizumoto K, Cui L, Kozono S, Fujita H, Maeyama R, Toma H, Tanaka M. Significance of combination therapy of zoledronic acid and gemcitabine on pancreatic cancer. Cancer Sci 2012; 103:58-66. [PMID: 21954965 PMCID: PMC11164147 DOI: 10.1111/j.1349-7006.2011.02113.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
In the present study, we examined the cytotoxic effects of combination therapy with zoledronic acid (ZOL) and gemcitabine (GEM) on pancreatic cancer cells in vitro and in vivo. Four human pancreatic cancer cell lines were treated with ZOL, GEM or a combination of both, and the effects of the respective drug regimens on cell proliferation, invasion and matrix metalloproteinase (MMP) expression were examined. A pancreatic cancer cell line was also intrasplenically or orthotopically implanted into athymic mice and the effects of these drugs on tumor metastasis and growth in vivo were evaluated by histological and immunohistochemical analyses. Combination treatment with low doses of ZOL and GEM efficiently inhibited the proliferation (P < 0.001) and invasion (P < 0.001) of pancreatic cancer cells in vitro. Western blotting assay revealed that MMP-2 and MMP-9 expression levels were decreased after ZOL treatment. In vivo, combined treatment significantly inhibited tumor growth (P < 0.05) and the development of liver metastasis (P < 0.05). These data revealed that ZOL and GEM, when used in combination, have significant antitumor, anti-metastatic and anti-angiogenic effects on pancreatic cancer cells. The present study is the first to report the significance of the combination treatment of ZOL and GEM in pancreatic cancer using an in vivo model. These data are promising for the future application of this drug regimen in patients with pancreatic cancer.
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Affiliation(s)
- Ming Zhao
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Lambe M, Eloranta S, Wigertz A, Blomqvist P. Pancreatic cancer; reporting and long-term survival in Sweden. Acta Oncol 2011; 50:1220-7. [PMID: 21812626 DOI: 10.3109/0284186x.2011.599338] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The overall completeness of the Swedish Cancer Register is high, although underreporting for certain sites must be acknowledged. The aims of the present study were twofold. Firstly to assess the completeness of reporting of pancreatic cancer to the Swedish Cancer Register, and secondly to identify and characterise long-term survivors based on information from two separate population-based register resources. MATERIAL AND METHODS To assess the completeness of the Cancer Register, pancreatic cancer cases registered in the National Patient Register between 1987 and 1999 were compared to cases reported to the Cancer Register. For estimations of long-term survival, the study population was restricted to 4321 cases identified both in the Cancer Register and the Patient Register with a histopathologically confirmed diagnosis of pancreatic ductal adenocarcinoma. A complete follow-up of survival in this group was performed till December 31, 2004. RESULTS There was a considerable underreporting of pancreatic cancer to the Cancer Register. During the period under study, a total of 19 745 patients were identified with a diagnosis of pancreatic cancer. Of these, only 73% had been reported to the Cancer Register. The underreporting increased markedly with age at diagnosis and was more pronounced during the second period under study. Only 2.8% of patients with a histopathologically confirmed diagnosis of pancreatic ductal adenocarcinoma survived five years or longer. The likelihood of long-term survival was strongly associated with younger age and surgery. Pancreatic resection was reported in 20.4% of all patients. Median survival among those operated on was 12 months compared to 4.6 months in all patients. CONCLUSIONS Underreporting of pancreatic cancer to the Swedish Cancer Register was pronounced and increased with older age. Less than 3% of patients with a record of pancreatic cancer both in the Cancer Register and the Patient Register survived five years or longer.
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Affiliation(s)
- Mats Lambe
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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van der Zee JA, van Eijck CHJ, Hop WCJ, van Dekken H, Dicheva BM, Seynhaeve ALB, Koning GA, Eggermont AMM, ten Hagen TLM. Angiogenesis: a prognostic determinant in pancreatic cancer? Eur J Cancer 2011; 47:2576-84. [PMID: 21958461 DOI: 10.1016/j.ejca.2011.08.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Revised: 07/24/2011] [Accepted: 08/25/2011] [Indexed: 01/01/2023]
Abstract
Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression. The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome. Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n=98) or periampullary cancer (n=108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors. MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p<.01). Furthermore, MVD was associated with lymph node involvement in pancreatic head (p=.014), but not in periampullary cancer (p=.55). Interestingly, MVD was not associated with RFS, CSS or with OS. In conclusion, angiogenesis is higher in periampullary cancer and although associated with nodal involvement in pancreatic head cancer, pancreatic cancer prognosis seems indeed angiogenesis independent.
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Affiliation(s)
- Jill A van der Zee
- Laboratory of Experimental Surgical Oncology, Section of Surgical Oncology, Department of Surgery, Erasmus Medical Center, 's Gravendijkwal 230, Rotterdam, The Netherlands.
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Winter JM, Brennan MF, Tang LH, D’Angelica MI, DeMatteo RP, Fong Y, Klimstra DS, Jarnagin WR, Allen PJ. Survival after Resection of Pancreatic Adenocarcinoma: Results from a Single Institution over Three Decades. Ann Surg Oncol 2011; 19:169-75. [DOI: 10.1245/s10434-011-1900-3] [Citation(s) in RCA: 279] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Indexed: 12/20/2022]
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The Role of PPAR-gamma and Its Interaction with COX-2 in Pancreatic Cancer. PPAR Res 2011; 2008:326915. [PMID: 18615182 PMCID: PMC2442877 DOI: 10.1155/2008/326915] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2008] [Accepted: 05/22/2008] [Indexed: 01/10/2023] Open
Abstract
In recent years, the study of the peroxisome proliferators activated receptor gamma (PPAR-γ) as a potential target for cancer prevention and therapy has gained a strong interest. However, the overall biological significance of PPAR-γ in cancer development and progression is still controversial. While many reports documented antiproliferative effects in human cancer cell and animal models, several studies demonstrating potential tumor promoting actions of PPAR-γ ligands raised considerable concerns about the role of PPAR-γ in human cancers. Controversy also exists about the role of PPAR-γ in human pancreatic cancers. The current review summarizes the data about PPAR-γ in pancreatic cancer and highlights the biologically relevant interactions between the cyclooxygenase and PPAR system.
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Haugen F, Labori KJ, Noreng HJ, Buanes T, Iversen PO, Drevon CA. Altered expression of genes in adipose tissues associated with reduced fat mass in patients with pancreatic cancer. Arch Physiol Biochem 2011; 117:78-87. [PMID: 21457003 DOI: 10.3109/13813455.2011.560609] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Loss of adipose tissue in patients with pancreatic cancer may involve altered gene expression. Peri-operative mRNA levels of 44 genes were analysed by RT-PCR in intra-abdominal (IAAT) and subcutaneous adipose tissue (SCAT) sampled from pancreatic ductal adenocarcinoma (PDAC) patients undergoing tumour resection (n = 20), and control patients without cancer (n = 11). Peri- and post-operative IAAT and SCAT masses were measured by computerized tomography. PDAC patients displayed 2.6- and 1.7-fold higher Zn-α2-glycoprotein (AZGP1) mRNA levels than controls in IAAT and SCAT, respectively (P < 0.01), but expression was not correlated with post-operative changes in fat masses. IAAT mass changes correlated with genes in lipid metabolism, inflammation and apoptosis: e.g. stearoyl-Coenzyme A desaturase 1 (SCD), tumour necrosis factor (TNF) and chemokine (C-C motif) ligand 2 (CCL2; MCP-1). Patients with PDAC displayed increased AZGP1 mRNA levels in both IAAT and SCAT, but expression of other genes may predict IAAT loss.
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Affiliation(s)
- F Haugen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway.
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