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Chan AHY, Zhao Y, Tan HL, Chua DW, Ng KYY, Lee SY, Lee JJX, Tai D, Goh BKP, Koh YX. Clinical Outcomes of Neoadjuvant Therapy Versus Upfront Surgery in Resectable Pancreatic Cancer: Systematic Review and Meta-analysis of Latest Randomized Controlled Trials. Ann Surg Oncol 2025; 32:4094-4107. [PMID: 39987384 DOI: 10.1245/s10434-024-16674-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/23/2024] [Indexed: 02/24/2025]
Abstract
BACKGROUND Survival and surgical benefits of neoadjuvant treatments (NAT) in resectable pancreatic cancer (RPC) remains unclear. The role of NAT in providing additional benefits to reduce biological aggressiveness and recurrence is worth elucidating. We assessed the latest randomized controlled trials (RCTs). METHODS A systematic review and meta-analysis was performed including trials published from inception to February 2024 to evaluate survival, surgical, and short-term oncological benefits with RCTs for RPC, comparing NAT with upfront surgery. RESULTS Eight RCTs with 982 patients were analyzed. RPC treated with NAT conferred better median disease-free survival (DFS) compared to upfront surgery (HR = 0.66, p = 0.01) with a significantly improved R0 resection (RR = 1.20, p = 0.04) and pN0 rate (RR = 1.68, p < 0.001). These benefits did not translate into overall survival benefits (HR = 0.81, p = 0.06). Postoperative major morbidity and mortality did not differ significantly between treatment approaches. No significant difference was noted in resection rate (RR = 0.95, p = 0.21). However, a significantly lower surgical exploration rate was exhibited in the NAT group (RR = 0.84, p = 0.007). CONCLUSION NAT conferred better DFS with significantly improved R0 resection rate and pN0 rate compared with upfront surgery. Our findings highlight the potential benefits of NAT in enhancing survival, surgical, and short-term oncological outcomes without increasing postoperative risks.
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Affiliation(s)
- Anna Ho Yin Chan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
| | - Yun Zhao
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Hwee Leong Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Darren Weiquan Chua
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Kennedy Yao Yi Ng
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Suat Ying Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joycelyn Jie Xin Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - David Tai
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Brian Kim Poh Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Ye Xin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore.
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
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Harimoto N, Sugimachi K, Nishijima TF, Takahiro T, Shimagaki T, Mano Y, Onishi E, Sugiyama M, Kimura Y, Morita M. Combined effect of frailty and sarcopenia on postoperative complications in older adults undergoing curative surgery for hepato-biliary-pancreatic cancer. Ann Gastroenterol Surg 2025; 9:587-594. [PMID: 40385335 PMCID: PMC12080199 DOI: 10.1002/ags3.12897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/22/2024] [Accepted: 12/05/2024] [Indexed: 01/03/2025] Open
Abstract
Aim Older adults with cancer are often at increased risk for postoperative complications following major surgeries. This study aimed to evaluate the combined role of frailty and sarcopenia in predicting postoperative complications in older adults with hepatobiliary and pancreatic cancer undergoing surgery. Methods This retrospective study included 107 Japanese patients who underwent comprehensive geriatric assessment (CGA) at the geriatric oncology service before cancer treatment decisions and subsequent curative surgery for hepatobiliary and pancreatic cancer. Frailty status was measured using the validated 10-item frailty index based on a CGA (FI-CGA-10) and categorized as fit, prefrail, or frail. Sarcopenia was assessed using bioelectrical impedance analysis and grip strength. The primary outcome was postoperative complications, defined as Clavien-Dindo grade ≥ III, within 1 month of surgery. Results The median age of the 107 patients was 79 (range, 75-89) years. Patients were categorized as fit (n = 36, 33.7%), prefrail (n = 57, 53.2%), or frail (n = 14, 13.1%). Of these, 21 patients (20%) were diagnosed with sarcopenia; 16 patients (15%) experienced postoperative complications. Patients classified as prefrail or frail had a higher incidence of postoperative complications compared with those classified as fit (19.7% vs. 5.6%, p = 0.08). Patients with both prefrail or frail and sarcopenia had a significantly higher risk of postoperative complications. This association remained significant in the multivariable model (OR 4.74; 95% CI, 1.10-20.29; p = 0.04). Conclusion In this study, patients classified as prefrail/frail and sarcopenic were at significantly higher risk for postoperative complications.
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Affiliation(s)
- Norifumi Harimoto
- Department of Hepato‐Biliary‐Pancreatic SurgeryNHO Kyushu Medical CenterFukuokaJapan
- Department of Hepatobiliary and Pancreatic SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Keishi Sugimachi
- Department of Hepatobiliary and Pancreatic SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Tomohiro F. Nishijima
- Geriatric Oncology ServiceNHO Kyushu Cancer CenterFukuokaJapan
- Department of Gastrointestinal and Medical OncologyNHO Kyushu Cancer CenterFukuokaJapan
| | - Tomino Takahiro
- Department of Hepatobiliary and Pancreatic SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Tomonari Shimagaki
- Department of Hepatobiliary and Pancreatic SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Yohei Mano
- Department of Hepatobiliary and Pancreatic SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Emi Onishi
- Department of Hepatobiliary and Pancreatic SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Masahiko Sugiyama
- Department of Gastroenterological SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Yasue Kimura
- Department of Gastroenterological SurgeryNHO Kyushu Cancer CenterFukuokaJapan
| | - Masaru Morita
- Department of Gastroenterological SurgeryNHO Kyushu Cancer CenterFukuokaJapan
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3
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Liu W, Li J, Yuan X, Chen C, Shen Y, Zhang X, Yu J, Zhu M, Fang X, Liu F, Wang T, Wang L, Fan J, Jiang H, Lu J, Shao C, Bian Y. A Novel Deep Learning-based Pathomics Score for Prognostic Stratification in Pancreatic Ductal Adenocarcinoma. Pancreas 2025; 54:e430-e441. [PMID: 40314741 DOI: 10.1097/mpa.0000000000002463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/27/2024] [Indexed: 05/03/2025]
Abstract
BACKGROUND AND OBJECTIVES Accurate survival prediction for pancreatic ductal adenocarcinoma (PDAC) is crucial for personalized treatment strategies. This study aims to construct a novel pathomics indicator using hematoxylin and eosin-stained whole slide images and deep learning to enhance PDAC prognosis prediction. METHODS A retrospective, 2-center study analyzed 864 PDAC patients diagnosed between January 2015 and March 2022. Using weakly supervised and multiple instance learning, pathologic features predicting 2-year survival were extracted. Pathomics features, including probability histograms and TF-IDF, were selected through random survival forests. Survival analysis was conducted using Kaplan-Meier curves, log-rank tests, and Cox regression, with AUROC and C-index used to assess model discrimination. RESULTS The study cohort comprised 489 patients for training, 211 for validation, and 164 in the neoadjuvant therapy (NAT) group. A pathomics score was developed using 7 features, dividing patients into high-risk and low-risk groups based on the median score of 131.11. Significant survival differences were observed between groups (P<0.0001). The pathomics score was a robust independent prognostic factor [Training: hazard ratio (HR)=3.90; Validation: HR=3.49; NAT: HR=4.82; all P<0.001]. Subgroup analyses revealed higher survival rates for early-stage low-risk patients and NAT responders compared to high-risk counterparts (both P<0.05 and P<0.0001). The pathomics model surpassed clinical models in predicting 1-, 2-, and 3-year survival. CONCLUSIONS The pathomics score serves as a cost-effective and precise prognostic tool, functioning as an independent prognostic indicator that enables precise stratification and enhances the prediction of prognosis when combined with traditional pathologic features. This advancement has the potential to significantly impact PDAC treatment planning and improve patient outcomes.
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Affiliation(s)
- Wenbin Liu
- Department of Radiology, Changhai Hospital
| | - Jing Li
- Department of Radiology, Changhai Hospital
| | | | | | | | | | - Jieyu Yu
- Department of Radiology, Changhai Hospital
| | | | - Xu Fang
- Department of Radiology, Changhai Hospital
| | - Fang Liu
- Department of Radiology, Changhai Hospital
| | | | - Li Wang
- Department of Radiology, Changhai Hospital
| | - Jie Fan
- Department of Pathology, Huashan Hospital
| | - Hui Jiang
- Department of Pathology, Changhai Hospital, Shanghai, China
| | | | | | - Yun Bian
- Department of Radiology, Changhai Hospital
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Amrutkar M, Guttorm SJT, Finstadsveen AV, Labori KJ, Eide L, Rootwelt H, Elgstøen KBP, Gladhaug IP, Verbeke CS. Global metabolomic profiling of tumor tissue and paired serum samples to identify biomarkers for response to neoadjuvant FOLFIRINOX treatment of human pancreatic cancer. Mol Oncol 2025; 19:391-411. [PMID: 39545923 PMCID: PMC11793008 DOI: 10.1002/1878-0261.13759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/26/2024] [Accepted: 10/23/2024] [Indexed: 11/17/2024] Open
Abstract
Neoadjuvant chemotherapy (NAT) is increasingly used for the treatment of non-metastatic pancreatic ductal adenocarcinoma (PDAC) and is established as a standard of care for borderline resectable and locally advanced PDAC. However, full exploitation of its clinical benefits is limited by the lack of biomarkers that assess treatment response. To address this unmet need, global metabolomic profiling was performed on tumor tissue and paired serum samples from patients with treatment-naïve (TN; n = 18) and neoadjuvant leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX)-treated (NAT; n = 17) PDAC using liquid chromatography mass spectrometry. Differentially abundant metabolites (DAMs) in TN versus NAT groups were identified and their correlation with various clinical parameters was assessed. Metabolomics profiling identified 40 tissue and five serum DAMs in TN versus NAT PDAC. In general, DAMs associated with amino acid and nucleotide metabolism were lower in NAT compared to TN. Four DAMs-3-hydroxybutyric acid (BHB), 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), glycochenodeoxycholate and citrulline-were common to both tissue and serum and showed a similar pattern of differential abundance in both groups. A strong positive correlation was observed between serum carbohydrate 19-9 antigen (CA 19-9) and tissue carnitines (C12, C18, C18:2) and N8-acetylspermidine. The reduction in CA 19-9 following NAT correlated negatively with serum deoxycholate levels, and the latter correlated positively with survival. This study revealed neoadjuvant-chemotherapy-induced changes in metabolic pathways in PDAC, mainly amino acid and nucleotide metabolism, and these correlated with reduced CA 19-9 following neoadjuvant FOLFIRINOX treatment.
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Affiliation(s)
- Manoj Amrutkar
- Department of Pathology, Division of Laboratory MedicineOslo University HospitalNorway
| | - Sander Johannes Thorbjørnsen Guttorm
- Department of Medical Biochemistry, Division of Laboratory MedicineOslo University HospitalNorway
- Core Facility for Global Metabolomics and Lipidomics, Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
| | | | - Knut Jørgen Labori
- Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
- Department of Hepato‐Pancreato‐Biliary SurgeryOslo University HospitalOsloNorway
| | - Lars Eide
- Department of Medical Biochemistry, Division of Laboratory MedicineOslo University HospitalNorway
- Department of Medical Biochemistry, Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
| | - Helge Rootwelt
- Department of Medical Biochemistry, Division of Laboratory MedicineOslo University HospitalNorway
- Core Facility for Global Metabolomics and Lipidomics, Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
| | - Katja Benedikte Prestø Elgstøen
- Department of Medical Biochemistry, Division of Laboratory MedicineOslo University HospitalNorway
- Core Facility for Global Metabolomics and Lipidomics, Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
| | - Ivar P. Gladhaug
- Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
- Department of Hepato‐Pancreato‐Biliary SurgeryOslo University HospitalOsloNorway
| | - Caroline S. Verbeke
- Department of Pathology, Division of Laboratory MedicineOslo University HospitalNorway
- Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloNorway
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5
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Wei D, Yuan L, Xu X, Wu C, Huang Y, Zhang L, Zhang J, Jing T, Liu Y, Wang B. Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-β-catenin axis in modulating gemcitabine resistance in pancreatic cancer. Cancer Lett 2024; 605:217284. [PMID: 39366545 DOI: 10.1016/j.canlet.2024.217284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/06/2024]
Abstract
Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.
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MESH Headings
- Gemcitabine
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Humans
- Drug Resistance, Neoplasm/genetics
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/metabolism
- Epigenesis, Genetic
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- beta Catenin/genetics
- beta Catenin/metabolism
- Cell Line, Tumor
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Enhancer Elements, Genetic
- Wnt Signaling Pathway/genetics
- Wnt Signaling Pathway/drug effects
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Affiliation(s)
- Dianhui Wei
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Lili Yuan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Xiaoli Xu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Chengsi Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Yiwen Huang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Lili Zhang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jilong Zhang
- Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, China.
| | - Tiantian Jing
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
| | - Yizhen Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Boshi Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
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6
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Bryant JM, Nakashima J, Khatri VM, Sinnamon AJ, Denbo JW, Hodul P, Malafa M, Hoffe S, Frakes JM. The Evolving Role of Neoadjuvant Radiation Therapy in Pancreatic Adenocarcinoma. J Clin Med 2024; 13:6800. [PMID: 39597944 PMCID: PMC11594810 DOI: 10.3390/jcm13226800] [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: 10/12/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND/OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Surgical resection is the most reliable chance for cure, but high rates of positive margins and local failure persist. Neoadjuvant therapies (NAT), including chemotherapy and radiation therapy (RT), are being explored to improve surgical outcomes, particularly in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). This review aims to summarize the current landscape and future directions for neoadjuvant RT (NART) in PDAC. METHODS The review includes a detailed analysis of past and ongoing clinical trials investigating various NART approaches in PDAC, with an emphasis on different RT techniques, fractionation schemes, and their integration into multimodal treatment strategies. RESULTS Early evidence suggests that NART can improve resection margins and local control. However, recent trials, including the Alliance A021501 and LAP-07 trials, have failed to demonstrate significant survival benefits with the addition of RT to NAT. Nevertheless, nuances in trial design and execution continue to keep the question of NART open. Newer approaches, such as stereotactic magnetic resonance-guided adaptive radiation therapy (SMART), show promise in improving local control and survival, but further phase 3 trials are needed. CONCLUSIONS While NART has shown potential in improving local control in PDAC, its impact on overall survival remains unclear. Ongoing trials, particularly those utilizing advanced techniques like SMART, are critical in defining the role of RT in the neoadjuvant setting for PDAC. Collaboration across multidisciplinary teams is essential to optimize treatment strategies and trial outcomes.
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Affiliation(s)
- John Michael Bryant
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Justyn Nakashima
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Vaseem M. Khatri
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Andrew J. Sinnamon
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Jason W. Denbo
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Pamela Hodul
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Mokenge Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Sarah Hoffe
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Jessica M. Frakes
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
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7
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van Goor IWJM, Andel PCM, Buijs FS, Besselink MG, Bonsing BA, Bosscha K, Busch OR, Cirkel GA, van Dam RM, Festen S, Koerkamp BG, van der Harst E, de Hingh IHJT, Kazemier G, Liem MSL, Meijer G, de Meijer VE, Nieuwenhuijs VB, Roos D, Schreinemakers JMJ, Stommel MWJ, Wit F, Verdonk RC, van Santvoort HC, Molenaar IQ, Intven MPW, Daamen LA. Prediction of Isolated Local Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Study. Ann Surg Oncol 2024; 31:8264-8275. [PMID: 38937412 PMCID: PMC11467030 DOI: 10.1245/s10434-024-15664-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 06/10/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND Distinguishing postoperative fibrosis from isolated local recurrence (ILR) after resection of pancreatic ductal adenocarcinoma (PDAC) is challenging. A prognostic model that helps to identify patients at risk of ILR can assist clinicians when evaluating patients' postoperative imaging. This nationwide study aimed to develop a clinically applicable prognostic model for ILR after PDAC resection. PATIENTS AND METHODS An observational cohort study was performed, including all patients who underwent PDAC resection in the Netherlands (2014-2019; NCT04605237). On the basis of recurrence location (ILR, systemic, or both), multivariable cause-specific Cox-proportional hazard analysis was conducted to identify predictors for ILR and presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A predictive model was developed using Akaike's Information Criterion, and bootstrapped discrimination and calibration indices were assessed. RESULTS Among 1194/1693 patients (71%) with recurrence, 252 patients (21%) developed ILR. Independent predictors for ILR were resectability status (borderline versus resectable, HR 1.42; 95% CI 1.03-1.96; P = 0.03, and locally advanced versus resectable, HR 1.11; 95% CI 0.68-1.82; P = 0.66), tumor location (head versus body/tail, HR 1.50; 95% CI 1.00-2.25; P = 0.05), vascular resection (HR 1.86; 95% CI 1.41-2.45; P < 0.001), perineural invasion (HR 1.47; 95% CI 1.01-2.13; P = 0.02), number of positive lymph nodes (HR 1.04; 95% CI 1.01-1.08; P = 0.02), and resection margin status (R1 < 1 mm versus R0 ≥ 1 mm, HR 1.64; 95% CI 1.25-2.14; P < 0.001). Moderate performance (concordance index 0.66) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS This nationwide study identified factors predictive of ILR after PDAC resection. Our prognostic model, available through www.pancreascalculator.com , can be utilized to identify patients with a higher a priori risk of developing ILR, providing important information in patient evaluation and prognostication.
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Affiliation(s)
- I W J M van Goor
- Department of Surgery, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht, The Netherlands.
- Department of Radiation Oncology, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.
| | - P C M Andel
- Department of Surgery, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht, The Netherlands
| | - F S Buijs
- Department of Surgery, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht, The Netherlands
| | - M G Besselink
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - B A Bonsing
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - K Bosscha
- Department of Surgery, Jeroen Bosch Hospital, Den Bosch, The Netherlands
| | - O R Busch
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - G A Cirkel
- Department of Medical Oncology, University Medical Center Utrecht Cancer Center & Meander Medical Center Amersfoort, Regional Academic Cancer Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - R M van Dam
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - S Festen
- Department of Surgery, OLVG, Amsterdam, The Netherlands
| | - B Groot Koerkamp
- Department of Surgery, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
| | - E van der Harst
- Department of Surgery, Maasstad Hospital, Rotterdam, The Netherlands
| | - I H J T de Hingh
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - G Kazemier
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Surgery, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands
| | - M S L Liem
- Department of Surgery, Medisch Spectrum Twente, Enschede, The Netherlands
| | - G Meijer
- Department of Radiation Oncology, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands
| | - V E de Meijer
- Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - D Roos
- Department of Surgery, Renier de Graaf Gasthuis, Delft, The Netherlands
| | | | - M W J Stommel
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - F Wit
- Department of Surgery, Tjongerschans Hospital, Heerenveen, The Netherlands
| | - R C Verdonk
- Department of Gastroenterology, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| | - H C van Santvoort
- Department of Surgery, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht, The Netherlands
| | - I Q Molenaar
- Department of Surgery, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht, The Netherlands
| | - M P W Intven
- Department of Radiation Oncology, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands
| | - L A Daamen
- Department of Surgery, Regional Academic Cancer Center Utrecht, Utrecht University, University Medical Center Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht, The Netherlands.
- Imaging Division, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
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Yang J, Xu T, Wang H, Wang L, Cheng Y. Mechanisms of Berberine in anti-pancreatic ductal adenocarcinoma revealed by integrated multi-omics profiling. Sci Rep 2024; 14:22929. [PMID: 39358545 PMCID: PMC11446930 DOI: 10.1038/s41598-024-74943-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 09/30/2024] [Indexed: 10/04/2024] Open
Abstract
This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.
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Affiliation(s)
- Jia Yang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tingting Xu
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongwei Wang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Wang
- Shanghai Putuo District People's Hospital, Shanghai, China
| | - Yanmei Cheng
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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9
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Yao Y, Fan D. Advances in MUC1 resistance to chemotherapy in pancreatic cancer. J Chemother 2024; 36:449-456. [PMID: 38006297 DOI: 10.1080/1120009x.2023.2282839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 11/27/2023]
Abstract
The incidence of pancreatic cancer (PC), a highly fatal malignancy, is increasing every year. Chemotherapy is an important treatment for it in addition to surgery, yet most patients become resistant to chemotherapeutic agents within a few weeks of treatment initiation. MUC1 is a highly glycosylated transmembrane protein, and studies have shown that aberrantly glycosylated overexpression of MUC1 is involved in regulating the biology of chemoresistance in cancer cells. This article summarizes the mechanism of MUC1 in PC chemoresistance and reviews MUC1-based targeted therapies.
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Affiliation(s)
- Youhao Yao
- The Fifth Clinical Medical College of Shanxi Medical University, Shanxi, PR China
- Surgery Department, Shanxi Provincial People's Hospital, Taiyuan, PR China
| | - Daguang Fan
- Surgery Department, Shanxi Provincial People's Hospital, Taiyuan, PR China
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10
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Girolimetti G, Balena B, Cordella P, Verri T, Eusebi LH, Bozzetti MP, Bucci C, Guerra F. Characterization of Chemoresistance in Pancreatic Cancer: A Look at MDR-1 Polymorphisms and Expression in Cancer Cells and Patients. Int J Mol Sci 2024; 25:8515. [PMID: 39126083 PMCID: PMC11312866 DOI: 10.3390/ijms25158515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
Pancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is also characterized by a high chemoresistance, due in part to the activity of the ATP Binding Cassette (ABC) pumps accounting for the reduction in the intracellular concentration of the drugs. In this work, we analyze the occurrence of single-nucleotide polymorphisms (SNPs) in the MDR-1 gene, in different pancreatic cancer cell lines, and in tissues from pancreatic cancer patients by DNA sequencing, as well as the expression levels of MDR-1 mRNA and protein, by qRT-PCR and Western Blot analysis. We found that gemcitabine-resistant cells, in conjunction with homozygosis of analyzed SNPs, showed high MDR-1 basal levels with further increases after gemcitabine treatment. Nevertheless, we did not observe in the human PDAC samples a correlation between the level of MDR-1 mRNA and protein expression and SNPs. Preliminary, we conclude that in our small cohort, these SNPs cannot be used as molecular markers for predicting the levels of MDR-1 mRNA/protein levels and drug responses in patients with PDAC.
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Affiliation(s)
- Giulia Girolimetti
- Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (G.G.); (P.C.)
| | - Barbara Balena
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (B.B.); (T.V.); (M.P.B.)
| | - Paola Cordella
- Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (G.G.); (P.C.)
| | - Tiziano Verri
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (B.B.); (T.V.); (M.P.B.)
| | - Leonardo Henry Eusebi
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy;
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Maria Pia Bozzetti
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (B.B.); (T.V.); (M.P.B.)
| | - Cecilia Bucci
- Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (G.G.); (P.C.)
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy; (B.B.); (T.V.); (M.P.B.)
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11
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Saúde-Conde R, El Ghali B, Navez J, Bouchart C, Van Laethem JL. Total Neoadjuvant Therapy in Localized Pancreatic Cancer: Is More Better? Cancers (Basel) 2024; 16:2423. [PMID: 39001485 PMCID: PMC11240662 DOI: 10.3390/cancers16132423] [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: 05/15/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its advanced stage upon diagnosis and limited treatment options. Surgical resection, the primary curative approach, often results in poor long-term survival rates, leading to the exploration of alternative strategies like neoadjuvant therapy (NAT) and total neoadjuvant therapy (TNT). While NAT aims to enhance resectability and overall survival, there appears to be potential for improvement, prompting consideration of alternative neoadjuvant strategies integrating full-dose chemotherapy (CT) and radiotherapy (RT) in TNT approaches. TNT integrates chemotherapy and radiotherapy prior to surgery, potentially improving margin-negative resection rates and enabling curative resection for locally advanced cases. The lingering question: is more always better? This article categorizes TNT strategies into six main groups based on radiotherapy (RT) techniques: (1) conventional chemoradiotherapy (CRT), (2) the Dutch PREOPANC approach, (3) hypofractionated ablative intensity-modulated radiotherapy (HFA-IMRT), and stereotactic body radiotherapy (SBRT) techniques, which further divide into (4) non-ablative SBRT, (5) nearly ablative SBRT, and (6) adaptive ablative SBRT. A comprehensive analysis of the literature on TNT is provided for both borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), with detailed sections for each.
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Affiliation(s)
- Rita Saúde-Conde
- Digestive Oncology Department, Hôpitaux Universitaires de Bruxelles (HUB), Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Benjelloun El Ghali
- Department of Radiation Oncology, Hôpitaux Universitaires de Bruxelles (HUB), Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; (B.E.G.); (C.B.)
| | - Julie Navez
- Department of Abdominal Surgery and Transplantation, Hôpitaux Universitaires de Bruxelles (HUB), Hopital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Christelle Bouchart
- Department of Radiation Oncology, Hôpitaux Universitaires de Bruxelles (HUB), Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; (B.E.G.); (C.B.)
| | - Jean-Luc Van Laethem
- Digestive Oncology Department, Hôpitaux Universitaires de Bruxelles (HUB), Université Libre de Bruxelles, 1070 Brussels, Belgium;
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12
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Poiraud C, Lenne X, Bruandet A, Theis D, Bertrand N, Turpin A, Truant S, El Amrani M. Adjuvant chemotherapy omission after pancreatic cancer resection: a French nationwide study. World J Surg Oncol 2024; 22:123. [PMID: 38711136 DOI: 10.1186/s12957-024-03393-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/17/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Adjuvant chemotherapy (AC) improves the prognosis after pancreatic ductal adenocarcinoma (PDAC) resection. However, previous studies have shown that a large proportion of patients do not receive or complete AC. This national study examined the risk factors for the omission or interruption of AC. METHODS Data of all patients who underwent pancreatic surgery for PDAC in France between January 2012 and December 2017 were extracted from the French National Administrative Database. We considered "omission of adjuvant chemotherapy" (OAC) all patients who failed to receive any course of gemcitabine within 12 postoperative weeks and "interruption of AC" (IAC) was defined as less than 18 courses of AC. RESULTS A total of 11 599 patients were included in this study. Pancreaticoduodenectomy was the most common procedure (76.3%), and 31% of the patients experienced major postoperative complications. OACs and IACs affected 42% and 68% of the patients, respectively. Ultimately, only 18.6% of the cohort completed AC. Patients who underwent surgery in a high-volume centers were less affected by postoperative complications, with no impact on the likelihood of receiving AC. Multivariate analysis showed that age ≥ 80 years, Charlson comorbidity index (CCI) ≥ 4, and major complications were associated with OAC (OR = 2.19; CI95%[1.79-2.68]; OR = 1.75; CI95%[1.41-2.18] and OR = 2.37; CI95%[2.15-2.62] respectively). Moreover, age ≥ 80 years and CCI 2-3 or ≥ 4 were also independent risk factors for IAC (OR = 1.54, CI95%[1.1-2.15]; OR = 1.43, CI95%[1.21-1.68]; OR = 1.47, CI95%[1.02-2.12], respectively). CONCLUSION Sequence surgery followed by chemotherapy is associated with a high dropout rate, especially in octogenarian and comorbid patients.
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Affiliation(s)
- Charles Poiraud
- Digestive Surgery and Transplantation Department, CHU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Xavier Lenne
- Department of Medical Information, CHRU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Amélie Bruandet
- Department of Medical Information, CHRU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Didier Theis
- Department of Medical Information, CHRU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Nicolas Bertrand
- Medical Oncology Department, CHU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Anthony Turpin
- Medical Oncology Department, CHU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Stephanie Truant
- Digestive Surgery and Transplantation Department, CHU de Lille, 59000, Lille, France
- University of Lille, 59000, Lille, France
| | - Mehdi El Amrani
- Digestive Surgery and Transplantation Department, CHU de Lille, 59000, Lille, France.
- University of Lille, 59000, Lille, France.
- Service de Chirurgie Digestive Et Transplantation, Hôpital CLAUDE HURIEZ, Rue Michel Polonovski LILLE CEDEX, 59037, Lille, France.
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13
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Liu T, Xie XM, He YP, Zhang JY, Mou JY. circ_WASF2 regulates ferroptosis by miR-634/ GPX4 signaling in pancreatic cancer. Discov Oncol 2024; 15:143. [PMID: 38704809 PMCID: PMC11070409 DOI: 10.1007/s12672-024-01001-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/29/2024] [Indexed: 05/07/2024] Open
Abstract
PURPOSE Pancreatic cancer (PC) is one of the most lethal malignant gastrointestinal tumors (GI) characterized by a poor prognosis. Ferroptosis is an emerging programmed cell death that plays an essential role in the progression of various cancers. Ferroptosis is driven by iron-dependent phospholipid peroxidation and is regulated by mitochondrial activity, lipid peroxidation, and reactive oxygen species (ROS). The function and mechanism of ferroptosis in PC need more research. METHODS The levels of circRNAs, miRNAs, and mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used for protein detection. CCK8 assays were used to detect cell proliferation. Cell death, lipid peroxidation, ROS, and Fe2+ were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were conducted to confirm the interaction between circRNAs, miRNAs, and mRNAs. RESULTS In this research, we found that circular RNA hsa_circ_0000003(circ_WASF2) was upregulated in pancreatic cancer cells. The silence of circ_WASF2 inhibited cancer proliferation and increased cell death by increasing ferroptosis accompanied by up-regulation of lipid peroxidation, ROS, and Fe2+. Further studies showed that circ_WASF2 could attenuate ferroptosis by targeting miR-634 and the downstream glutathione peroxidase 4 (GPX4). GPX4 has been well-reported as a central factor in ferroptosis. Our research revealed a new pathway for regulating ferroptosis in PC. CONCLUSION In summary, we have determined that circ_WASF2/miR-634/GPX4 contributed to ferroptosis-induced cell death, and provided a possible therapeutic target in PC.
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Affiliation(s)
- Tao Liu
- Department of Hepatobiliary Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158, Wuyang Avenue, Enshi, 445000, Hubei, China
| | - Xing-Ming Xie
- Department of Hepatobiliary Surgery, The Key Laboratory of Advanced Interdisciplinary Studies Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
| | - Ya-Peng He
- Department of Anesthesiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158, Wuyang Avenue, Enshi, 445000, Hubei, China
| | - Jia-Yao Zhang
- Department of Hepatobiliary Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158, Wuyang Avenue, Enshi, 445000, Hubei, China.
| | - Jun-Ying Mou
- Department of Anesthesiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158, Wuyang Avenue, Enshi, 445000, Hubei, China.
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14
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Labori KJ, Bratlie SO, Andersson B, Angelsen JH, Biörserud C, Björnsson B, Bringeland EA, Elander N, Garresori H, Grønbech JE, Haux J, Hemmingsson O, Liljefors MG, Myklebust TÅ, Nymo LS, Peltola K, Pfeiffer P, Sallinen V, Sandström P, Sparrelid E, Stenvold H, Søreide K, Tingstedt B, Verbeke C, Öhlund D, Klint L, Dueland S, Lassen K. Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2024; 9:205-217. [PMID: 38237621 DOI: 10.1016/s2468-1253(23)00405-3] [Citation(s) in RCA: 80] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 11/19/2023] [Accepted: 11/20/2023] [Indexed: 02/12/2024]
Abstract
BACKGROUND In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.
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Affiliation(s)
- Knut Jørgen Labori
- Department of Hepato Pancreato Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Svein Olav Bratlie
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Bodil Andersson
- Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden
| | - Jon-Helge Angelsen
- Department of Gastrointestinal Surgery, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Christina Biörserud
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Bergthor Björnsson
- Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Erling Audun Bringeland
- Department of Gastrointestinal Surgery, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Nils Elander
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK
| | - Herish Garresori
- Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Jon Erik Grønbech
- Department of Gastrointestinal Surgery, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Johan Haux
- Department of Oncology, Skaraborg Hospital Skövde, Skövde, Sweden; School of Health Sciences, University of Skövde, Skövde, Sweden
| | - Oskar Hemmingsson
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Maria Gustafsson Liljefors
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Tor Åge Myklebust
- Department of Registration, Cancer Registry of Norway, Oslo, Norway; Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway
| | - Linn Såve Nymo
- Department of Gastrointestinal Surgery, University Hospital of North Norway, Tromsø, Norway; Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway
| | - Katriina Peltola
- Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland
| | - Per Pfeiffer
- Department of Medical Oncology, Odense University Hospital, Odense, Denmark
| | - Ville Sallinen
- Gastroenterological Surgery/ Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Per Sandström
- Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Ernesto Sparrelid
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Helge Stenvold
- Department of Oncology, University Hospital of North Norway, Tromsø, Norway
| | - Kjetil Søreide
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
| | - Bobby Tingstedt
- Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden
| | - Caroline Verbeke
- Department of Pathology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Daniel Öhlund
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden; Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Leif Klint
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Svein Dueland
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Kristoffer Lassen
- Department of Hepato Pancreato Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway
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Kirkegård J, Ladekarl M, Lund A, Mortensen F. Impact on Survival of Early Versus Late Initiation of Adjuvant Chemotherapy After Pancreatic Adenocarcinoma Surgery: A Target Trial Emulation. Ann Surg Oncol 2024; 31:1310-1318. [PMID: 37914923 PMCID: PMC10761389 DOI: 10.1245/s10434-023-14497-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/10/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND We examined the impact of early (0-4 weeks after discharge) versus late (> 4-8 weeks after discharge) initiation of adjuvant chemotherapy on pancreatic adenocarcinoma survival. METHODS We used Danish population-based healthcare registries to emulate a hypothetical target trial using the clone-censor-weight approach. All eligible patients were cloned with one clone assigned to 'early initiation' and one clone assigned to 'late initiation'. Clones were censored when the assigned treatment was no longer compatible with the actual treatment. Informative censoring was addressed using inverse probability of censoring weighting. RESULTS We included 1491 patients in a hypothetical target trial, of whom 32.3% initiated chemotherapy within 0-4 weeks and 38.3% between > 4 and 8 weeks after discharge for pancreatic adenocarcinoma surgery; 206 (13.8%) initiated chemotherapy after > 8 weeks, and 232 (15.6%) did not initiate chemotherapy. Median overall survival was 30.4 and 29.9 months in late and early initiators, respectively. The absolute differences in OS, comparing late with early initiators, were 3.2% (95% confidence interval [CI] - 1.5%, 7.9%), - 0.7% (95% CI - 7.2%, 5.8%), and 3.2% (95% CI - 2.8%, 9.3%) at 1, 3, and 5 years, respectively. Late initiators had a higher increase in albumin levels as well as higher pretreatment albumin values. CONCLUSIONS Postponement of adjuvant chemotherapy up to 8 weeks after discharge from pancreatic adenocarcinoma surgery is safe and may allow more patients to receive adjuvant therapy due to better recovery.
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Affiliation(s)
- Jakob Kirkegård
- HPB Section, Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Morten Ladekarl
- Department of Oncology and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Andrea Lund
- HPB Section, Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Frank Mortensen
- HPB Section, Department of Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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16
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Feng Y, Yang J, Duan W, Cai Y, Liu X, Peng Y. LASSO-derived prognostic model predicts cancer-specific survival in advanced pancreatic ductal adenocarcinoma over 50 years of age: a retrospective study of SEER database research. Front Oncol 2024; 13:1336251. [PMID: 38288098 PMCID: PMC10822877 DOI: 10.3389/fonc.2023.1336251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Background This study aimed to develop a prognostic model for patients with advanced ductal adenocarcinoma aged ≥50 years. Methods Patient information was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to screen the model variables. Cases from Nanchang Central Hospital were collected for external validation. The new nomogram and the American Joint Committee on Cancer (AJCC) criteria were evaluated using integrated discrimination improvement (IDI) and net reclassification index (NRI) indicators. Survival curves presented the prognosis of the new classification system and AJCC criteria. Results In total, 17,621 eligible patients were included. Lasso Cox regression selected 4 variables including age, chemotherapy, radiotherapy and AJCC stage. The C-index of the training cohort was 0.721. The C-index value of the validation cohort was 0.729. The AUCs for the training cohorts at 1, 2, and 3 years were 0.749, 0.729, and 0.715, respectively. The calibration curves showed that the predicted and actual probabilities at 1, 2, and 3 years matched. External validation confirmed the model's outstanding predictive power. Decision curve analysis indicated that the clinical benefit of the nomogram was higher than that of the AJCC staging system. The model evaluation indices preceded the AJCC staging with NRI (1-year: 0.88, 2-year: 0.94, 3-year: 0.72) and IDI (1-year: 0.24, 2-year: 0.23, 3-year: 0.22). The Kaplan-Meier curves implied that the new classification system was more capable of distinguishing between patients at different risks. Conclusions This study established a prognostic nomogram and risk classification system for advanced pancreatic cancer in patients aged ≥50 years to provide a practical tool for the clinical management of patients with pancreatic ductal adenocarcinoma.
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Affiliation(s)
| | | | | | | | | | - Yong Peng
- Department of Hepatobiliary Pancreatic and Spleen Surgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
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17
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Lee YS, Kim HS, Kim HJ, Kang HW, Lee DE, Kim MJ, Hong WC, Kim JH, Kim M, Cheong JH, Park JS. The role of LOXL2 induced by glucose metabolism-activated NF-κB in maintaining drug resistance through EMT and cancer stemness in gemcitabine-resistant PDAC. J Mol Med (Berl) 2023; 101:1449-1464. [PMID: 37737908 PMCID: PMC10663195 DOI: 10.1007/s00109-023-02369-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 08/23/2023] [Accepted: 08/31/2023] [Indexed: 09/23/2023]
Abstract
Gemcitabine is considered a standard treatment for pancreatic cancer, but developing drug resistance greatly limits the effectiveness of chemotherapy and increases the rate of recurrence. Lysyl oxide-like 2 (LOXL2) is highly expressed in pancreatic cancer and is involved in carcinogenesis and EMT regulation. However, studies on the role of LOXL2 in drug resistance are limited. Here, we investigated the mechanism of LOXL2 induction and the effect of LOXL2 on EMT and CSC in gemcitabine-resistant pancreatic cancer. Glucose metabolism was activated in gemcitabine-resistant pancreatic cancer cells, and NF-κB signaling was regulated accordingly. Activated NF-κB directly induces transcription by binding to the promoters of LOXL2 and ZEB1. The EMT process was significantly inhibited by the coregulation of ZEB1 and LOXL2. In addition, LOXL2 inhibition reduced the expression of cancer stemness markers and stemness by regulating MAPK signaling activity. LOXL2 inhibits tumor growth of gemcitabine-resistant pancreatic cancer cells and increases the sensitivity to gemcitabine in mouse models. KEY MESSAGES: We identified a specific mechanism for inducing LOXL2 overexpression in gemcitabine-resistant pancreatic cancer. Taken together, our results suggest LOXL2 has an important regulatory role in maintaining gemcitabine resistance and may be an effective therapeutic target to treat pancreatic cancer.
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Affiliation(s)
- Yun Sun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyung Sun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyo Jung Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyeon Woong Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Da Eun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Myeong Jin Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Woosol Chris Hong
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Ju Hyun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Minsoo Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
- Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Joon Seong Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
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18
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Wu VS, Elshami M, Stitzel HJ, Lee JJ, Hue JJ, Kyasaram RK, Hardacre JM, Ammori JB, Winter JM, Selfridge JE, Mohamed A, Chakrabarti S, Bajor D, Mahipal A, Ocuin LM. Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer. Ann Surg 2023; 278:e677-e684. [PMID: 37071769 DOI: 10.1097/sla.0000000000005830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
OBJECTIVE To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (β = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.
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Affiliation(s)
- Victoria S Wu
- Case Western Reserve University School of Medicine, Cleveland, OH
| | - Mohamedraed Elshami
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Henry J Stitzel
- Case Western Reserve University School of Medicine, Cleveland, OH
| | - Jonathan J Lee
- Case Western Reserve University School of Medicine, Cleveland, OH
| | - Jonathan J Hue
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Ravi K Kyasaram
- Department of Cancer Informatics, University Hospitals Cleveland Medical Center/Seidman Cancer Center, Cleveland, OH
| | - Jeffrey M Hardacre
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - John B Ammori
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Jordan M Winter
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Jennifer Eva Selfridge
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Amr Mohamed
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Sakti Chakrabarti
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - David Bajor
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Amit Mahipal
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Lee M Ocuin
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
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19
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Russell TB, Labib PL, Ausania F, Pando E, Roberts KJ, Kausar A, Mavroeidis VK, Marangoni G, Thomasset SC, Frampton AE, Lykoudis P, Maglione M, Alhaboob N, Bari H, Smith AM, Spalding D, Srinivasan P, Davidson BR, Bhogal RH, Croagh D, Dominguez I, Thakkar R, Gomez D, Silva MA, Lapolla P, Mingoli A, Porcu A, Shah NS, Hamady ZZR, Al-Sarrieh B, Serrablo A, Aroori S. Serious complications of pancreatoduodenectomy correlate with lower rates of adjuvant chemotherapy: Results from the recurrence after Whipple's (RAW) study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:106919. [PMID: 37330348 DOI: 10.1016/j.ejso.2023.04.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/29/2023] [Accepted: 04/24/2023] [Indexed: 06/19/2023]
Abstract
INTRODUCTION Adjuvant chemotherapy (AC) can prolong overall survival (OS) after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, fitness for AC may be influenced by postoperative recovery. We aimed to investigate if serious (Clavien-Dindo grade ≥ IIIa) postoperative complications affected AC rates, disease recurrence and OS. MATERIALS AND METHODS Data were extracted from the Recurrence After Whipple's (RAW) study (n = 1484), a retrospective study of PD outcomes (29 centres from eight countries). Patients who died within 90-days of PD were excluded. The Kaplan-Meier method was used to compare OS in those receiving or not receiving AC, and those with and without serious postoperative complications. The groups were then compared using univariable and multivariable tests. RESULTS Patients who commenced AC (vs no AC) had improved OS (median difference: (MD): 201 days), as did those who completed their planned course of AC (MD: 291 days, p < 0.0001). Those who commenced AC were younger (mean difference: 2.7 years, p = 0.0002), more often (preoperative) American Society of Anesthesiologists (ASA) grade I-II (74% vs 63%, p = 0.004) and had less often experienced a serious postoperative complication (10% vs 18%, p = 0.002). Patients who developed a serious postoperative complication were less often ASA grade I-II (52% vs 73%, p = 0.0004) and less often commenced AC (58% vs 74%, p = 0.002). CONCLUSION In our multicentre study of PD outcomes, PDAC patients who received AC had improved OS, and those who experienced a serious postoperative complication commenced AC less frequently. Selected high-risk patients may benefit from targeted preoperative optimisation and/or neoadjuvant chemotherapy.
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Affiliation(s)
- Thomas B Russell
- University Hospitals Plymouth NHS Trust, Plymouth, UK; University of Plymouth, Plymouth, UK
| | - Peter L Labib
- University Hospitals Plymouth NHS Trust, Plymouth, UK
| | | | | | - Keith J Roberts
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Vasileios K Mavroeidis
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK; The Royal Marsden NHS Foundation Trust, London, UK
| | | | | | | | | | | | | | - Hassaan Bari
- Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan
| | | | | | | | | | | | | | - Ismael Dominguez
- Salvador Zubiran National Institute of Health Sciences and Nutrition, Mexico City, Mexico
| | - Rohan Thakkar
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Dhanny Gomez
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Michael A Silva
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Andrea Mingoli
- Policlinico Umberto I University Hospital Sapienza, Rome, Italy
| | - Alberto Porcu
- Azienda Ospedaliero Universitaria di Sassari, Sassari, Italy
| | - Nehal S Shah
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Zaed Z R Hamady
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | | | | | - Somaiah Aroori
- University Hospitals Plymouth NHS Trust, Plymouth, UK; University of Plymouth, Plymouth, UK.
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20
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Jain AJ, Maxwell JE, Katz MHG, Snyder RA. Surgical Considerations for Neoadjuvant Therapy for Pancreatic Adenocarcinoma. Cancers (Basel) 2023; 15:4174. [PMID: 37627202 PMCID: PMC10453019 DOI: 10.3390/cancers15164174] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/04/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease process with a 5-year survival rate of only 11%. Neoadjuvant therapy in patients with localized pancreatic cancer has multiple theoretical benefits, including improved patient selection for surgery, early delivery of systemic therapy, and assessment of response to therapy. Herein, we review key surgical considerations when selecting patients for neoadjuvant therapy and curative-intent resection. Accurate determination of resectability at diagnosis is critical and should be based on not only anatomic criteria but also biologic and clinical criteria to determine optimal treatment sequencing. Borderline resectable or locally advanced pancreatic cancer is best treated with neoadjuvant therapy and resection, including vascular resection and reconstruction when appropriate. Lastly, providing nutritional, prehabilitation, and supportive care interventions to improve patient fitness prior to surgical intervention and adequately address the adverse effects of therapy is critical.
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Affiliation(s)
| | | | | | - Rebecca A. Snyder
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (A.J.J.)
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21
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Lintern N, Smith AM, Jayne DG, Khaled YS. Photodynamic Stromal Depletion in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:4135. [PMID: 37627163 PMCID: PMC10453210 DOI: 10.3390/cancers15164135] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/13/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies, with a five-year survival of less than 10%. The resistance of the disease and the associated lack of therapeutic response is attributed primarily to its dense, fibrotic stroma, which acts as a barrier to drug perfusion and permits tumour survival and invasion. As clinical trials of chemotherapy (CT), radiotherapy (RT), and targeted agents have not been successful, improving the survival rate in unresectable PDAC remains an urgent clinical need. Photodynamic stromal depletion (PSD) is a recent approach that uses visible or near-infrared light to destroy the desmoplastic tissue. Preclinical evidence suggests this can resensitise tumour cells to subsequent therapies whilst averting the tumorigenic effects of tumour-stromal cell interactions. So far, the pre-clinical studies have suggested that PDT can successfully mediate the destruction of various stromal elements without increasing the aggressiveness of the tumour. However, the complexity of this interplay, including the combined tumour promoting and suppressing effects, poses unknowns for the clinical application of photodynamic stromal depletion in PDAC.
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Affiliation(s)
- Nicole Lintern
- School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
| | - Andrew M. Smith
- Leeds Institute of Medical Research, St James’s University Hospital, Leeds LS9 7TF, UK
| | - David G. Jayne
- Leeds Institute of Medical Research, St James’s University Hospital, Leeds LS9 7TF, UK
| | - Yazan S. Khaled
- Leeds Institute of Medical Research, St James’s University Hospital, Leeds LS9 7TF, UK
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22
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Thobie A, Robin F, Menahem B, Lubrano J, Boudjema K, Alves A, Dejardin O, Sulpice L. Influence of Hemorrhagic Complications of Pancreatoduodenectomy in Patients with Cancer on Short- and Long-Term Mortality. J Clin Med 2023; 12:jcm12082852. [PMID: 37109189 PMCID: PMC10143756 DOI: 10.3390/jcm12082852] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND With a mortality rate of up to 30%, post-pancreatectomy hemorrhage (PPH) remains a serious complication after pancreatoduodenectomy (PD) for cancer. Little is known about the long-term survival of patients after PPH. This retrospective study aimed to evaluate the impact of PPH on long-term survival after PD. METHODS The study included 830 patients (PPH, n = 101; non-PPH, n = 729) from two centers, who underwent PD for oncological indications. PPH was defined as any bleeding event occurring within 90 days after surgery. A flexible parametric survival model was used to determine the evolution of the risk of death over time. RESULTS At postoperative day 90, PPH significantly increased the mortality rate (PPH vs. non-PPH: 19.8% vs. 3.7%, p < 0.0001) and severe postoperative complication rate (85.1% vs. 14.1%, p < 0.0001), and decreased median survival (18.6 months vs. 30.1 months, p = 0.0001). PPH was associated with an increased mortality risk until the sixth postoperative month. After this 6-month period, PPH had no more influence on mortality. CONCLUSIONS PPH had a negative impact on the short-term overall survival beyond postoperative day 90 and up to six months after PD. However, compared to non-PPH patients, this adverse event had no impact on mortality after a 6-month period.
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Affiliation(s)
- Alexandre Thobie
- Department of Digestive Surgery, University Hospital of Caen, CS 30001, CEDEX 9, 14033 Caen, France
- "ANTICIPE" U1086 INSERM, Team Ligue Contre le Cancer, Centre François Baclesse, University of Caen Normandy, 14000 Caen, France
| | - Fabien Robin
- Department of Digestive Surgery, University Hospital of Rennes, 35000 Rennes, France
| | - Benjamin Menahem
- Department of Digestive Surgery, University Hospital of Caen, CS 30001, CEDEX 9, 14033 Caen, France
- "ANTICIPE" U1086 INSERM, Team Ligue Contre le Cancer, Centre François Baclesse, University of Caen Normandy, 14000 Caen, France
| | - Jean Lubrano
- Department of Digestive Surgery, University Hospital of Caen, CS 30001, CEDEX 9, 14033 Caen, France
| | - Karim Boudjema
- Department of Digestive Surgery, University Hospital of Rennes, 35000 Rennes, France
| | - Arnaud Alves
- Department of Digestive Surgery, University Hospital of Caen, CS 30001, CEDEX 9, 14033 Caen, France
- "ANTICIPE" U1086 INSERM, Team Ligue Contre le Cancer, Centre François Baclesse, University of Caen Normandy, 14000 Caen, France
| | - Olivier Dejardin
- "ANTICIPE" U1086 INSERM, Team Ligue Contre le Cancer, Centre François Baclesse, University of Caen Normandy, 14000 Caen, France
- Department of Clinical Research, University Hospital of Caen, 14000 Caen, France
| | - Laurent Sulpice
- Department of Digestive Surgery, University Hospital of Rennes, 35000 Rennes, France
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23
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Villano AM, Ruth K, Castellanos J, Farma JM, Reddy SS. Discrepancies in survival after conversion to open in minimally invasive pancreatoduodenectomy. Am J Surg 2023; 225:728-734. [PMID: 36333156 PMCID: PMC10656078 DOI: 10.1016/j.amjsurg.2022.10.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 11/01/2022]
Abstract
BACKGROUND The extent by which conversion to open (CTO) during minimally invasive procedures for pancreatic cancer impact survival outcomes is not fully understood. METHODS The 2010-2017 National Cancer Database identified 12,424 non-metastatic patients who underwent pancreatoduodenectomy for ductal adenocarcinoma. Patients were stratified into three cohorts: open (OPD), completed MIPD (cMIPD), and CTO. Subgroups were dichotomized by hospital MIPD volume. RESULTS Across the study period, 80.6% of patients underwent OPD, 19.4% MIPD, and 24% were CTO. Median overall survival was worse after CTO (21.8 months) than for OPD (23.6 months) or cMIPD (25.2 months) (p < 0.001). Although this effect persisted for <10 MIPD/year, CTO did comparably to OPD at hospitals performing ≥10MIPD/year (CTO = 26.8 months, OPD = 27.9 months; p = 0.128). Ninety-day mortality after CTO was worse at ≤ 10 MIPD/year hospitals (9.3% vs. 2.6%). CONCLUSIONS Short and long-term survival is impacted by CTO after MIPD, especially at lower surgical volumes, stressing careful adoption while ascending the learning curve.
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Affiliation(s)
- Anthony M Villano
- Division of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
| | - Karen Ruth
- Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jason Castellanos
- Division of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jeffrey M Farma
- Division of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Sanjay S Reddy
- Division of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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24
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de Geus SWL, Sachs TE. A Paradigm Shifts: Neoadjuvant Therapy for Clearly Resectable Pancreatic Cancer. Ann Surg Oncol 2023; 30:3427-3436. [PMID: 36869916 DOI: 10.1245/s10434-023-13281-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 02/12/2023] [Indexed: 03/05/2023]
Abstract
Over the past decade, neoadjuvant therapy has become the standard of care for patients with borderline resectable and locally advanced pancreatic cancer. The surgical community remains divided regarding the value of neoadjuvant therapy for patients who present with clearly resectable disease. Thus far, randomized controlled trials comparing neoadjuvant therapy with conventional upfront surgical strategies for patients with clearly resectable pancreatic cancer have been plagued by poor accrual, and are often underpowered. Nonetheless, meta-analyses of the results of these trials suggest that neoadjuvant therapy can be offered as an acceptable standard of care for patients with clearly resectable pancreatic cancer. Previous trials used neoadjuvant gemcitabine, but more recent studies have demonstrated superior survival for patients who were able to tolerate neoadjuvant FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin). The increased utilization of FOLFIRINOX may be shifting the treatment paradigm in favor of neoadjuvant therapy among patients with clearly resectable disease. Randomized controlled trials assessing the value of neoadjuvant FOLFIRINOX in clearly resectable pancreatic cancer, which are expected to provide more conclusive recommendations, are still ongoing. This review outlines the rationale, considerations, and current level of evidence for the use of neoadjuvant therapy in patients with clearly resectable pancreatic cancer.
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Affiliation(s)
- Susanna W L de Geus
- Department of Surgical Oncology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Teviah E Sachs
- Department of Surgical Oncology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
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25
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Djokovic N, Djuric A, Ruzic D, Srdic-Rajic T, Nikolic K. Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma. Pharmaceuticals (Basel) 2023; 16:294. [PMID: 37259439 PMCID: PMC9964546 DOI: 10.3390/ph16020294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/23/2023] [Accepted: 02/11/2023] [Indexed: 11/25/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.
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Affiliation(s)
- Nemanja Djokovic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Ana Djuric
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Dusan Ruzic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Tatjana Srdic-Rajic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Katarina Nikolic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
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26
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Andersson R, Tingstedt B. Neoadjuvant chemo(radio)therapy in upfront resectable pancreatic cancer - can we stratify patients better in the future? Scand J Gastroenterol 2023; 58:1-2. [PMID: 35856841 DOI: 10.1080/00365521.2022.2100226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023]
Affiliation(s)
- Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
| | - Bobby Tingstedt
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
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Nassoiy S, Christopher W, Marcus R, Keller J, Weiss J, Chang SC, Essner R, Foshag L, Fischer T, Goldfarb M. Evolving management of early stage pancreatic adenocarcinoma in older patients. Am J Surg 2023; 225:212-219. [PMID: 36058752 DOI: 10.1016/j.amjsurg.2022.07.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/25/2022] [Accepted: 07/28/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Due to the aging population, the number of older patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) will continue to rise. STUDY DESIGN Utilizing the NCDB from 2010 to 2016, patients with early stage, clinically node negative PDAC who were ≥70 years old and had a Whipple were identified. Multivariable logistic regressions were used to determine independent factors for R0 resection and NAT. Cox-proportional-hazards regression analyses examined for the impact of NAT on the risk of death. RESULTS Of 5086 patients, 51.7% received upfront surgery + adjuvant therapy (UFS + AT), followed by 29.9% UFS only, and the remainder NAT. NAT significantly improved OS compared to a combined cohort of those that had UFS ± AT. NAT retained its independent survival benefit when compared to only patients that had UFS + AT. CONCLUSION For older patients diagnosed with early stage PDAC, NAT was associated with improved R0 resection rates and a significant survival benefit when compared to the current standard of care.
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Affiliation(s)
- Sean Nassoiy
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
| | | | - Rebecca Marcus
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
| | - Jennifer Keller
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
| | - Jessica Weiss
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
| | | | - Richard Essner
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
| | - Leland Foshag
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
| | - Trevan Fischer
- Providence St. John's Cancer Institute, Santa Monica, CA, USA
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28
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Kohil A, Amir SS, Behrens A, Khan OM. A small Rho GTPase RAB25 with a potential role in chemotherapy resistance in pancreatic cancer. Cancer Biomark 2022; 36:133-145. [PMID: 36565104 DOI: 10.3233/cbm-220214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDA) is one of the major human health challenges with minimal therapeutic benefits due to its late detection, and de novo - and acquired chemotherapy resistance. OBJECTIVE In this work we unravel the potential pro-survival role of RAB25 in pancreatic cancer chemotherapy resistance and aim to identify if RAB25 is a prognostic marker of patients' survival in PDA. METHODS We used RNA sequencing, shRNA mediated gene knockdown, BioGRID open repository of CRISPR screens (ORCS), GEPIA, kmplot.com, and cBioPortal.org databases to identify the role of RAB25 in PDA cell proliferation, chemotherapy response, expression in tumour versus normal tissues, and overall patients' survival. RESULTS RNA sequencing show Rab25 to be one of the top upregulated genes in gemcitabine resistance mouse PDA cells. Knockdown of Rab25 in these cells enhanced gemcitabine toxicity. In addition, re-analysis of previously published CRISPR/Cas9 data confirm RAB25 to be responsible for chemotherapy resistance in KRASG12D mutant human pancreatic cancer cell line. Finally, we used publicly available TCGA datasets and identify the upregulation of RAB25 in tumour tissues compared to the adjacent normal tissue, co-occurrence of KRASG12 mutations with RAB25 amplifications, and poor patients' survival in cohorts with higher mRNA expression of RAB25. CONCLUSION RAB25 expression is a prognostic marker for patient's survival and gemcitabine resistance in PDA.
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Affiliation(s)
- Amira Kohil
- Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Sayeda S Amir
- Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Axel Behrens
- The Francis Crick Institute, London, UK.,Cancer Stem Cell Team, Institute of Cancer Research, London, UK
| | - Omar M Khan
- Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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29
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Zhang Q, Tang Y, Sun S, Xie Q, Yao J, Wang X, Qian J, Li Z. An extensive bioinformatics study on the role of mitochondrial solute carrier family 25 in PC and its mechanism behind affecting immune infiltration and tumor energy metabolism. J Transl Med 2022; 20:592. [PMID: 36514121 PMCID: PMC9746138 DOI: 10.1186/s12967-022-03756-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/05/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Several metabolic disorders and malignancies are directly related to abnormal mitochondrial solute carrier family 25 (SLC25A) members activity. However, its biological role in pancreatic cancer (PC) is not entirely understood. METHODS The lasso method was used to create a novel prognostic risk model for PC based on SLC25A members, and its roles in tumor immunology and energy metabolism were explored. Furthermore, co-expression networks were constructed for SLC25A11, SLC25A29, and SLC25A44. Single-cell RNA sequencing (ScRNA-seq) revealed the distribution of gene expression in PC. Tumor immune infiltration was examined with the TIMER database. Lastly, drug sensitivity was investigated, and co-transcriptional factors were predicted. RESULTS In the present study, a novel prognostic risk model was established and validated for PC based on SLC25A members. The high-risk group had a lower activation of oxidative phosphorylation and a more abundant immune infiltration phenotype than the low-risk group. According to co-expression network studies, SLC25A11, SLC25A29, and SLC25A44 were involved in the energy metabolism of PC and prevented tumor growth, invasion, and metastasis. ScRNA-seq research also pointed to their contribution to the tumor microenvironment. Moreover, the recruitment of numerous immune cells was positively correlated with SLC25A11 and SLC25A44 but negatively correlated with SLC25A29. Additionally, the sensitivity to 20 Food and Drug Administration-approved antineoplastic medicines was strongly linked to the aforementioned genes, where cisplatin sensitivity increased with the up-regulation of SLC25A29. Finally, the Scleraxis BHLH Transcription Factor (SCX) and other proteins were hypothesized to co-regulate the mRNA transcription of the genes. CONCLUSION SLC25A members are crucial for tumor immune and energy metabolism in PC, and SLC25A11, SLC25A29, and SLC25A44 can be used as favorable prognostic markers. The use of these markers will provide new directions to unravel their action mechanisms in PC.
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Affiliation(s)
- Qiang Zhang
- grid.268415.cMedical College of Yangzhou University, Yangzhou, Jiangsu 225000 China
| | - Yubao Tang
- grid.268415.cMedical College of Yangzhou University, Yangzhou, Jiangsu 225000 China
| | - Shuai Sun
- grid.411971.b0000 0000 9558 1426Dalian Medical University, Dalian, 111600 Liaoning China
| | - Qiuyi Xie
- grid.268415.cMedical College of Yangzhou University, Yangzhou, Jiangsu 225000 China
| | - Jie Yao
- grid.452743.30000 0004 1788 4869Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People’s Hospital, Yangzhou, 225001 Jiangsu China
| | - Xiaodong Wang
- grid.452743.30000 0004 1788 4869Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People’s Hospital, Yangzhou, 225001 Jiangsu China
| | - Jianjun Qian
- grid.452743.30000 0004 1788 4869Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People’s Hospital, Yangzhou, 225001 Jiangsu China
| | - Zhennan Li
- grid.452743.30000 0004 1788 4869Department of Hepatobiliary and Pancreatic Surgery, Northern Jiangsu People’s Hospital, Yangzhou, 225001 Jiangsu China
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30
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Amrutkar M, Verbeke CS, Finstadsveen AV, Dorg L, Labori KJ, Gladhaug IP. Neoadjuvant chemotherapy is associated with an altered metabolic profile and increased cancer stemness in patients with pancreatic ductal adenocarcinoma. Mol Oncol 2022; 17:59-81. [PMID: 36400567 PMCID: PMC9812839 DOI: 10.1002/1878-0261.13344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/03/2022] [Accepted: 11/17/2022] [Indexed: 11/21/2022] Open
Abstract
The modest clinical benefits of neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) are associated with a lack of robust data on treatment-induced changes in the tumor. To this end, comparative proteomic profiling of tumor tissue samples from treatment-naïve (TN, n = 20) and NAT-treated (n = 22) PDACs was performed. Differentially expressed proteins were identified and correlation with overall survival (OS) was performed. Tumors were also examined for histopathological changes and expression of cancer stem cell (CSC) markers. Serum from 33 matched patients was analyzed for metabolic markers. Cytotoxicity, proliferation, and expression of CSC markers were assessed in chemoresistant Panc-1 and Mia PaCa-2 cells. Of the 2265 proteins identified, 227 and 144 proteins showed significantly altered expression and differential phosphorylation, respectively, in NAT compared with TN samples. The majority of these were metabolism-related proteins, and 14 of these correlated moderately with OS. NAT-treated tumors and chemoresistant cancer cells showed increased expression of CSC markers. Serum ALDH1A1 was higher in NAT compared with TN. Differentially phosphorylated proteins were mainly involved in cytoskeleton organization, cell locomotion, motility, and migration, and 17 of these showed a strong positive correlation with OS. This study provides evidence of the effects of NAT on PDAC metabolism at both the tumor and the systemic levels. NAT-treated tumors showed significantly lower expression of metabolic proteins, and patients who underwent NAT showed reduced serum lactate and high-density lipoprotein-cholesterol. Lastly, cancer cells that survived cytotoxic treatment expressed higher CSC markers, both in vivo and in vitro.
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Affiliation(s)
- Manoj Amrutkar
- Department of PathologyOslo University HospitalNorway,Department of Pharmacology, Institute of Clinical MedicineUniversity of OsloNorway
| | - Caroline S. Verbeke
- Department of PathologyOslo University HospitalNorway,Department of Pathology, Institute of Clinical MedicineUniversity of OsloNorway
| | | | - Linda Dorg
- Department of Pathology, Institute of Clinical MedicineUniversity of OsloNorway
| | - Knut Jørgen Labori
- Department of Hepato‐Pancreato‐Biliary Surgery, Institute of Clinical MedicineUniversity of OsloNorway,Department of Hepato‐Pancreato‐Biliary SurgeryOslo University HospitalNorway
| | - Ivar P. Gladhaug
- Department of Hepato‐Pancreato‐Biliary Surgery, Institute of Clinical MedicineUniversity of OsloNorway,Department of Hepato‐Pancreato‐Biliary SurgeryOslo University HospitalNorway
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31
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Pan Y, Tang H, Li Q, Chen G, Li D. Exosomes and their roles in the chemoresistance of pancreatic cancer. Cancer Med 2022; 11:4979-4988. [PMID: 35587712 PMCID: PMC9761084 DOI: 10.1002/cam4.4830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/26/2022] [Accepted: 05/04/2022] [Indexed: 02/03/2023] Open
Abstract
Pancreatic cancer (PC) remains one of the most lethal human malignancies worldwide. Due to the insidious onset and the rapid progression, most patients with PC are diagnosed at an advanced stage rendering them inoperable. Despite the development of multiple promising chemotherapeutic agents as recommended first-line treatment for PC, the therapeutic efficacy is largely limited by unwanted drug resistance. Recent studies have identified exosomes as essential mediators of intercellular communications during the occurrence of drug resistance. Understanding the underlying molecular mechanisms and complex signaling pathways of exosome-mediated drug resistance will contribute to the improvement of the design of new oncologic therapy regimens. This review focuses on the intrinsic connections between the chemoresistance of PC cells and exosomes in the tumor microenvironment (TME).
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Affiliation(s)
- Yubin Pan
- Department of Medical Oncology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Honglin Tang
- Department of Medical Oncology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Qijun Li
- Department of Medical Oncology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Guangpeng Chen
- Department of Medical Oncology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
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32
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Christopher W, Nassoiy S, Marcus R, Keller J, Chang SC, Fischer T, Bilchik A, Goldfarb M. Neoadjuvant chemotherapy improves outcomes in resectable pancreatic adenocarcinoma. SURGERY IN PRACTICE AND SCIENCE 2022; 11:100136. [PMID: 39845164 PMCID: PMC11749821 DOI: 10.1016/j.sipas.2022.100136] [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: 05/12/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022] Open
Abstract
Background/Objectives Systemic chemotherapy is recommended for all stages of pancreatic ductal adenocarcinoma (PDAC), with a recent shift towards neoadjuvant chemotherapy (NAC) for resectable PDAC. The objective of this study was to compare outcomes of NAC versus AC for early stage resectable PDAC in the NCDB. Methods: Patients aged 18 or older with stage I or II PDAC in the National Cancer Database (NCDB) from 2010 to 2017 were identified. Logistic regression evaluated oncologic outcomes. Kaplan-Meier method followed by Cox proportional-hazards regression with inverse probability of treatment weighting (IPTW) using propensity score matching was used to compare overall survival (OS). Results NAC led to a 13% risk reduction of a positive resection margin (OR:0.87; 95%CI 0.78-0.97), and a 59% decreased risk of positive lymph nodes (OR:0.41; 95%CI 0.38-0.45). The median OS for all patients treated with NAC was 2.56 years versus 1.95 years for surgery +/- AC (p< 0.001). NAC had an OS benefit for all patients (HR:0.80; 95%CI 0.78-0.83), as well as for Stage I (HR:0.89; 95%CI 0.84-0.94) and Stage II patients (HR:0.71; 95%CI 0.68-0.75). Conclusions NAC appears to be associated with a survival benefit for patients with resectable PDAC. NAC also decreased the risk of a positive resection margin and positive lymph nodes at the time of surgery.
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Affiliation(s)
- Wade Christopher
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
| | - Sean Nassoiy
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
| | - Rebecca Marcus
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
| | - Jennifer Keller
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
| | - Shu-Ching Chang
- Providence Health and Services, Beaverton, OR, United States
| | - Trevan Fischer
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
| | - Anton Bilchik
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
| | - Melanie Goldfarb
- Providence St. John's Cancer Institute, Santa Monica, CA, United States
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Chase M, Friedman HS, Joo S, Navaratnam P. Adjuvant and neoadjuvant treatment patterns among resectable pancreatic cancer patients in the USA. Future Oncol 2022; 18:3929-3939. [PMID: 36520480 DOI: 10.2217/fon-2021-1583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Aim: Chemotherapy is standard before and/or after pancreatic cancer resection, yet benefits of pre-resection chemotherapy are unclear. Real-world pre- and post-resection treatment patterns were evaluated retrospectively. Methods: Neoadjuvant (3-months pre-surgery) and adjuvant (6-months post-surgery) treatment claims from 1 January 2016 to 31 December 2019 in US adults with resectable pancreatic cancer were analyzed. Results: Of the 737 patients, 29% received no chemotherapy in either setting; 22% received chemotherapy in both settings. In the neoadjuvant and adjuvant settings, 69 and 33% of patients, respectively, received no treatment at all. FOLFIRINOX and gemcitabine monotherapy were the most common chemotherapies in the neoadjuvant and adjuvant settings, respectively. Adjuvant FOLFIRINOX increased post-2018, whereas gemcitabine-based regimens decreased. Conclusion: Several chemotherapy regimens were used in both settings. Treatment patterns differed between the two settings.
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34
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Cheng H, Yang J, Fu X, Mao L, Chu X, Lu C, Li G, Qiu Y, He W. Folate receptor-positive circulating tumor cells predict survival and recurrence patterns in patients undergoing resection for pancreatic cancer. Front Oncol 2022; 12:1012609. [PMID: 36313690 PMCID: PMC9606765 DOI: 10.3389/fonc.2022.1012609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/26/2022] [Indexed: 12/03/2022] Open
Abstract
Objective To evaluate the prognostic impact of folate receptor (FR)-positive circulating tumor cells (FR+ CTCs) for patients with pancreatic cancer (PC). Background Risk stratification before surgery for PC patients remains challenging as there are no reliable prognostic markers currently. FR+ CTCs, detected by ligand-targeted polymerase chain reaction (LT-PCR), have shown excellent diagnostic value for PC in our previous study and prognostic value in a variety of cancer types. Methods Peripheral blood samples from 44 consecutive patients diagnosed with PC were analyzed for FR+ CTCs. 25 patients underwent tumor resection and were assigned to the surgical group. 19 patients failed to undergo radical resection because of local advance or distant metastasis and were assigned to the non-surgical group. The impact of CTCs on relapse and survival were explored. Results For the prognostic stratification, the optimal cut-off value of CTCs analyzed by receiver operating characteristic (ROC) curve was 14.49 folate units (FU)/3 ml. High CTC levels (> 14.49 FU/3 ml) were detected in 52.0% (13/25) of the patients in the surgical group and 63.2% (12/19) in the non-surgical group. In the surgical group, median disease-free survival (DFS) for patients with high CTC levels versus low CTC levels (< 14.49 FU/3 ml) was 8.0 versus 26.0 months (P = 0.008). In multivariable analysis, CTCs were an independent risk factor for DFS (HR: 4.589, P = 0.012). Concerning the recurrence patterns, patients with high CTC levels showed a significantly frequent rate of distant and early recurrence (P = 0.017 and P = 0.011). CTC levels remained an independent predictor for both distant (OR: 8.375, P = 0.014) and early recurrence (OR: 8.412, P = 0.013) confirmed by multivariable logistic regression. However, CTCs did not predict survival in the non-surgical group (P = 0.220). Conclusion FR+ CTCs in resected PC patients could predict impaired survival and recurrence patterns after surgery. Preoperative CTC levels detected by LT-PCR may help guide treatment strategies and further studies in a larger cohort are warranted.
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Affiliation(s)
- Hao Cheng
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Yang
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xu Fu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Mao
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xuehui Chu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chenglin Lu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Gang Li
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yudong Qiu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Yudong Qiu, ; Wei He,
| | - Wei He
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Yudong Qiu, ; Wei He,
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35
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Andersson R, Haglund C, Seppänen H, Ansari D. Pancreatic cancer - the past, the present, and the future. Scand J Gastroenterol 2022; 57:1169-1177. [PMID: 35477331 DOI: 10.1080/00365521.2022.2067786] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Pancreatic cancer has been and still is associated with a very poor prognosis. This is due to a lack of major breakthroughs with respect to early diagnosis, prognostication, prediction, as well as novel, targeted therapies. The benefits of surgery and chemotherapy are evident, but the fact that only some 10% of all patients have early, localized disease highlights the unmet need for new early detection methods. An improved understanding of tumor biology and the development of molecular markers detectable both in the circulation and in cancer tissues may underlie the development of new tools for optimizing both diagnosis and treatment. MATERIAL AND METHODS Review of the literature. RESULTS AND CONCLUSION If we do not improve precision oncology for pancreatic ductal adenocarcinoma, the prognosis will still remain dismal and the" burden" on society will increase substantially.
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Affiliation(s)
- Roland Andersson
- Surgery, Department of Clinical Sciences Lund Lund University, Skåne University Hospital, Lund, Sweden
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Seppänen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Daniel Ansari
- Surgery, Department of Clinical Sciences Lund Lund University, Skåne University Hospital, Lund, Sweden
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36
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Drake JA, Fleming AM, Behrman SW, Glazer ES, Deneve JL, Yakoub D, Tsao MW, Dickson PV. Tumor Location in the Pancreatic Tail Is Associated with Decreased Likelihood of Receiving Chemotherapy for Pancreatic Adenocarcinoma. J Gastrointest Surg 2022; 26:2136-2147. [PMID: 35768717 DOI: 10.1007/s11605-022-05381-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/02/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND Chemotherapy (CTX) is associated with improved survival for patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). The current study evaluated the influence of tumor location on receipt of CTX. METHODS The NCDB (2006-2017) was queried to identify patients with clinical stage I-III PDAC. Predictors of receipt of CTX, sequencing of CTX, and overall survival (OS) were analyzed. RESULTS Among 14,557 patients who underwent resection for PDAC 3,453 (24%) did not receive CTX. On multivariable analysis, patients with tail tumors were 15% less likely to receive CTX (OR 0.85, 95% CI 0.747-0.968) and 58% less likely to receive neoadjuvant CTX (OR 0.42, 95% CI 0.351-0.509) relative to patients with head/neck tumors. For patients with body tumors, there was no difference in rates of administration or sequence of CTX. For patients with resected tail tumors, median OS was 29.9 vs 18.9 months (p < 0.001) between those who did and did not receive CTX. For patients with tail tumors, independent predictors of not receiving CTX, regardless of sequence, were increasing age (OR 0.95, 95% CI 0.935-0.965), increasing post-op length of stay (OR 0.95, 95% CI 0.932-0.968), and 30-day post-op readmission (OR 0.46, 95% CI 0.315-0.670). CONCLUSIONS In patients with clinical stage I-III PDAC, tumor location within the tail was independently associated with not receiving CTX. Given the marked improvement in OS when CTX is administered, strategies aimed at increasing the number of these patients who receive CTX are necessary.
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Affiliation(s)
- Justin A Drake
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Andrew M Fleming
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Stephen W Behrman
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Evan S Glazer
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Jeremiah L Deneve
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Danny Yakoub
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Miriam W Tsao
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA
| | - Paxton V Dickson
- Department of Surgery, Division of Surgical Oncology, University of Tennessee Health Science Center, 910 Madison Ave., 3rdFloor, Memphis, TN, 38163, USA.
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Identification of Candidate Therapeutic Target Genes and Profiling of Tumor-Infiltrating Immune Cells in Pancreatic Cancer via Integrated Transcriptomic Analysis. DISEASE MARKERS 2022; 2022:3839480. [PMID: 36061357 PMCID: PMC9428685 DOI: 10.1155/2022/3839480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/02/2022] [Accepted: 08/10/2022] [Indexed: 11/18/2022]
Abstract
Pancreatic cancer (PC) has a dismal prognosis despite advancing scientific and technological knowledge. The exploration of novel genes is critical to improving current therapeutic measures. This research is aimed at selecting hub genes that can act as candidate therapeutic target genes and as prognostic biomarkers in PC. Gene expression profiles of datasets GSE101448, GSE15471, and GSE62452 were extracted from the GEO database. The “limma” package was performed to select differentially expressed genes (DEGs) between PC and normal tissue samples in each dataset. Robust rank aggregation (RRA) algorithm was conducted to integrate multiple expression profiles and identify robust DEGs. GO analysis and KEGG analysis were conducted to identify the functional correlation of the DEGs. The CIBERSORT algorithm was conducted to estimate the immune cell composition of each tissue sample. STRING and Cytoscape were used to establish the protein-protein interaction (PPI) network. The cytoHubba plugin in Cytoscape was performed to identify hub genes. Survival analysis based on hub gene expression was performed with clinical information from TCGA database. 566 robust DEGs (338 upregulated genes and 226 downregulated genes) were identified. Tumor tissue had a higher infiltration of resting dendritic cells and tumor-associated macrophages (TAM), including M0, M1, and M2 macrophages, while infiltration levels of B memory cells, plasma cells, T cells CD8, T follicular helper cells, and NK cells in normal tissue were relatively higher. GO terms and KEGG pathway analysis results revealed enrichment in tumor-associated pathways, including the extracellular matrix organization, cell−substrate adhesion cytokine−cytokine receptor interaction, calcium signaling pathway, and glycine, serine, and threonine metabolism, to name a few. Finally, FN1, MSLN, PLAU, and VCAN were selected as hub genes. High expression of FN1, MSLN, PLAU, and VCAN in PC significantly correlated with poor prognosis. Integrated transcriptomic analysis was used to provide new insights into PC pathogenesis. FN1, MSLN, PLAU, and VCAN may be considered as novel biomarkers of PC.
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Landa K, Schmitz R, Farrow NE, Rushing C, Niedzwiecki D, Cerullo M, Herbert GS, Shah KN, Zani S, Blazer DG, Allen PJ, Lidsky ME. Surgical resection is associated with improved long-term survival of patients with resectable pancreatic head cancer compared to multiagent chemotherapy. HPB (Oxford) 2022; 24:1153-1161. [PMID: 34987008 DOI: 10.1016/j.hpb.2021.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/02/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Standard of care for resectable pancreatic cancer is a combination of surgical resection (SR) and multiagent chemotherapy (MCT). We aim to determine whether SR or MCT is associated with superior survival for patients receiving only single-modality therapy. METHODS Patients with stage I-IIb pancreatic head adenocarcinoma who received either MCT or SR were identified in the NCDB (2013-2015). Following a piecewise approach to estimating hazards over the course of follow-up, conditional overall survival (OS) at 30, 60, and 90 days after treatment initiation was estimated using landmark analyses. RESULTS 3103 patients received MCT alone (60.3%) and 2043 underwent SR alone (39.7%). SR had an OS disadvantage at 30 (HR 3.99, 95% CI 3.12-5.11) and 60 days (HR 1.85, 95% CI 1.4-2.45), but an OS advantage after 90 days (HR 0.59, 95% CI 0.55-0.64). In a landmark analysis conditioned on 90 days survival post treatment initiation, median OS was improved for SR (17.0 vs. 12.2 months, p < 0.0001); SR improved 3-year OS by 21.3% (p < 0.05), despite patients being older (median 72 vs. 67 years, p < 0.0001) with higher Charlson-Deyo comorbidity scores (≥2: 11.2 vs. 8.6%, p = 0.006). CONCLUSION For patients with resectable pancreatic cancer, SR is associated with superior long-term survival compared to MCT.
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Affiliation(s)
- Karenia Landa
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Robin Schmitz
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
| | - Norma E Farrow
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Christel Rushing
- Department of Biostatistics & Bioinformatics, Duke University, Durham, NC 27710, USA
| | - Donna Niedzwiecki
- Department of Biostatistics & Bioinformatics, Duke University, Durham, NC 27710, USA
| | - Marcelo Cerullo
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Garth S Herbert
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Kevin N Shah
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Sabino Zani
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Dan G Blazer
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Peter J Allen
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Michael E Lidsky
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
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Zhang W, Ji L, Zhong X, Zhu S, Zhang Y, Ge M, Kang Y, Bi Q. Two Novel Nomograms Predicting the Risk and Prognosis of Pancreatic Cancer Patients With Lung Metastases: A Population-Based Study. Front Public Health 2022; 10:884349. [PMID: 35712294 PMCID: PMC9194823 DOI: 10.3389/fpubh.2022.884349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 05/16/2022] [Indexed: 11/19/2022] Open
Abstract
Background Pancreatic cancer (PC) is one of the most common malignant types of cancer, with the lung being the frequent distant metastatic site. Currently, no population-based studies have been done on the risk and prognosis of pancreatic cancer with lung metastases (PCLM). As a result, we intend to create two novel nomograms to predict the risk and prognosis of PCLM. Methods PC patients were selected from the Surveillance, Epidemiology, and End Results Program (SEER) database from 2010 to 2016. A multivariable logistic regression analysis was used to identify risk factors for PCLM at the time of diagnosis. The multivariate Cox regression analysis was carried out to assess PCLM patient's prognostic factors for overall survival (OS). Following that, we used area under curve (AUC), time-dependent receiver operating characteristics (ROC) curves, calibration plots, consistency index (C-index), time-dependent C-index, and decision curve analysis (DCA) to evaluate the effectiveness and accuracy of the two nomograms. Finally, we compared differences in survival outcomes using Kaplan-Meier curves. Results A total of 803 (4.22%) out of 19,067 pathologically diagnosed PC patients with complete baseline information screened from SEER database had pulmonary metastasis at diagnosis. A multivariable logistic regression analysis revealed that age, histological subtype, primary site, N staging, surgery, radiotherapy, tumor size, bone metastasis, brain metastasis, and liver metastasis were risk factors for the occurrence of PCLM. According to multivariate Cox regression analysis, age, grade, tumor size, histological subtype, surgery, chemotherapy, liver metastasis, and bone metastasis were independent prognostic factors for PCLM patients' OS. Nomograms were constructed based on these factors to predict 6-, 12-, and 18-months OS of patients with PCLM. AUC, C-index, calibration curves, and DCA revealed that the two novel nomograms had good predictive power. Conclusion We developed two reliable predictive models for clinical practice to assist clinicians in developing individualized treatment plans for patients.
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Affiliation(s)
- Wei Zhang
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Qingdao University, Qingdao, China
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Lichen Ji
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xugang Zhong
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Qingdao University, Qingdao, China
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Senbo Zhu
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Zhang
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Qingdao University, Qingdao, China
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Meng Ge
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Yao Kang
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, Hangzhou Medical College People's Hospital, Hangzhou, China
| | - Qing Bi
- Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, China
- Department of Orthopedics, Hangzhou Medical College People's Hospital, Hangzhou, China
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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Roy-Luzarraga M, Reynolds LE, de Luxán-Delgado B, Maiques O, Wisniewski L, Newport E, Rajeeve V, Drake RJ, Gómez-Escudero J, Richards FM, Weller C, Dormann C, Meng YM, Vermeulen PB, Saur D, Sanz-Moreno V, Wong PP, Géraud C, Cutillas PR, Hodivala-Dilke K. Suppression of Endothelial Cell FAK Expression Reduces Pancreatic Ductal Adenocarcinoma Metastasis after Gemcitabine Treatment. Cancer Res 2022; 82:1909-1925. [PMID: 35350066 PMCID: PMC9381116 DOI: 10.1158/0008-5472.can-20-3807] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/07/2022] [Accepted: 03/25/2022] [Indexed: 02/02/2023]
Abstract
Despite substantial advances in the treatment of solid cancers, resistance to therapy remains a major obstacle to prolonged progression-free survival. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a high level of liver metastasis. Primary PDAC is highly hypoxic, and metastases are resistant to first-line treatment, including gemcitabine. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy-induced angiocrine factors and chemosensitivity in primary tumor models. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC is not sufficient to affect primary tumor growth but reduces liver and lung metastasis load and improves survival rates in gemcitabine-treated, but not untreated, mice. EC-FAK loss did not affect primary tumor angiogenesis, tumor blood vessel leakage, or early events in metastasis, including the numbers of circulating tumor cells, tumor cell homing, or metastatic seeding. Phosphoproteomics analysis showed a downregulation of the MAPK, RAF, and PAK signaling pathways in gemcitabine-treated FAK-depleted ECs compared with gemcitabine-treated wild-type ECs. Moreover, low levels of EC-FAK correlated with increased survival and reduced relapse in gemcitabine-treated patients with PDAC, supporting the clinical relevance of these findings. Altogether, we have identified a new role of EC-FAK in regulating PDAC metastasis upon gemcitabine treatment that impacts outcome. SIGNIFICANCE These findings establish the potential utility of combinatorial endothelial cell FAK targeting together with gemcitabine in future clinical applications to control metastasis in patients with pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Marina Roy-Luzarraga
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Louise E. Reynolds
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Beatriz de Luxán-Delgado
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Oscar Maiques
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Laura Wisniewski
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Emma Newport
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Vinothini Rajeeve
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Rebecca J.G. Drake
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Jesús Gómez-Escudero
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Frances M. Richards
- Translational Medicine Operations, Astrazeneca Oncology, Darwin Building, Cambridge Science Park, Milton Road, Cambridge, United Kingdom
| | - Céline Weller
- Department of Dermatology, Section of Clinical and Molecular Dermatology, Venereology and Allergology, University Medical Center and European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christof Dormann
- Department of Dermatology, Section of Clinical and Molecular Dermatology, Venereology and Allergology, University Medical Center and European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ya-Ming Meng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Peter B. Vermeulen
- Department of Oncological Research, Translational Cancer Research Unit, Oncology Center GZA—GZA Hospitals St. Augustinus and University of Antwerp, Antwerp, Belgium
| | - Dieter Saur
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg and Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, München, Germany
| | - Victoria Sanz-Moreno
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Ping-Pui Wong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cyrill Géraud
- Department of Dermatology, Section of Clinical and Molecular Dermatology, Venereology and Allergology, University Medical Center and European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Pedro R. Cutillas
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
| | - Kairbaan Hodivala-Dilke
- Barts Cancer Institute—A CR-UK Center of Excellence, Queen Mary University of London, John Vane Science Center, Charterhouse Square, London, United Kingdom
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Labori KJ. Short-Course or Total Neoadjuvant Chemotherapy in Resectable and Borderline Resectable Pancreatic Cancer - Current Status and Future Perspectives. Front Surg 2022; 9:839339. [PMID: 35548190 PMCID: PMC9082635 DOI: 10.3389/fsurg.2022.839339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 02/28/2022] [Indexed: 12/27/2022] Open
Abstract
Neoadjuvant therapy improves overall survival compared with a surgery-first approach in patients with borderline resectable pancreatic cancer (BRPC). Evidence of higher quality is required to determine whether neoadjuvant therapy has potential benefits and improves survival for patients with resectable pancreatic cancer (RPC). Most randomized controlled trials (RCTs) have explored short-course neoadjuvant chemotherapy (SNT), but total neoadjuvant chemotherapy (TNT) is now the experimental arm of ongoing RCTs. This article reviews the current status of SNT and TNT in RPC and BRPC, and provides perspectives of future challenges and research directions in this field.
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Affiliation(s)
- Knut Jørgen Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Xiao W, Pahlavanneshan M, Eun CY, Zhang X, DeKalb C, Mahgoub B, Knaneh-Monem H, Shah S, Sohrabi A, Seidlits SK, Hill R. Matrix stiffness mediates pancreatic cancer chemoresistance through induction of exosome hypersecretion in a cancer associated fibroblasts-tumor organoid biomimetic model. Matrix Biol Plus 2022; 14:100111. [PMID: 35619988 PMCID: PMC9126837 DOI: 10.1016/j.mbplus.2022.100111] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/05/2022] [Accepted: 05/11/2022] [Indexed: 12/26/2022] Open
Abstract
Pancreatic cancer organoid-stromal fibroblasts co-culture displayed significant chemoresistance in 3D culture system. Cancer associated fibroblasts in the physiologically relevant matrix system tended to be more phenotypically activated. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting exosomes in a cancer associated fibroblasts-tumor organoid biomimetic model system. In pancreatic ductal adenocarcinoma (PDAC), the abundant stromal cells which comprise the tumor microenvironment constitute more than 90% of the primary tumor bulk. Moreover, this desmoplastic environment has been found to be three times stiffer than normal pancreas tissue. Despite the importance of studying the desmoplastic environment of PDAC, there is still a lack of models designed to adequately recapitulate this complex stiff microenvironment, a critical hallmark of the disease that has been shown to induce chemoresistance. Here, we present a bio-mimetic, 3-dimensional co-culture system that integrates tumor organoids and host-matching stromal cancer associated-fibroblasts (CAFs) that recapitulates the complex, fibrotic matrix of PDAC using advanced biomaterials. With this model, we show that matrix-activated CAFs are able to “re-engineer” the fibrotic environment into a significantly stiffer environment through lysyl-oxidase dependent crosslinking. Moreover, we show that culture of CAFs in this model leads to an increase of exosomes; extracellular vesicles known to promote chemoresistance. Finally, using previously identified exosome inhibitors, climbazole and imipramine, we demonstrate how abrogation of exosome hypersecretion can reduce matrix stiffness-induced chemoresistance. These data highlight the importance of the development of new models that recapitulate not only the cellular composition found in PDAC tumors, but also the biophysical stresses, like stiffness, that the cells are exposed to in order to identify therapies that can overcome this critical feature which can contribute to the chemoresistance observed in patients. We believe that the 3D bio-mimetic model we have developed will be a valuable tool for the development, testing, and optimization of “mechano-medicines” designed to target the biophysical forces that lead to tumor growth and chemoresistance.
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Affiliation(s)
- Weikun Xiao
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
| | - Mahsa Pahlavanneshan
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90007, United States
| | - Chae-Young Eun
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
| | - Xinyu Zhang
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
| | - Charlene DeKalb
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
| | - Bayan Mahgoub
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
| | - Hanaa Knaneh-Monem
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
| | - Sana Shah
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
- Health Promotion and Disease Prevention Studies, University of Southern California, Los Angeles, CA 90033, United States
| | - Alireza Sohrabi
- Department of Bioengineering, University of California, Los Angeles, CA 90095, United States
| | - Stephanie K. Seidlits
- Department of Bioengineering, University of California, Los Angeles, CA 90095, United States
| | - Reginald Hill
- Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
- Corresponding author at: Lawrence J. Ellison Institute for Transformative Medicine of USC, Los Angeles, CA 90064, United States.
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A Randomized Placebo-Controlled Phase 2 Study of Gemcitabine and Capecitabine with or without T-ChOS as Adjuvant Therapy in Patients with Resected Pancreatic Cancer (CHIPAC). Pharmaceutics 2022; 14:pharmaceutics14030509. [PMID: 35335885 PMCID: PMC8955369 DOI: 10.3390/pharmaceutics14030509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/17/2022] [Accepted: 02/23/2022] [Indexed: 02/07/2023] Open
Abstract
The antitumor activity of chitooligosaccharides has been suggested. This phase 2 trial evaluated the efficacy and safety of T-ChOS™, in addition to adjuvant chemotherapy, in patients after resection of pancreatic ductal adenocarcinoma (PDAC). In this single-center, randomized, double-blind, placebo-controlled trial using patients ≥18 years of age after complete macroscopic resection for PDAC, patients were randomly assigned (1:1) to either a continuous oral T-ChOS group or a placebo group, in combination with gemcitabine (GEM) and oral capecitabine (CAP), for a maximum of six cycles. The primary endpoint was disease-free survival (DFS). Recruitment was stopped prematurely in July 2018, with 21 of planned 180 patients included, due to poor accrual and because modified FOLFIRINOX replaced GEM/CAP for the target population. Nine patients received T-ChOS and twelve received the placebo. The median DFS was 10.8 months (95% CI 5.9–15.7) for the T-ChOS arm and 8.4 months (95% CI 0–21.5) in the placebo arm. Overall, seven patients (78%) in the T-ChOS arm and eight patients (67%) in the placebo arm experienced at least one grade 3–4 treatment-related adverse event, most frequently neutropenia. Altogether, the addition of T-ChOS to chemotherapy in patients after resection of PDAC seems safe. However, the clinical benefit cannot be assessed due to the premature cessation of the trial.
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Xing Y, Zhang X, Qin F, Yang J, Ai L, Wang Q, Zhai Y. The clinical significance of circulating tumor cells and T lymphocyte subtypes in pancreatic cancer patients. Bioengineered 2022; 13:2130-2138. [PMID: 35034581 PMCID: PMC8973992 DOI: 10.1080/21655979.2021.2023800] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Circulating tumor cells (CTCs) are sensitive and reliable biomarkers for tracing relapsed and metastatic cancer. Here, we explore the clinical significance of CTCs and T lymphocyte subtypes in patients with pancreatic cancer. A total of 106 patients with the pancreatic cancer were enrolled in this study. The enrichment and identification of CTCs were achieved before treatment by a PatrolCTC detection technique. Flow cytometry (FACS) was used to characterize CD4, CD8, natural killer (NK) cells, and Tregulatory (Treg) lymphocyte subtypes. Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-17A (IL-17A), Interleukin-10 (IL-10), and Interferon γ (IFN-γ) were measured by meso-scale discovery (MSD) assay. Among these patients, 44 (41.5%) patients with pancreatic ductal adenocarcinoma (PDAC) were female and 62 (58.5%) cases were male. Case numbers with II-IV tumor-node-metastasis (TNM) stages were 32 (30.2%), 50 (47.2%), and 24 (22.6%), respectively. The positive rate of CTCs before surgery was 37.5% (12/32), 88.0% (44/50) and 100% (24/24) in stage II, III, and IV patients, respectively. Total CTCs, mixed CTCs, and mesenchymal CTCs (MCTCs) were strongly relevant to shorter progression-free survival (PFS) of the patients. In addition, total CTCs (≥6) and positive MCTCs were also significantly correlated with recurrence and metastasis. The patients with high CTCs also had low levels of CD4, CD4/CD8 ratio, NK cells, IL-2, and IFNγ. In contrast, Treg cells had significant elevation in PDAC patients. These results indicated that CTCs number in PDAC patients was an independent indicator for worse PFS. High CTCs also had strong correlation with weak cellular immunity functions.
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Affiliation(s)
- Yasi Xing
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Xinfa Zhang
- General Surgery, Shandong Provincial Coal Taishan Sanatorium, Taian, Shandong, China
| | - Fangyuan Qin
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Jingwen Yang
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Lei Ai
- Department of Clinical Laboratory, Shandong Provincial Coal Taishan Sanitarium, Taian, Shandong, China
| | - Qingsong Wang
- General Surgery, Shandong Provincial Coal Taishan Sanatorium, Taian, Shandong, China
| | - Yaping Zhai
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
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Yamamichi T, Ichinose J, Omura K, Hashimoto K, Matsuura Y, Nakao M, Okumura S, Ikeda N, Mun M. Impact of postoperative complications on the long-term outcome in lung cancer surgery. Surg Today 2022; 52:1254-1261. [PMID: 35041090 DOI: 10.1007/s00595-022-02452-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/26/2021] [Indexed: 12/09/2022]
Abstract
PURPOSE Postoperative complications have a significant impact on perioperative outcomes; however, their association with the long-term prognosis remains unclear. We evaluated the impact of postoperative complications on the long-term outcomes after curative surgery in lung cancer patients. METHODS This study included 1129 patients with primary lung cancer who underwent lobectomy between April 2011 and March 2017. Univariate and multivariate analyses were performed to assess the association of postoperative complications with the overall and recurrence-free survival. RESULTS Postoperative complications were observed in 147 (13.0%) patients over a median follow-up period of 5-years. Compared to patients without complications, those with complications showed had worse long-term outcomes, including the 5-year overall survival (75.3% vs. 86.1%, p < 0.001) and 5-year recurrence-free survival (64.2% vs. 74.4%, p = 0.004). A multivariate analysis revealed that the incidence of postoperative complications was significantly associated with the overall survival (hazard ratio = 1.665, p = 0.006) and recurrence-free survival (hazard ratio = 1.416, p = 0.025) in all patients. The prognostic influence was greater in patients with pathological stages II and III cancer (overall survival: hazard ratio = 2.019, p = 0.005; recurrence-free survival: hazard ratio = 1.90, p = 0.001) than in those with pathological stage I cancer. CONCLUSION Postoperative complications are independent predictors of the overall and recurrence-free survival in lung cancer patients, especially advanced-stage cancer patients.
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Affiliation(s)
- Takashi Yamamichi
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Junji Ichinose
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Kenshiro Omura
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Kohei Hashimoto
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Yosuke Matsuura
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Masayuki Nakao
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Sakae Okumura
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Norihiko Ikeda
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Mingyon Mun
- Department of Thoracic Surgical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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Hall WA, Dawson LA, Hong TS, Palta M, Herman JM, Evans DB, Tsai S, Ferrone CR, B. Fleming J, Chang DT, Crane C, Koong AC, Oar A, Parikh P, Erickson B, Hoffe S, Goodman KA. Value of Neoadjuvant Radiation Therapy in the Management of Pancreatic Adenocarcinoma. J Clin Oncol 2021; 39:3773-3777. [PMID: 34623894 PMCID: PMC8608256 DOI: 10.1200/jco.21.01220] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/10/2021] [Accepted: 09/09/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- William A. Hall
- Medical College of Wisconsin, Department of Radiation Oncology and the LaBahn Pancreatic Cancer Program, Milwaukee, WI
- Medical College of Wisconsin, Department of Surgery and the LaBahn Pancreatic Cancer Program, Milwaukee, WI
| | - Laura A. Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre; Department of Radiation Oncology, University of Toronto, Toronto, Canada
| | - Theodore S. Hong
- Massachusetts General Hospital, Department of Radiation Oncology, Boston, MA
| | - Manisha Palta
- Duke University, Department of Radiation Oncology, Durham, NC
| | - Joseph M. Herman
- Northwell Health, Department of Radiation Oncology, New Hyde Park, NY
| | - Douglas B. Evans
- Medical College of Wisconsin, Department of Surgery and the LaBahn Pancreatic Cancer Program, Milwaukee, WI
| | - Susan Tsai
- Medical College of Wisconsin, Department of Surgery and the LaBahn Pancreatic Cancer Program, Milwaukee, WI
| | | | | | - Daniel T. Chang
- Stanford Health Care, Department of Radiation Oncology, Stanford, CA
| | - Christopher Crane
- Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY
| | - Albert C. Koong
- MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX
| | - Andrew Oar
- Gold Coast University Hospital, Gold Coast, Queensland, Australia
| | - Parag Parikh
- Henry Ford Health System, Department of Radiation Oncology, Detroit, MI
| | - Beth Erickson
- Medical College of Wisconsin, Department of Radiation Oncology and the LaBahn Pancreatic Cancer Program, Milwaukee, WI
- Medical College of Wisconsin, Department of Surgery and the LaBahn Pancreatic Cancer Program, Milwaukee, WI
| | - Sarah Hoffe
- Moffitt Cancer Center, Department of Surgery, Tampa, FL
| | - Karyn A. Goodman
- Mount Sinai Hospital, Department of Radiation Oncology, New York, NY
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Lee SH, Hwang HK, Lee WJ, Kang CM. MCT4 as a potential therapeutic target to augment gemcitabine chemosensitivity in resected pancreatic cancer. Cell Oncol (Dordr) 2021; 44:1363-1371. [PMID: 34791637 DOI: 10.1007/s13402-021-00643-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pancreatic cancer is a devastating disease with a high relapse rate, even in case of resectable pancreatic cancer. Here, we aimed to identify the prognostic significance and therapeutic options of metabolic subtypes of resectable pancreatic cancer. METHOD Transcriptomic data were obtained from the TCGA-PAAD cohort in the The Cancer Genome Atlas (TCGA) data portal (n = 182). After integrative analysis of transcriptomic data in the discovery cohort, immunohistochemical (IHC) staining was performed in an independent cohort (n = 51) to validate the molecules of interest. Experimental testing for the molecules of interest was performed in vitro using pancreatic cancer cell line models AsPC1, BxPC3, MIA PaCa-2 and PANC-1. RESULTS Two subtypes showing distinct gene expression patterns in the TCGA-PAAD dataset were identified. Of these, the active glucose metabolism subtype showed a significantly lower survival rate related to relapse after surgical resection. The genes SLC2A1 (GLUT1) and SLC16A3 (MCT4) were highly enriched in this subtype. The validation cohort showed a high MCT4 staining and a high relapse rate (p = 0.01). Several molecular pathways associated with aggressive tumor biology, including cell cycle regulation and Myc and mTOR downstream signaling, were highly enriched in the active glucose metabolism subtype, as well as with distinct responses to immunotherapy. MCT4 inhibition suppressed the in vitro malignant characteristics of pancreatic cancer cells and showed a synergistic effect with gemcitabine treatment. CONCLUSIONS From our data we conclude that MCT4 may serve as a potential therapeutic target in resectable pancreatic cancer. The precision medicine strategy for resectable pancreatic cancer should be validated in a clinical setting with a prospective study design.
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Affiliation(s)
- Sung Hwan Lee
- Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
- Laboratory of HBP Integrative Precision Oncology, CHA Bio Complex, CHA Health System, Seongnam, Republic of Korea
| | - Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
| | - Woo Jung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
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Bukhari N, Abdalla K, Ibnshamsa F, Alselwi W, Al-Shakir S, Alqahtani M. Exceptional Response to Second-Line Gemcitabine/Nab-Paclitaxel Chemotherapy in Patients With Metastatic Pancreatic Adenocarcinoma. Cureus 2021; 13:e18756. [PMID: 34796055 PMCID: PMC8589452 DOI: 10.7759/cureus.18756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2021] [Indexed: 12/27/2022] Open
Abstract
Pancreatic cancer is an extremely lethal malignancy with the majority of patients presenting with advanced disease. Typically, fit patients with advanced unresectable disease are treated with chemotherapy, which comprises either first-line folfirinox (FNX) or gemcitabine/nab-paclitaxel (GNP) regimens based on level 1 evidence. To our knowledge, robust evidence for second-line GNP post FNX does not exist. We herein report four cases treated at our institute with second-line GNP. Amongst those were patients with durable responses lasting over a year, which is extremely rare in stage 4 pancreatic cancer.
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Affiliation(s)
- Nedal Bukhari
- Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU.,Department of Internal Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU
| | - Khalda Abdalla
- Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU
| | - Fahad Ibnshamsa
- Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU
| | - Waleed Alselwi
- Department of Medical Oncology, King Fahad Specialist Hospital, Dammam, SAU
| | - Shakir Al-Shakir
- Department of Radiation Oncology, King Fahad Specialist Hospital, Dammam, SAU
| | - Mohammed Alqahtani
- Multiorgan Transplant Center, King Fahad Specialist Hospital, Dammam, SAU
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Kwon J, Park SY, Park Y, Jun E, Lee W, Song KB, Lee JH, Hwang DW, Kim SC. A comparison of minimally invasive vs open distal pancreatectomy for resectable pancreatic ductal adenocarcinoma: Propensity score matching analysis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:967-982. [PMID: 33091208 DOI: 10.1002/jhbp.853] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/05/2020] [Accepted: 09/22/2020] [Indexed: 11/08/2022]
Abstract
BACKGROUND Owing to concerns regarding adequate oncological outcomes and perioperative complications, minimally invasive distal pancreatectomy (MIDP) for pancreatic ductal adenocarcinoma (PDAC) has limited generalizability. The aim of this study was to assess the perioperative and oncologic outcomes of MIDP compared with open distal pancreatectomy (ODP) for resectable PDAC after propensity score matching (PSM). METHODS The patients who underwent MIDP and ODP for PDAC between January 2010 and December 2017 were retrospectively reviewed. Demographics, perioperative outcomes, pathological outcomes, and overall and disease-free survival data were collected to compare MIDP and ODP. After PSM, perioperative and oncologic outcomes were analyzed. RESULTS A total of 156 MIDP patients were compared with 156 ODP patients for resectable PDAC after PSM. Tumor size, TNM stage, differentiation, harvested lymph nodes, and positive lymph nodes were not different except for R1 resection and lymphovascular invasion between the MIDP and ODP groups. Operation times, overall complications, POPF, and adjuvant treatment were also not different between the two groups. The MIDP group had shorter hospital stays (10.0 vs 13.4 days, P < 0.001) and shorter interval times from surgery to adjuvant treatment (37.6 days vs 46.0 days, P = 0.002) than the ODP group. The MIDP group had better overall survival (34.9 vs 24.5 months, P = 0.012) and disease-free survival (16.2 vs 10.3 months, P = 0.001). CONCLUSION Minimally invasive distal pancreatectomy has advantages with respect to postoperative hospital stay, interval between surgery, and adjuvant treatment. MIDP is associated with the possibility of improved survival rate for resectable PDAC.
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Affiliation(s)
- Jaewoo Kwon
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
| | - Seo Young Park
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yejong Park
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
| | - Eunsung Jun
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
- Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Woohyung Lee
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
| | - Ki Byung Song
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
| | - Jae Hoon Lee
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
| | - Dae Wook Hwang
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
| | - Song Cheol Kim
- Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan college of Medicine, Seoul, South Korea
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